Journal articles on the topic 'Tumour-promoting stroma'
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Tone, Tatjana, Elīna Tauvēna, Ilze Štrumfa, and Jānis Gardovskis. "Inflammatory Cells in Gastric Cancer: Promoting the Tumour or Protecting the Host?" Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences. 74, no. 2 (April 1, 2020): 111–17. http://dx.doi.org/10.2478/prolas-2020-0018.
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AbstractThe study represents a comprehensive retrospective morphological profiling of gastric carcinoma in order to reveal associations between certain tumour-infiltrating inflammatory cells and clinical and/or pathological parameters. Patients’ age and gender, the extent of local tumour spread (pT), presence of metastases in regional lymph nodes (pN), tumour grade (G) as well as type according to World Health Organisation (WHO) and Lauren classifications were assessed in 211 consecutive surgically resected gastric carcinomas. Tumour-infiltrating inflammatory cells including eosinophils, neutrophils and lymphocytes were counted within the cancer stroma in five randomly selected high-power fields representative of the tumour. Descriptive statistics, Mann–Whitney and Kruskal–Wallis tests were applied; p < 0.05 was considered significant. Higher number of stromal eosinophils was associated with absence of metastases in regional lymph nodes (pN0) and histological structure of adenocarcinoma by WHO classification (p = 0.005 and p = 0.002, respectively). Higher count of stromal neutrophils showed significant associations with younger age (less than 65 years), and intestinal type by Lauren classification (p = 0.029 and p = 0.007, respectively). The density of stromal lymphocytes lacked any statistically significant association with the evaluated clinical or morphological parameters. In conclusion, the current study highlights the links between certain innate immune system cells and morphological features of gastric carcinoma.
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Seufferlein, Thomas, Michel Ducreux, Manuel Hidalgo, Gerald Prager, and Eric Van Cutsem. "More than a Gel & Hyaluronic Acid, a Central Component in the Microenvironment of Pancreatic Cancer." European Oncology & Haematology 14, no. 1 (2018): 40. http://dx.doi.org/10.17925/eoh.2018.14.1.40.
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Hyaluronic acid or hyaluronan (HA) is a major stromal component and its accumulation has been shown to play a central role in promoting tumourigenesis and progression of disease. Thus, overexpression of HA in tumours is associated with poor prognosis. Therapeutic targeting of HA is therefore an attractive strategy, particularly in pancreatic ductal adenocarcinoma (PDA), which is associated with an extremely poor prognosis and less sensitivity towards chemotherapy. PDA is characterised by a high stromal content. The accumulation of dense, fibrotic extracellular matrix components within the stroma, termed desmoplasia, results in increased tumour interstitial fluid pressure and vascular compression that impair the delivery and efficacy of therapeutic agents. While some elements of the stroma may be protective for the patient and prevent a more aggressive phenotype of PDA, a pegylated recombinant human hyaluronidase (pegvorhyaluronidase alfa) has been found to inhibit tumour growth in preclinical studies. In a clinical phase II randomised trial, the addition of pegvorhyaluronidase alfa to nab-paclitaxel and gemcitabine suggested significantly longer progression-free survival in patients with advanced PDA compared with nab-paclitaxel and gemcitabine alone. This benefit was even more pronounced in a subgroup of patients who expressed high levels of tumour HA.
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Ketteler, Julia, Andrej Panic, Henning Reis, Alina Wittka, Patrick Maier, Carsten Herskind, Ernesto Yagüe, Verena Jendrossek, and Diana Klein. "Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1." Journal of Clinical Medicine 8, no. 3 (March 12, 2019): 348. http://dx.doi.org/10.3390/jcm8030348.
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Tumour resistance to chemo- and radiotherapy, as well as molecularly targeted therapies, limits the effectiveness of current cancer treatments. We previously reported that the radiation response of human prostate tumours is critically regulated by CAV1 expression in stromal fibroblasts and that loss of stromal CAV1 expression in advanced tumour stages may contribute to tumour radiotherapy resistance. Here we investigated whether fibroblast secreted anti-apoptotic proteins could induce radiation resistance of prostate cancer cells in a CAV1-dependent manner and identified TRIAP1 (TP53 Regulated Inhibitor of Apoptosis 1) as a resistance-promoting CAV1-dependent factor. TRIAP1 expression and secretion was significantly higher in CAV1-deficient fibroblasts and secreted TRIAP1 was able to induce radiation resistance of PC3 and LNCaP prostate cancer cells in vitro, as well as of PC3 prostate xenografts derived from co-implantation of PC3 cells with TRIAP1-expressing fibroblasts in vivo. Immunohistochemical analyses of irradiated PC3 xenograft tumours, as well as of human prostate tissue specimen, confirmed that the characteristic alterations in stromal-epithelial CAV1 expression were accompanied by increased TRIAP1 levels after radiation in xenograft tumours and within advanced prostate cancer tissues, potentially mediating resistance to radiation treatment. In conclusion, we have determined the role of CAV1 alterations potentially induced by the CAV1-deficient, and more reactive, stroma in radio sensitivity of prostate carcinoma at a molecular level. We suggest that blocking TRIAP1 activity and thus avoiding drug resistance may offer a promising drug development strategy for inhibiting resistance-promoting CAV1-dependent signals.
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Elisha, Yair, Yael Sagi, Georg Klein, Ravid Straussman, and Benjamin Geiger. "Cooperativity between stromal cytokines drives the invasive migration of human breast cancer cells." Philosophical Transactions of the Royal Society B: Biological Sciences 374, no. 1779 (July 2019): 20180231. http://dx.doi.org/10.1098/rstb.2018.0231.
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The cross-talk between cancer cells and the stromal microenvironment plays a key role in regulating cancer invasion. Here, we employed an ex vivo invasion model system for exploring the regulation of breast cancer cells infiltration into a variety of stromal fibroblast monolayers. Our results revealed considerable variability in the stromal induction of invasiveness, with some lines promoting and others blocking invasion. It was shown that conditioned medium (CM), derived from invasion-promoting fibroblasts, can induce epithelial–mesenchymal transition-like process in the cancer cells, and trigger their infiltration into a monolayer of invasion-blocking fibroblasts. To identify the specific invasion-promoting molecules, we analysed the cytokines in stimulatory CM, screened a library of purified cytokines for invasion-promoting activity and tested the effect of specific inhibitors of selected cytokine receptors on the CM-induced invasion. Taken together, these experiments indicated that the invasiveness of BT-474 is induced by the combined action of IL1 and IL6 and that IL1 can induce IL6 secretion by invasion-blocking fibroblasts, thereby triggering cancer cell invasion into the stroma. This unexpected observation suggests that stromal regulation of cancer invasion may involve not only cross-talk between stromal and cancer cells, but also cooperation between different stromal subpopulations. This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.
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Maeda, Masahiro, Hideyuki Takeshima, Naoko Iida, Naoko Hattori, Satoshi Yamashita, Hiroshi Moro, Yoshimi Yasukawa, et al. "Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3." Gut 69, no. 2 (May 13, 2019): 243–51. http://dx.doi.org/10.1136/gutjnl-2018-317645.
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ObjectiveCancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells.DesignTwelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database.ResultsCAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such asWNT5A,GREM1,NOGandIGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration.ConclusionsH3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.
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Leonard, Niamh A., Eileen Reidy, Kerry Thompson, Emma McDermott, Eleonora Peerani, Elena Tomas Bort, Frances R. Balkwill, Daniela Loessner, and Aideen E. Ryan. "Stromal Cells Promote Matrix Deposition, Remodelling and an Immunosuppressive Tumour Microenvironment in a 3D Model of Colon Cancer." Cancers 13, no. 23 (November 29, 2021): 5998. http://dx.doi.org/10.3390/cancers13235998.
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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. CRC develops in a complex tumour microenvironment (TME) with both mesenchymal stromal cells (MSCs) and immune infiltrate, shown to alter disease progression and treatment response. We hypothesised that an accessible, affordable model of CRC that combines multiple cell types will improve research translation to the clinic and enable the identification of novel therapeutic targets. A viable gelatine-methacrloyl-based hydrogel culture system that incorporates CRC cells with MSCs and a monocyte cell line was developed. Gels were analysed on day 10 by PCR, cytokine array, microscopy and flow cytometry. The addition of stromal cells increased transcription of matrix remodelling proteins FN1 and MMP9, induced release of tumour-promoting immune molecules MIF, Serpin E1, CXCL1, IL-8 and CXCL12 and altered cancer cell expression of immunotherapeutic targets EGFR, CD47 and PD-L1. Treatment with PD153035, an EGFR inhibitor, revealed altered CRC expression of PD-L1 but only in gels lacking MSCs. We established a viable 3D model of CRC that combined cancer cells, MSCs and monocytic cells that can be used to research the role the stroma plays in the TME, identify novel therapeutic targets and improve the transitional efficacy of therapies.
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Spunde, Karina, Ksenija Korotkaja, and Anna Zajakina. "Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations." Biomedicines 10, no. 9 (August 31, 2022): 2142. http://dx.doi.org/10.3390/biomedicines10092142.
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Viral vectors have been widely investigated as tools for cancer immunotherapy. Although many preclinical studies demonstrate significant virus-mediated tumour inhibition in synergy with immune checkpoint molecules and other drugs, the clinical success of viral vector applications in cancer therapy currently is limited. A number of challenges have to be solved to translate promising vectors to clinics. One of the key elements of successful virus-based cancer immunotherapy is the understanding of the tumour immune state and the development of vectors to modify the immunosuppressive tumour microenvironment (TME). Tumour-associated immune cells, as the main component of TME, support tumour progression through multiple pathways inducing resistance to treatment and promoting cancer cell escape mechanisms. In this review, we consider DNA and RNA virus vectors delivering immunomodulatory genes (cytokines, chemokines, co-stimulatory molecules, antibodies, etc.) and discuss how these viruses break an immunosuppressive cell development and switch TME to an immune-responsive “hot” state. We highlight the advantages and limitations of virus vectors for targeted therapeutic programming of tumour immune cell populations and tumour stroma, and propose future steps to establish viral vectors as a standard, efficient, safe, and non-toxic cancer immunotherapy approach that can complement other promising treatment strategies, e.g., checkpoint inhibitors, CAR-T, and advanced chemotherapeutics.
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Petrella, Francesco, Isabella Rimoldi, Stefania Rizzo, and Lorenzo Spaggiari. "Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery." Medicines 4, no. 4 (November 23, 2017): 87. http://dx.doi.org/10.3390/medicines4040087.
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Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.
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Sevenich, Lisa, Robert L. Bowman, Steven D. Mason, Daniela F. Quail, Franck Rapaport, Benelita T. Elie, Edi Brogi, et al. "Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S." Nature Cell Biology 16, no. 9 (August 3, 2014): 876–88. http://dx.doi.org/10.1038/ncb3011.
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RIPPMANN, Jörg F., Klaus PFIZENMAIER, Ralf MATTES, Wolfgang J. RETTIG, and Dieter MOOSMAYER. "Fusion of the tissue factor extracellular domain to a tumour stroma specific single-chain fragment variable antibody results in an antigen-specific coagulation-promoting molecule." Biochemical Journal 349, no. 3 (July 25, 2000): 805–12. http://dx.doi.org/10.1042/bj3490805.
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Solid tumours growing beyond a size of 1–2mm in diameter induce supporting connective tissue structures, the tumour stroma, comprising activated fibroblasts and newly formed blood vessels, embedded in an extracellular matrix. The selective destruction of this tissue or the inhibition of its function (e.g. tumour neoangiogenesis) may result in the destruction of tumour nodules, thus providing novel opportunities for tumour therapy. Our approach aims at an antibody-mediated induction of coagulation in tumour nodules to cut off their blood supply. As a target structure the fibroblast activation protein (FAP) is used, which is specifically and abundantly expressed on the activated fibroblasts of the tumour stroma. We constructed a fusion protein comprising a single-chain module of a FAP-specific humanized antibody [single-chain fragment variable (scFv) OS4] and the extracellular domain of human tissue factor. The fusion protein, designated TFOS4, was produced in the Proteus mirabilis protoplast expression system with a yield of 15µg/ml. Biochemical characterization of TFOS4 revealed high-affinity binding to cellular FAP. Further, TFOS4 bound to factor VIIa and also exerted allosteric activation of factor VIIa. A complex of TFOS4 and factor VIIa bound to FAP-expressing cells efficiently generated activated factor X. Finally, cell-bound TFOS4 selectively induced plasma coagulation, implying its activity under physiological conditions, notably with relevant concentrations of coagulation factors and their natural inhibitors. These findings suggest that TFOS4 has the potential to increase the procoagulant state in a cell-type-specific fashion. No systemic coagulation or side effects were observed when TFOS4 was injected intravenously into normal mice, indicating the biosafety and specificity of the recombinant protein.
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Balaziova, Eva, Petr Vymola, Petr Hrabal, Rosana Mateu, Michal Zubal, Robert Tomas, David Netuka, et al. "Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis." Cancers 13, no. 13 (July 1, 2021): 3304. http://dx.doi.org/10.3390/cancers13133304.
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Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.
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Bryce, Adam S., Stephan B. Dreyer, Fieke E. M. Froeling, and David K. Chang. "Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer." Cancers 14, no. 21 (October 28, 2022): 5302. http://dx.doi.org/10.3390/cancers14215302.
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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.
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Patras, Laura, Marcel H. A. M. Fens, Pieter Vader, Arjan Barendrecht, Alina Sesarman, Manuela Banciu, and Raymond Schiffelers. "Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro." International Journal of Molecular Sciences 21, no. 17 (August 19, 2020): 5951. http://dx.doi.org/10.3390/ijms21175951.
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Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.
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Lutzny, Gloria, Zhoulei Li, Madlen Oelsner, Jolanta Slawska, Thomas Kocher, Alexander Egle, Christian Peschel, Ulrich Keller, and Ingo Ringshausen. "Proteinkinase C-β Inhibitors Mitigate Microenvironment-Mediated Survival Of CLL Cells and Sensitise Malignant B Cells To Cytotoxic Drugs." Blood 122, no. 21 (November 15, 2013): 669. http://dx.doi.org/10.1182/blood.v122.21.669.669.
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Abstract Heterotypic interactions between bone marrow stromal cells (BMSCs) and malignant B cells contribute to apoptosis-resistance of tumour cells, based on the provision of anti-apoptotic factors by stromal cells. For this reason, interference with the microenvironment may offer an alternative approach to chemotherapy to target B cell lymphomas/ leukaemias. However, the success of such treatments critically relies on specific targets expressed in the lymphoma microenvironment. We have previously reported that monoclonal B cells from patients with CLL, MCL und ALL activate and reprogram BMSCs. This activation of stromal cells is an essential prerequisite for microenvironment-mediated survival of malignant B cells and requires the induction and activation of protein-kinase C-β in stromal cells in vitro and in vivo. This is underscored by a complete resistance of PKC-β knockout mice to adoptively transferred B cell lymphomas from TCL1 transgenic mice (Lutzny et al. Cancer Cell. 2013 Jan 14; 23(1):77-92.). Analyses of primary CLL cells co-cultured on human or mouse BMSCs indicate that stromal cells protect malignant B cells from apoptosis primarily by enhancing the expression of the anti-apoptotic proteins Mcl1, XIAP, BclXL and Bcl2A1. Knockdown of Mcl1 expressed in CLL cells further demonstrates that its expression is crucial for stroma-mediated survival even in the presence of BMSCs. Since BMSC-mediated survival and propagation of CLL depends on the kinase activity of PKC-β, we hypothesized that pharmacological inhibition of the activation of stromal cells using small molecule inhibitors against PKC-β may display anti-leukemic effects. Here we report that the PKC-β inhibitor enzastaurin enhances the cytotoxic effects of standard chemotherapeutic drugs and of the BCL2-inhibitor ABT737. Dose-response analyses indicate that enzastaurin potentiates the cytotoxic effects of ABT737 in a synergistic manner, rapidly causing caspase-mediated apoptosis of malignant B cells. This drug-sensitising effect of enzastaurin is mediated by inhibition of PKC-β induced and expressed in activated stromal cells and not related to a direct cytotoxic effect on malignant B cells: PKC-β deficient BMSCs fail to maintain high expression levels of the anti-apoptotic proteins Mcl1, XIAP and Bcl2A1 in CLL cells, which show a significantly enhanced sensitivity to ABT737 compared to CLL cells cultured on PKC-β proficient stromal cells. These data provide evidence that PKC-β inhibitors can therapeutically be used to abolish microenvironment-mediated survival of malignant B cells. In order to assess whether drug combinations of enzastaurin and BCL2 inhibitors demonstrate synergistic anti-lymphoma effects in vivo, we adoptively transferred malignant B cells from diseased TCL1 mice into wild-type recipient mice. Tumour-bearing mice were treated with enzastaurin, ABT199 or a combination of both drugs. Response to treatment, assessed by PET-CT scan, indicates that the combination of enzastaurin and ABT199 is superior to single agent treatment. These data indicate that malignant B cells can be sensitized to cytotoxic drugs by inhibiting the tumour-promoting effects of the lymphoma microenvironment with PKC-β inhibitors. Our preclinical in vitro and in vivo experiments justify testing this drug combination as a new approach to leukaemia/ lymphoma therapy in a phase I/II clinical trial. Disclosures: No relevant conflicts of interest to declare.
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Bruns, Heiko, Dimitrios Mougiakakos, Mario Fabri, Shirin Pasemann, Regina Jitschin, Kerstin Amann, Maike Büttner, Andreas Mackensen, and Armin Gerbitz. "Vitamin D Triggers Killing of Burkitt Lymphoma Cells by Human Macrophages." Blood 120, no. 21 (November 16, 2012): 1035. http://dx.doi.org/10.1182/blood.v120.21.1035.1035.
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Abstract Abstract 1035 Introduction: Distinct macrophage subsets have been linked with either protective or pathogenic roles in cancer. M2 macrophages have been shown to suppress adaptive tumour-specific immune responses and promote tumour growth, while M1 macrophages eliminate neoplastic cells and activate tumour-killing mechanisms. Macrophages isolated from solid tumours (tumor-associated macrophages, TAM) reveal a suppressive and tumor promoting M2-like phenotype. However, it remains unclear which tumoricidal effector mechanisms are compromised in theses immune cells. While infilatration of macrophages is a characteristic morphological hallmark in Burkitts' lymphoma (BL), the phenotype and functional properties of TAM as part of the stroma are poorly understood. In this study we investigated the phenotype of lymphoma associated macrophages (LAM) and the mechanisms by which macrophages are able to modulate the growth of tumor cells. Methods: We included 19 patients diagnosed with BL and 20 patients with benign reactive lymphadenopathy as a control group. Phenotypic characterizations of LAM were evaluated by immunohistochemistry and by qPCR in paraffin embedded tissues. To investigate anti lymphoma cytotoxicity of distinct macrophage subsets we generated macrophages from PBMC either by GM-CSF to create the M1 phenotype, or by M-CSF to obtain the M2 phenotype. M1 and M2 macrophages were coincubated them with several BL cell lines and cytotoxicity was analyzed by flow cytometry, qPCR and immunofluorescence. Results: First, we could demonstrate that BL infiltrating macrophages displayed an anti-inflammatory M2-phenotype characterized by expression of surface markers such as CD68 and CD163. Second, we identified impaired vitamin D metabolism in LAM and M2 macrophages as demonstrated by low expression of vitamin D receptor and Cyp27B1, and increased expression of Cyp24A1. Third, macrophages revealed a reduced cytotoxic potential towards lymphoma cells which was dependent on the expression of the vitamin D dependent peptide cathelicidin. Finally, we could demonstrate that excess supplementation of calcitriol led to increased cytotoxicity of M1- and M2 macrophages towards BL cells. Conclusions: These results suggest a mechanism in which vitamin D is required for innate immunity to overcome the ability of lymphoma cells to evade macrophage-mediated antitumoral responses. The present findings underscore the importance of vitamin D for sustaining innate immunity and imply that the therapeutic activation of the vitamin D pathway may even result in triggering tumoricidal effector mechanisms of LAM. Disclosures: No relevant conflicts of interest to declare.
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Haselager, Marco, Eduard Perelaer, Arnon P. Kater, and Eric Eldering. "Development of a Novel Lymph Node-Based 3D Culture System Promoting Chronic Lymphocytic Leukemia Proliferation and Survival." Blood 136, Supplement 1 (November 5, 2020): 47–48. http://dx.doi.org/10.1182/blood-2020-141962.
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INTRODUCTION. Primary chronic lymphocytic leukemia (CLL) cells, despite originating from a proliferative disease, rapidly undergo apoptosis in vitro in absence of microenvironmental survival signals1. Although co-culture with stromal cells or the addition of soluble factors can increase and extend CLL survival, no system permits the long-term expansion of CLL cells in vitro2. The difficulties of mimicking a physiologic microenvironment supporting CLL cells hinder in vitro studies of proliferation, drug screens and prevent propagation of rare subclones. For other cancers, various types of 3D cultures have been introduced utilizing scaffolds, gels, spheroid cultures and fluidic systems, representing a more accurate representation of the in vivo microenvironment3. Unlike solid tumors, secondary lymphoid tissues where CLL cells proliferate in vivo, do not derive from a single stem cell progenitor. Developing an appropriate 3D in vitro culture system for CLL is of obvious importance and may contribute pathophysiological relevance to study long-term CLL proliferation and more accurate drug screening4,5. Within the field of CLL, attempts have focused on bone marrow stroma, but it may be biologically and clinically more relevant to investigate the lymph node niche as this is the critical site of CLL proliferation6. METHODS. Primary CLL cells were cultured in various 3D systems including hydrogels, hanging drop cultures and ultra-low attachment plates (ULA) plates in parallel to an optimal 2D system, consisting of the culture of primary CLL cells on a monolayer of CD40L-presenting fibroblasts (3T40) or 3T3 negative control fibroblasts. CLL cells were either cultured as PBMCs alone, with or without T cells, or co-cultured with 3T40 or primary lymph node fibroblasts. CLL cells were either stimulated directly with IL-2, IL-15, IL-21 and CpG and/or indirectly via a T cell stimulation of anti-CD3/CD28. RESULTS. After testing and comparing multiple systems for the in vitro culture of CLL cells, we optimized a novel CLL culture system utilizing ULA plates creating spheroids of PBMCs isolated from peripheral blood. Without the addition of soluble factors or stroma, primary CLL cells in the ULA 3D model could be maintained in culture for 6 weeks as opposed to 1 week in the 2D system. Aside from significantly promoting CLL survival, cultures could be expanded approximately 3-4-fold over a course of 6 weeks using the ULA 3D model. 3D cultures showed a more consistent and significantly increased CLL proliferation compared to 2D cultures, independent of IGHV mutation status, increasing the average proliferation index of 2.87 to 3.90 (n=10). Additionally, co-culture with LN-derived stromal cells further increased CLL proliferation, reaching a maximum of 8 generations (n=6) (Figure 1). Lastly, when PBMCs were stimulated with IL-2, IL-15, IL-21 and CpG, spheroids developed proliferation center-like structures after 4 weeks of culture. CONCLUSIONS. We established a lymph node-based 3D in vitro culture system for CLL leading to increased CLL proliferation and survival compared to 2D systems. The set-up allows long-term expansion of CLL cells in vitro, as well as formation of proliferation center-like structures. We are currently optimizing drug resistance studies, expansion of specific CLL subclones and performing competition experiments. References: 1. Hamilton et al., Mimicking the tumour microenvironment: three different co-culture systems induce a similar phenotype but distinct proliferative signals in primary chronic lymphocytic leukaemia cells, 2012. 2. Asslaber et al., Mimicking the microenvironment in chronic lymphocytic leukaemia - where does the journey go?, 2013. 3. Gurski et al., 3D Matrices for Anti-Cancer Drug Testing and Development, 2010. 4. Nunes et al., 3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs, 2019. 5. Aljitwai et al., A novel three-dimensional stromal-based model for in vitro chemotherapy sensitivity testing of leukemia cells, 2014. 6. Van Gent et al., In vivo dynamics of stable chronic lymphocytic leukemia inversely correlates with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow, 2008. Disclosures Kater: Genentech: Research Funding; Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Eldering:Celgene: Research Funding; Janssen: Research Funding; Genentech: Research Funding.
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Webber, J. P., L. K. Spary, A. J. Sanders, R. Chowdhury, W. G. Jiang, R. Steadman, J. Wymant, et al. "Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes." Oncogene 34, no. 3 (January 20, 2014): 290–302. http://dx.doi.org/10.1038/onc.2013.560.
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Neesse, Albrecht, Christian Alexander Bauer, Daniel Öhlund, Matthias Lauth, Malte Buchholz, Patrick Michl, David A. Tuveson, and Thomas M. Gress. "Stromal biology and therapy in pancreatic cancer: ready for clinical translation?" Gut 68, no. 1 (September 3, 2018): 159–71. http://dx.doi.org/10.1136/gutjnl-2018-316451.
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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.
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Quattrone, Anna, Barbara Dewaele, Agnieszka Wozniak, Marijke Bauters, Vanessa Vanspauwen, Giuseppe Floris, Patrick Schöffski, et al. "Promoting role of cholecystokinin 2 receptor (CCK2R) in gastrointestinal stromal tumour pathogenesis." Journal of Pathology 228, no. 4 (September 28, 2012): 565–74. http://dx.doi.org/10.1002/path.4071.
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Morgan, Jonathan J., Roisin M. McAvera, and Lisa J. Crawford. "TRAF6 Silencing Attenuates Multiple Myeloma Cell Adhesion to Bone Marrow Stromal Cells." International Journal of Molecular Sciences 20, no. 3 (February 6, 2019): 702. http://dx.doi.org/10.3390/ijms20030702.
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The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in particular, is central to the pathogenesis of MM. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator of NFκB activation and has previously been highlighted as a potential therapeutic target in MM. Here, we demonstrate that adherence of MM cell lines to stromal cells results in a reciprocal increase in TRAF6 expression. Knockdown of TRAF6 expression attenuates the ability of MM cells to bind to stromal cells and this is associated with a decrease in NFκB-induced expression of the adhesion molecules ICAM1 and VCAM1. Finally, we show that knockdown of TRAF6 sensitizes MM cells to treatment with bortezomib when co-cultured with stromal cells. Inhibiting TRAF6 represents a promising strategy to target MM cells in the BM microenvironment.
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Toledo, Belén, Manuel Picon-Ruiz, Juan Antonio Marchal, and Macarena Perán. "Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives." International Journal of Molecular Sciences 23, no. 24 (December 8, 2022): 15576. http://dx.doi.org/10.3390/ijms232415576.
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Tumours are complex systems with dynamic interactions between tumour cells, non-tumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME’s cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal–cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs “re-education” and/or targeting tumour progression inhibition.
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Roninson, Igor B. "Oncogenic functions of tumour suppressor p21Waf1/Cip1/Sdi1: association with cell senescence and tumour-promoting activities of stromal fibroblasts." Cancer Letters 179, no. 1 (May 2002): 1–14. http://dx.doi.org/10.1016/s0304-3835(01)00847-3.
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Akerman, Anouschka, George Sharbeen, Jeff Holst, Janet Youkhana, Joshua McCarroll, David Goldstein, Mert Erkan, and Phoebe Phillips. "Targeting a solute carrier to metabolically reprogram tumour-promoting stromal cells in pancreatic cancer." Pancreatology 18, no. 4 (June 2018): S156. http://dx.doi.org/10.1016/j.pan.2018.05.419.
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Egan, Hannah, Oliver Treacy, Kevin Lynch, Niamh Leonard, Amir Nader, Margaret Sheehan, Sean Hynes, et al. "865 Sugar high: Does the sialic acid profile of cancer-associated fibroblasts induce a more tumour-permissive microenvironment?" Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A918. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0865.
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BackgroundImmunosuppressive tumour microenvironments (TME) inhibit the effectiveness of cancer immunotherapies. Sialic acids, which exist as terminal sugars of glyco-conjugates, are highly expressed on cancer cells and are involved in various pathological processes including increased immune evasion, tumour invasiveness and tumour cell metastasis.1 Siglecs (Sialic acid-binding immunoglobulin-type lectins) are expressed on immune cell surfaces and bind sialic acid. Siglec binding to hypersialylated tumour glycans blocks immune cell activation to promote immunosuppression.1 2Intestinal stromal cells (iSCs), precursors to cancer-associated fibroblasts (CAFs), are a key component of the TME and play a vital role in tumour progression by enhancing a tumour-promoting microenvironment. The aim of this study was therefore to investigate if iSC/CAF sialylation contributes to enhanced immunosuppression in the TME.Methods iSCs were isolated from colorectal cancer patient biopsies and cultured ex vivo. Informed consent was obtained from all patients prior to sampling. Tumour-derived iSCs were termed CAFs while control iSCs, isolated from tumour-adjacent non-cancerous tissue, were termed normal-associated fibroblasts (NAFs). NAFs/CAFs were then co-cultured with healthy allogeneic PBMCs and their immunosuppressive properties were assessed by flow cytometry.ResultsCAFs significantly supressed the proliferation of CD8+ and CD4+ T-cells and induced a more exhausted T-cell phenotype as evidenced by increased expression of the exhaustion markers TIM-3, LAG-3 and PD-1 when compared to co-culture with control NAFs, thereby demonstrating their potent immunosuppressive properties. Strikingly, CAFs also induced significantly higher expression of both Siglec-7 and Siglec-9 receptors on CD8+ T-cells specifically.To elucidate the role of sialylation on CAF-mediated immunosuppression, NAFs/CAFs were treated with the sialyltransferase inhibitor (SI) P-3FAX-Neu5Ac prior to co-culture. Reduction of sialic acid expression on NAFs/CAFs was confirmed by flow cytometry and the SI-treated NAFs/CAFs were then co-cultured with allogeneic T-cells to assess the functional consequences of reduced NAF/CAF sialylation. SI-treated CAFs induced significantly less CD4+TIM-3+ and both CD4+LAG-3+ and CD8+LAG-3+ T-cells compared to their untreated counterparts. Interestingly, SI-treated CAFs also induced significantly less Siglec-7 and -9 receptor-expressing CD8+ T-cells.ConclusionsThese results demonstrate that non-haematopoietic stromal cells in the tumour-microenvironment can suppress activated T-cells and that this immunosuppressive effect can be significantly reversed through the modulation of sialylation on the stromal cell surface. These results support the hypothesis that stromal cell sialylation plays a role in their immunosuppressive properties. Understanding how sialylation of stromal cells is regulated and functions to enhance immunosuppression in the TME could uncover novel immune checkpoints to reactivate anti-tumour immunity, allowing for tumour cell clearance.Ethics ApprovalThis study was approved by Galway University Hospitals’ Clinical Research Ethics Committee, approval number C.A 2074.ConsentN/AReferencesWang L, Liu Y, Wu L, Sun XL. Sialyltransferase inhibition and recent advances. Biochim Biophys Acta 2016 Jan; 1864(1):143-53.Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel) 2019 Oct 13;6(4):102.
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Peta, Kimberly Thando, Melvin Anyasi Ambele, and Michael Sean Pepper. "Similarities between Tumour Immune Response and Chronic Wound Microenvironment: Influence of Mesenchymal Stromal/Stem Cells." Journal of Immunology Research 2021 (March 29, 2021): 1–11. http://dx.doi.org/10.1155/2021/6649314.
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Tumours are characterized by a state of chronic inflammation and are regarded as wounds that never heal. Mesenchymal stromal/stem cells (MSCs) are being considered as a possible treatment option. While MSCs can regulate the immune system, migrate to sites of inflammation, and are naturally immune-privileged, there have been contradictory reports on the role of these cells in the tumour microenvironment (TME). Some studies have suggested that MSCs promote tumourigenesis while others have suggested the contrary. To better evaluate the role of MSCs in the TME, it may be helpful to understand the role of MSCs in chronic wounds. Here, we discuss the role of MSCs in chronic wounds and extrapolate this to the TME. Chronic wounds are stuck in the inflammatory phase of wound healing, while in the case of the TME, both the inflammatory and proliferative phases are exploited. MSCs in chronic wounds promote a switch in macrophage phenotype from proinflammatory (M1) to anti-inflammatory (M2), thereby suppressing T, B, and natural killer cells, consequently promoting wound healing. In the case of the TME, MSCs are reported to promote tumorigenesis by suppressing T, B, and natural killer cells in addition to dendritic cells, cytotoxic T cells, and Th1-associated cytokines, thereby promoting tumour growth. Some studies have however suggested that MSCs inhibit tumourigenesis, depending on the source of the MSCs and the specific mediators involved. Therefore, the role of MSCs in the TME appears to be complex and may result in variable outcomes. Compelling evidence to suggest that MSCs are an effective treatment option against tumour progression is lacking.
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Gadea, Bedrick B., and Johanna A. Joyce. "Tumour–host interactions: implications for developing anti-cancer therapies." Expert Reviews in Molecular Medicine 8, no. 30 (December 2006): 1–32. http://dx.doi.org/10.1017/s1462399406000172.
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Cancers are a complex set of proliferative diseases that arise in most cases through multi-step pathways involving an accumulation of genetic and epigenetic changes. These steps include inactivation of tumour suppressor genes and activation of oncogenes. However, in addition to genetic mutations in the tumour cells themselves, the local host environment can act as a critical modulator of cancer progression, having either tumour-suppressive or tumour-promoting effects depending on the stage and site of cancer development. Because stromal cells can have these opposing functions during cancer development and progression, a recurring theme throughout this review will be that of balance: maintaining the normal functions of these co-opted cells, yet selectively inhibiting their pro-tumourigenic functions. To achieve this equilibrium, we need to understand the molecular mechanisms by which normal cells become modified by cancer cells before we can hope to target these functions selectively. Here, we will discuss recent efforts to address these key challenges and offer perspectives on the translation of discoveries made in model systems to the clinic.
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Pereira, Joana F. S., Cláudia Bessa, Paulo Matos, and Peter Jordan. "Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells." Cancers 14, no. 6 (March 9, 2022): 1393. http://dx.doi.org/10.3390/cancers14061393.
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An inflammatory microenvironment is a tumour-promoting condition that provides survival signals to which cancer cells respond with gene expression changes. One example is the alternative splicing variant Rat Sarcoma Viral Oncogene Homolog (Ras)-Related C3 Botulinum Toxin Substrate 1 (RAC1)B, which we previously identified in a subset of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-mutated colorectal tumours. RAC1B was also increased in samples from inflammatory bowel disease patients or in an acute colitis mouse model. Here, we used an epithelial-like layer of polarized Caco-2 or T84 colorectal cancer (CRC) cells in co-culture with fibroblasts, monocytes or macrophages and analysed the effect on RAC1B expression in the CRC cells by RT-PCR, Western blot and confocal fluorescence microscopy. We found that the presence of cancer-associated fibroblasts and M1 macrophages induced the most significant increase in RAC1B levels in the polarized CRC cells, accompanied by a progressive loss of epithelial organization. Under these conditions, we identified interleukin (IL)-6 as the main trigger for the increase in RAC1B levels, associated with Signal Transducer and Activator of Transcription (STAT)3 activation. IL-6 neutralization by a specific antibody abrogated both RAC1B overexpression and STAT3 phosphorylation in polarized CRC cells. Our data identify that pro-inflammatory extracellular signals from stromal cells can trigger the overexpression of tumour-related RAC1B in polarized CRC cells. The results will help to understand the tumour-promoting effect of inflammation and identify novel therapeutic strategies.
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Bianchini, Francesca, Elisa Giannoni, Sergio Serni, Paola Chiarugi, and Lido Calorini. "22 : 6n-3 DHA inhibits differentiation of prostate fibroblasts into myofibroblasts and tumorigenesis." British Journal of Nutrition 108, no. 12 (March 6, 2012): 2129–37. http://dx.doi.org/10.1017/s0007114512000359.
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Prostate cancer is one of the most common malignancies in men. Epidemiological and experimental studies have revealed that stromal cells of the tumour microenvironment contribute to the development of prostate cancers, while long-chainn-3 PUFA-enriched diets reduce the risk of this tumour histotype. These findings prompted us to investigate whether DHA, ann-3 PUFA, may abrogate differentiation of prostate fibroblasts into myofibroblasts, the activated form of fibroblasts generally involved in prostate cancer progression. We used the human prostate carcinoma cell line (PC3) as a prostate adenocarcinoma model and found that DHA (1) inhibits α-smooth muscle actin (α-SMA) expression, a typical marker of myofibroblast differentiation, in prostate fibroblasts stimulatedin vitrowith transforming growth factor-β (TGF-β), (2) blocks the matrix metalloproteinase-2-dependent enhanced invasiveness of PC3 prostate adenocarcinoma cells migrated in a medium conditioned by TGF-β-stimulated prostate fibroblasts, (3) prevents epithelial–mesenchymal transition (EMT) and invasiveness of PC3 cells promoted by a medium conditioned by TGF-β-stimulated prostate fibroblasts, and (4) reduces the growth rate of tumours obtained in immunodeficient animals injected with PC3 cells plus TGF-β-stimulated prostate fibroblasts. Moreover, DHA was found to revert α-SMA expression and the invasiveness-promoting activity exerted in PC3 cells by tumoral-activated fibroblasts. Thus, DHA represents a suitable agent to inhibit prostate myofibroblast differentiation, invasiveness and EMT, two most important tumour-promoting activities involved in the progression of prostate cancer cells.
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Al-Akkad, Walid, Pilar Acedo, Maria-Giovanna Vilia, Luca Frenguelli, Alexander Ney, Irene Rodriguez-Hernandez, Peter L. Labib, et al. "Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance." Cells 11, no. 22 (November 17, 2022): 3652. http://dx.doi.org/10.3390/cells11223652.
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Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.
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Pancione, Massimo, Guido Giordano, Andrea Remo, Antonio Febbraro, Lina Sabatino, Erminia Manfrin, Michele Ceccarelli, and Vittorio Colantuoni. "Immune Escape Mechanisms in Colorectal Cancer Pathogenesis and Liver Metastasis." Journal of Immunology Research 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/686879.
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Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced orde novosynthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.
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Leonard, Niamh, Oliver Treacy, Hannah Egan, Grace O’Malley, Elena Tomas Bort, Eleonora Peerani, Thomas Ritter, Daniela Loessner, Laurence Egan, and Aideen Ryan. "864 The mesenchymal stromal compartment in colorectal cancer greatly alters the innate tumour immune microenvironment both in 2D and 3D culture systems." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A917. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0864.
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BackgroundColorectal cancer is the fourth most common occurring cancer and despite new treatment options it remains the third leading cause of cancer related deaths worldwide.1 Of the four Consensus Molecular Subtypes (CMS), the mesenchymal stromal rich CMS4 tumours are shown to have the worst disease free progression survival. However the role mesenchymal stromal cells (MSC) play in the tumour immune microenvironment has yet to be fully elucidated. Understanding the complex communication in this stromal cell rich multicellular environment is challenging but may reveal novel targets for the treatment of colorectal cancer patients.MethodsTumour cell secretome (TCS) was generated from colon cancer cells with/without the addition of TNF-a, an inflammatory stimulus using both human and mouse cell lines. MSCs were then conditioned with the TCS and inflammatory TCS and changes in surface and secreted immunomodulatory molecules were assessed using RNA-seq, flow cytometry and ELISA analysis. Macrophage antigen processing and migration following co-culture with the TCS conditioned MSCs was observed using DQ-ova and transwell experiments. A Gelatin Methacryloyl hydrogel, 3D triple culture systems was established to study the role of MSC in the colon tumour immune microenvironment. HCT116 colon cancer cell line with THP1 monocytic cell line and primary bone marrow derived MSCs were embedded in the hydrogel and incubated for 10days, changing the media on Day 8 with/without the addition of TNF-a. Cell proliferation viability and protein secretion were assessed from the 3D CRC system.ResultsBioplex analysis revealed secretion of potent chemokines and cytokines from the cancer cells. This inflammatory TSC resulted in increased expression of cell surface MSC immunomodulatory markers PD-L1 and CD47 and a variety of secreted molecules. These conditioned MSCs reduced macrophage-mediated antigen processing and increase monocyte migration. A triple culture 3D model of CRC was successfully developed, and while the addition of MSC to the system did not alter spheroid size they increased the release of potent chemokines(CCL2, CXCL12), cytokines (IL-6, IL8) and growth factors (GM-CSF) from the culture system.ConclusionsThe inflammatory tumour cell secretome can alter MSC surface expression and secretion of a variety of immunomodulatory makers. These tumour conditioned MSCs can alter innate immune cell antigen processing and migration. When MSCs are combined in 3D with monocytes and colon cancer cells the MSC significantly alter the secretion of immune modulating and tumour promoting factors from the culture system. Targeting MSC immune suppression in the colon tumour microenvironment could be a novel therapeutic target.Ethics ApprovalHuman MSC (hMSC) were isolated from the bone marrow of three healthy volunteers at Galway University Hospital under an ethically approved protocol (NUIG Research Ethics Committee, Ref: 08/May/14) according to a standardized procedure.ReferenceRawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol 2019;14(2):89-103.
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Ciarletta, P., L. Foret, and M. Ben Amar. "The radial growth phase of malignant melanoma: multi-phase modelling, numerical simulations and linear stability analysis." Journal of The Royal Society Interface 8, no. 56 (July 23, 2010): 345–68. http://dx.doi.org/10.1098/rsif.2010.0285.
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Cutaneous melanoma is disproportionately lethal despite its relatively low incidence and its potential for cure in the early stages. The aim of this study is to foster understanding of the role of microstructure on the occurrence of morphological changes in diseased skin during melanoma evolution. The authors propose a biomechanical analysis of its radial growth phase, investigating the role of intercellular/stromal connections on the initial stages of epidermis invasion. The radial growth phase of a primary melanoma is modelled within the multi-phase theory of mixtures, reproducing the mechanical behaviour of the skin layers and of the epidermal–dermal junction. The theoretical analysis takes into account those cellular processes that have been experimentally observed to disrupt homeostasis in normal epidermis. Numerical simulations demonstrate that the loss of adhesiveness of the melanoma cells both to the basal laminae, caused by deregulation mechanisms of adherent junctions, and to adjacent keratynocytes, consequent to a downregulation of E-cadherin, are the fundamental biomechanical features for promoting tumour initiation. Finally, the authors provide the mathematical proof of a long wavelength instability of the tumour front during the early stages of melanoma invasion. These results open the perspective to correlate the early morphology of a growing melanoma with the biomechanical characteristics of its micro-environment.
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Alhussan, Abdulaziz, Nicholas Palmerley, Julian Smazynski, Joanna Karasinska, Daniel J. Renouf, David F. Schaeffer, Wayne Beckham, Abraham S. Alexander, and Devika B. Chithrani. "Potential of Gold Nanoparticle in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblast Cells." Cancers 14, no. 15 (July 22, 2022): 3586. http://dx.doi.org/10.3390/cancers14153586.
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Many cancer therapeutics are tested in vitro using only tumour cells. However, the tumour promoting effect of cancer associated fibroblasts (CAFs) within the tumour microenvironment (TME) is thought to reduce cancer therapeutics’ efficacy. We have chosen pancreatic ductal adenocarcinoma (PDAC) as our tumor model. Our goal is to create a co-culture of CAFs and tumour cells to model the interaction between cancer and stromal cells in the TME and allow for better testing of therapeutic combinations. To test the proposed co-culture model, a gold nanoparticle (GNP) mediated-radiation response was used. Cells were grown in co-culture with different ratios of CAFs to cancer cells. MIA PaCa-2 was used as our PDAC cancer cell line. Co-cultured cells were treated with 2 Gy of radiation following GNP incubation. DNA damage and cell proliferation were examined to assess the combined effect of radiation and GNPs. Cancer cells in co-culture exhibited up to a 23% decrease in DNA double strand breaks (DSB) and up to a 35% increase in proliferation compared to monocultures. GNP/Radiotherapy (RT) induced up to a 25% increase in DNA DSBs and up to a 15% decrease in proliferation compared to RT alone in both monocultured and co-cultured cells. The observed resistance in the co-culture system may be attributed to the role of CAFs in supporting cancer cells. Moreover, we were able to reduce the activity of CAFs using GNPs during radiation treatment. Indeed, CAFs internalize a significantly higher number of GNPs, which may have led to the reduction in their activity. One reason experimental therapeutics fail in clinical trials relates to limitations in the pre-clinical models that lack a true representation of the TME. We have demonstrated a co-culture platform to test GNP/RT in a clinically relevant environment.
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Melaccio, Assunta, Antonia Reale, Ilaria Saltarella, Vanessa Desantis, Aurelia Lamanuzzi, Sebastiano Cicco, Maria Antonia Frassanito, Angelo Vacca, and Roberto Ria. "Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance." Journal of Clinical Medicine 11, no. 21 (November 1, 2022): 6491. http://dx.doi.org/10.3390/jcm11216491.
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Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy.
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Sammarco, Giuseppe, Gilda Varricchi, Valentina Ferraro, Michele Ammendola, Michele De Fazio, Donato Francesco Altomare, Maria Luposella, et al. "Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer." International Journal of Molecular Sciences 20, no. 9 (April 29, 2019): 2106. http://dx.doi.org/10.3390/ijms20092106.
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Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.
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Godlewski, Janusz, and Zbigniew Kmiec. "Colorectal Cancer Invasion and Atrophy of the Enteric Nervous System: Potential Feedback and Impact on Cancer Progression." International Journal of Molecular Sciences 21, no. 9 (May 11, 2020): 3391. http://dx.doi.org/10.3390/ijms21093391.
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Colorectal cancer (CRC) invasion within the large intestine wall results in the replacement of normal tissue architecture by tumour mass. Cancer cells digest the extracellular matrix (ECM) by the release of proteolytic enzymes. The disintegration of matrix ground substance activates several deposited growth factors which stimulate cell proliferation. Stromal (mainly fibroblasts), immune and cancer cells dominate in this area and become involved in a network of multimodal interactions which significantly induce proliferation of colon cancer cells, inhibit their apoptosis and promote their spreading within the local tumour microenvironment. Cancer invasion destroys nerve fibres and neurons of the local enteric nervous system (ENS) and induces subsequent atrophy of the submucosal and myenteric plexuses in areas adjacent to the cancer boundary. Interestingly, the reduction of plexuses’ size is accompanied by the increased number of galanin-immunoreactive neurons and increased galanin content in parts of the colon located close to the tumour. Galanin, a neuroprotective peptide, may inhibit the extrinsic pathway of apoptosis and in this way promote cancer cell survival. The possible role of acetylcholine and some ENS neuropeptides was also discussed. Invasion of cancer cells spreads along nerve fibres with the involvement of locally-released neutrophins which promote, via their specific receptors, cancer cell proliferation and pro-survival signalling pathways. Thus, during CRC development cancer cells and neurons of the ENS release many neurotransmitters/neuropeptides which affect key cellular signalling pathways promoting cancer cell proliferation and pro-survival phenotype. The multiple interactions between ENS neurons, cancer cells and other cell types present in the colon wall increase cancer cell invasiveness and have a negative impact on the course of CRC.
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Steiro, Ida, Pegah Abdollahi, Magne Børset, and Tobias S. Slørdahl. "The Serine Protease Matriptase Acts As a Tumour Suppressor in Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 14. http://dx.doi.org/10.1182/blood-2020-140229.
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Both in newly diagnosed multiple myeloma (MM) and during progression of the disease, malignant plasma cells are found circulating in peripheral blood as well as in the bone marrow (BM). The disseminated nature of MM is strongly dependent on the interplay between the cancer cells and the BM microenvironment, promoting myeloma cell migration in the BM. Matriptase (ST14), a type-II transmembrane serine protease primarily found in epithelial tissues, is overexpressed in a variety of human malignancies and is sufficient to induce tumour formation in mice. Frequently, a concomitant reduction in the levels of its cognate inhibitor hepatocyte growth factor activator inhibitor (HAI)-1 (SPINT1) is observed in carcinomas, while expression and function of the related inhibitor HAI-2 (SPINT2) is yet to be clarified. Dysregulated expression causing increased matriptase proteolytic activity has been associated with cancer growth, survival and metastasis. Here, we show for the first time a role of matriptase as a possible tumour suppressor in myeloma pathogenesis. Gene expression analysis of primary cells from MM patients (n=24) and human myeloma cell lines (n=8) revealed highly variable levels of matriptase, HAI-1 and HAI-2. This observation prompted us to investigate the functional role of matriptase in vitro. We showed that stable overexpression of matriptase in INA-6, a MM cell line with no endogenous ST14 expression, reduced migration by more than 50% in response to the combination of the pro-migratory cytokines stromal cell-derived factor-1 alpha (SDF-1α) and hepatocyte growth factor (HGF, Fig. 1A). Conversely, stable knockdown of matriptase in two MM cell lines with high endogenous matriptase expression (RPMI-8226 and JJN-3) significantly enhanced migration in vitro. Mechanistically, matriptase overexpression blocked activation of Src kinase (Fig. 1B), well-known as a critical player in metastasis formation promoting cancer cell motility, invasiveness and angiogenesis. In agreement with our result, previous studies have demonstrated the activation of Src family kinases (SFK) downstream SDF-1/CXCR4-signaling. Finally, we performed survival analyses in the public available MMRF CoMMpass trial database (release version IA14). Low ST14 expression was associated with significant worse overall survival (P=0.05, Fig. 1C) and progression-free survival (P=0.02, Fig. 1D). Altogether, our data are in marked contrast to the role ascribed to matriptase in epithelial and certain non-epithelial tumours as an oncogenic protein and an unfavourable prognostic marker. In conclusion, these findings suggest a novel role of matriptase as a tumour suppressor in MM pathogenesis. Disclosures Slørdahl: Celgene: Consultancy; Janssen and Celgene: Honoraria.
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Salati, Massimiliano, Francesco Caputo, Andrea Spallanzani, Fabio Gelsomino, Beatrice Ricco', Gabriele Luppi, Luca Reggiani Bonetti, et al. "Clinicopathologic correlates and prognostic relevance of the immune checkpoint CD73 (NT5E) in resected biliary cancers (BC)." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 473. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.473.
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473 Background: CD73, an ecto-5’-nucleotidase (NT5E), creates an immunosuppressive tumour-promoting microenvironment by converting ATP to adenosine. The expression of CD73 has been linked to poorer patients (pts) outcome across several cancer types and the targeted inhibition of this immunoinhibitory protein has been recently advanced to clinical development. However, the clinicopathologic role of CD73 as well as its potential implications are largely unexplored in BC. Methods: The expression of CD73 was assessed by immunohistochemistry on both tumour (tCD73) and stromal tissue (sCD73) of a clinically-annotated cohort of radically-resected BC and scored for staining intensity as follows: +1, +2 and +3. RNAseq was performed on RNA isolated from surgical specimens. Differences between groups were evaluated using the Chi-square test. Survival functions were estimated by the Kaplan-Meier method and comparisons were made using the log-rank test. The Cox proportional hazards model was used to assess the impact of covariates on survival outcomes. Results: CD73 immunohistochimichal expression was evaluated on resected specimens of 70 BC pts. 43 pts (61%) were tCD73-positive, while 44 pts (62%) were sCD73-positive. Among the former group, the intensity score was 1+ in 19 pts (44%), 2+ in 16 pts (37%), 3+ in 10 pts (23%), while in the latter group was 1+ in 22 pts (50%), 2+ in 10 pts (22%) and 3+ in 12 pts (27%). CD73 positivity was associated with older age (> 70 years, p = 0.01), gallbladder subsite (p = 0.03), and nodal involvement (p = 0.04). Patients with tCD73-positive BC experienced a significantly shorter relapse-free survival (8,4 vs 39,4 months; p = 0.016) and overall survival (60,7 vs 13,7 months; p = 0.017). Notably, high tCD73 expressors (score 3+) displayed the poorest prognosis (12,03 months; p = 0.023). When evaluated on univariate and multivariate analysis, tCD73 positivity was an independent prognostic factor for both relapse-free survival (p = 0.038) and overall survival (p = 0.023), together with ECOG PS and pTNM stage. Whole-transcriptome sequencing is ongoing to correlate CD73 expression with cancer-related pathways. Conclusions: In this study, we provided a clinicopathologic characterization of CD73 expression in resected BC, demonstrating that tCD73 is an independent negative prognostic biomarker in this disease. Although these findings are in need of a validation in larger dataset, they foster novel combination of anti-CD73 agents with conventional therapy in the poorer-prognosis subset of CD73-positive BC.
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Carpenter, Ben, Sara Ghorashian, Emma Nicholson, James Edward Griffin, Maryam Ahmadi, Angelika Holler, Barry Flutter, et al. "Targeting Therapeutic T Cells to Tumour Niches." Blood 120, no. 21 (November 16, 2012): 3009. http://dx.doi.org/10.1182/blood.v120.21.3009.3009.
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Abstract Abstract 3009 Background: Interactions between tumour cells and host cells within the microenvironment are important in promoting the development of cancer. Tumor niches provide crucial anti-apoptotic and anti-proliferative signals that drive tumor chemoresistance. The CXCR4-CXCL12 chemokine axis forms a critical component of this niche. CXCL12 produced by stromal cells has direct pro-survival effects upon tumor cells, promotes metastasis and recruits CXCR4-expressing regulatory T cell populations that block anti-tumour immunity. In this study, we have tested the hypothesis that targeting therapeutic T cells to CXCR4-dependent niches will improve eradication of tumours in mice. Methods: The murine CXCR4 gene was inserted into retroviral vector, pMP71. Murine T cells were transduced with CXCR4 or control vector and tested for homing in vitro to CXCL12 through chemotaxis assays. In vivo imaging of the putative endosteal bone marrow (BM) niche was performed by multiphoton imaging through cranial frontal bones in osteoblast (collagen 1-α-GFP) reporter mice. In vivo trafficking, competitive transfer and memory recall experiments were performed following transfer of transduced T cells to syngeneic, sub-lethally irradiated mice. Anti-tumour reactivity of CXCR4-transduced T cells was tested in models of allogeneic BM transplantation (BMT). Results: CXCR4-transduced T cells demonstrated enhanced migration towards CXCL12 in vitro. No differences in viability, phenotype or function were observed in CXCR4-transduced versus control T cells in the presence or absence of CXCL12. In competitive assays, CXCR4-transduced CD8 T cells demonstrated a 2-fold greater capacity than controls to home to the BM by 24h after transfer to sub-lethally-irradiated recipients. Multiphoton imaging through cranial frontal bones indicated that fluorescently labelled CXCR4-transduced T cells were closer than control cells to the endosteum (13 μm versus 17 μm, p<0.01). By 14 days, the numbers of CXCR4-transduced CD8 T cells in the BM were 15-fold greater than controls. To test immunity to model antigen, CXCR4 or control vector-transduced OT-1 TCR-transgenic CD8 cells were transferred to sub-lethally irradiated mice before challenge with OVA peptide-loaded dendritic cells. Pre-vaccination, CXCR4-transduced OT-1 cells demonstrated greater engraftment than controls in the BM and spleen. Seven days following vaccination, CXCR4 OT-1 cells demonstrated a greater capacity than control cells to generate IFN-γ to OVA-peptide. Four weeks following vaccination, CXCR4-transduced CD8 T cells showed increased frequencies of cells with a CD44highIL-7Rαhigh memory phenotype than controls, with a greater proportion of cells undergoing proliferation as evaluated by BrdU incorporation. To test T cell immunity against a tumor that exploits the CXCR4-CXCL12 axis to recruit regulatory T cells, B6 BM and CXCR4- or control transduced B6 T cells were transferred to irradiated BALB/c recipients given A20 tumor. Tumor growth was delayed to a greater extent following transfer of CXCR4-compared to control-transduced donor T cells. Conclusion: Over-expression of CXCR4 in CD8 T cells potentiates engraftment, initial effector function and generation of memory cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.
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Goh, Sal Lee, Jean-Pierre Levesque, Allison R. Petitt, Valarie Barbier, and Ingrid G. Winkler. "Therapeutic Blockade of Macrophage Colony Stimulating Factor (CSF-1) Delays AML Progression in Mice In Vivo." Blood 128, no. 22 (December 2, 2016): 2835. http://dx.doi.org/10.1182/blood.v128.22.2835.2835.
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Abstract Macrophage colony-stimulating factor (M-CSF or CSF-1) plays a role in regulating innate immune responses promoting macrophage growth and differentiation. We hypothesized CSF-1 may also play a role in growth and progression of Acute Myeloid Leukaemia (AML). The aim of this study is to investigate the role of CSF-1 in survival and chemo-resistance of leukaemia stem and progenitor cells (LSPC). We further hypothesized that blocking CSF-1R signalling in LSPC may dampen leukaemia survival in vitro and delay leukaemia progression in vivo. AML was induced in mice by injecting murine Haematopoietic Stem and Progenitor Cells (HSPC) transduced with either MLL-AF9 or AML1- ETO fusion oncogenes for the development of either monomyelocytic or granulocytic leukaemia respectively. We found CSF-1R, the main receptor for CSF-1, was expressed on these acute myeloid leukaemia cells, thus it is possible that CSF-1 provide supportive microenvironment for leukemic growth. To identify whether CSF-1 in the bone marrow (BM) niche is essential for growth of malignant LSPC, we harvested normal or- leukaemic blasts from BM for in vitro studies using Long-Term Culture-Initiating-Cell (LT-CIC) assays. In these assays AML LSPC or normal HSPC cells were co-cultured with mesenchymal stromal cells (MSC) from either wildtype mice (MSC that produce CSF-1) or MSC from OP/OP mice (unable to produce functional CSF-1). We found normal (wild-type) HSPC were able to proliferate, survive and produce LT-CIC in the absence of niche-provided CSF-1, however AML blasts could not, unless rescued by addition of recombinant CSF-1 (100 ng/mL) in vitro. Together these data suggest CSF-1 signalling may be critical for AML LSPC but not normal HSPC. Next we investigated in mice whether therapeutic CSF-1 blockade could similarly dampen AML survival or progression in vivo. Cohorts of mice were injected with luciferase-expressing monomyelocytic (MLL-AF9) BM leukaemic blasts, then 7 days later administered the small molecule CSF-1 antagonist (GW2580, 160mg/kg daily for 10 days) or vehicle control. Leukaemia progression was tracked by biweekly bioluminescence and testbleeds for appearance of GFP+ leukaemia blasts in blood. We found therapeutic blockade of CSF-1 significantly reduced tumour burden in these mice by both bioluminescence and testbleed analysis. Mice were also monitored for duration of survival. As anticipated by the observed reduction in leukaemia burden, therapeutic CSF-1 blockade also significantly extended the duration of overall mouse survival (P<0.005, n= 8 mice/ group). Together these studies suggest therapeutic CSF-1 blockade may show promise as an adjunct therapy to help reduce tumour burden and improve success of AML leukaemia therapies. Disclosures Winkler: GlycoMimetics: Research Funding.
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Crassini, Kyle R., Yandong Shen, William S. Stevenson, Stephen P. Mulligan, Oliver Giles Best, and Richard Christopherson. "mRNA Profiling of CLL Cells Derived from the Blood, Bone Marrow and Lymph Node." Blood 132, Supplement 1 (November 29, 2018): 1850. http://dx.doi.org/10.1182/blood-2018-99-118264.
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Abstract Background Chemo-immunotherapy remains the backbone of therapy for patients with chronic lymphocytic leukaemia (CLL), with evidence pointing towards long term remission and even cure in patients with mutated IGHV status receiving this therapy frontline (1). However, relapse is common especially in those harbouring abnormalities in TP53 or ATM, unmutated IGHV status or a complex karyotype (2). It has become increasingly apparent that the bone marrow (BM) and lymph node (LN) play important roles in promoting the survival and proliferation of CLL cells. Signalling pathways triggered by interactions within these niches, such as the B cell receptor (BCR) pathway, and intracellular proteins such as Bcl-2 are vitally important in the biology of CLL. Novel therapeutic agents, such as ibrutinib, which target components of the BCR pathway, and the Bcl-2 inhibitor venetoclax, have demonstrated the potential of targeted therapies in CLL (3, 4). Novel therapeutic approaches must target the proliferative, drug-resistant compartments of disease within these microenvironments. The NanoString® nCounter platform enables mRNA profiling of archival samples, including formalin-fixed, paraffin-embedded tissue (FFPE). We have previously demonstrated the utility of this technology by comparing the mRNA expression profile of CLL cells derived from the peripheral blood (PB), archival BM and LN tissue as well as PB-derived CLL cells following in vitro co-culture with a human stromal cell line under either normoxic or hypoxic conditions. Here we present an update on our previous work with increased sample numbers in each of the tissues or culture conditions. Methods RNA was extracted from FFPE BM trephines (n = 5) and LN sections (n = 5), using the QIAGEN RNeasy FFPE Kit. All biopsies analysed were comprised of > 80 % lymphocytes, as determined by microscopic review. RNA from PBMC fractions (n = 5) was isolated either immediately or following co-culture with HS5 stromal cells for 24 h under normoxic (n = 5) or hypoxic (n = 5) conditions using the QIAGEN RNeasy Mini Kit. RNA from all preparations was quantified using a NanoDrop™ spectrophotometer. A total of 200ng of FFPE-derived RNA and 100ng of PBMC-derived RNA was analysed per sample on the NanoString® platform using a 260 gene panel. Three-fold changes in mRNA expression were considered significant. Results Of the 260 genes profiled, 89 were upregulated in the BM samples and 52 in the LN samples compared to expression in PB-derived CLL cells. Changes were seen in genes encoding for proteins involved in chemotaxis (CXCL9), the regulation of apoptosis (BCL2L1), surface receptors (FLT3) and genes associated with intracellular signalling, metabolism and cell division. 35 genes were downregulated in the LN samples and 31 in the BM samples. These changes were seen in genes coding for surface receptors (ROR1 and CXCR4), genes coding for intracellular signalling proteins (RAF1) and genes coding for transcription factors (JUN and FOS). Co-culture of PBMCs with HS5 cells induced similar changes to those observed in our comparison of the PBMCs and BM samples; genes coding for 61.5% and 50.0% of the mRNA expression changes observed in the LN were observed in PBMCs cultured under normoxic and hypoxic conditions respectively. A similar comparison of the BM samples identified concordant changes in expression of 46.5% and 39.2% of genes under normoxic and hypoxic conditions respectively. Importantly, changes observed in genes coding for the anti-apoptotic protein MCL1, the surface receptors CXCR4 and ROR1 and the transcription factors ATF, FOS and JUN were consistent across samples from LN, BM and the in vitro model. In summary, we have utilised the NanoString® nCounter platform to profile PB, BM and LN-derived CLL cells and have identified panels of genes that are either up or down-regulated in cells derived from these microenvironments. Furthermore, the high concordance between RNA changes in the in vitro model and the primary tissue suggest the HS5 co-culture system mimics aspects of the tumour microenvironment. These data provide a better understanding of how CLL cells populate and proliferate in the tumour microenvironment and may lead to novel therapeutic strategies. Disclosures No relevant conflicts of interest to declare.
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Cuthill, Kirsty M., Andrea Gail Sherman Buggins, Pj Chana, and Stephen Devereux. "Targeting The T Cell Component Of The Tumour Microenvironment In Chronic Lymphocytic Leukaemia; A Potential Therapeutic Strategy." Blood 122, no. 21 (November 15, 2013): 4147. http://dx.doi.org/10.1182/blood.v122.21.4147.4147.
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Abstract It has recently become clear that B cell receptor (BCR) activation plays an important role in the pathogenesis of chronic lymphocytic leukaemia (CLL); a fact that is underlined by the marked efficacy of drugs that inhibit components of this pathway. Although the underlying mechanisms remain unclear, CLL BCRs have been shown to recognize a variety of autoantigens and there is evidence of ongoing activation of a number of downstream signaling molecules including Syk, Erk, Akt and the NFkB and NFAT family of transcription factors. In addition to BCR activation, it is thought that signals from other cells in the tumour microenvironment such as T cells, the vascular endothelium and other stromal cells may also play a role in promoting the growth of the disease. In the present study we chose to revisit the effects of ciclosporin (CsA), a calcineurin antagonist with effects on antigen receptor signaling, in CLL. When this agent is used to treat the autoimmune complications of CLL, concurrent responses in the underlying disease have been noted in about 20% of patients, although the underlying mechanism has not been thoroughly investigated. Since CsA primarily inhibits T cell activation we hypothesized that its effects in CLL might be due to a reduction in T cell mediated co-stimulation in the lymph nodes. We therefore investigated the effect of CsA on the activation of CLL B and T cells using conventional and multispectral imaging flow cytometry to measure the expression of activation markers and the nuclear translocation of NFAT and NFKB family transcription factors. Cells were collected from eight unselected patients with a confirmed diagnosis of CLL for each study. T and B cells were purified by negative immunomagnetic selection and activated by incubation with phorbol ester and ionomycin (PMA/I) or CD40L transfected fibroblasts in the presence of absence of CsA. The activation of CD4+ T cells and CD19+ CLL cells was assessed by staining for CD69/interferon gamma (IFNΥ) and CD69/CD25 respectively. Nuclear translocation of NFATc2 and NFKB p65 was measured by image flow cytometry (Amnis Imagestream). Leukaemia and Lymphoma Research provided the funding for this study. NFkB(p65) translocation at 30 minutes was inhibited by a mean of 22.5% (p=0.0003) in activated CLL CD4+ T cells treated with CsA compared to those treated with vehicle control (VC). Similarly, in the presence of CsA, NFAT-c2 translocation was inhibited by a mean of 24.3% (p=0.008) at 10 minutes in CLL CD4+ T cells compared to those treated with VC. NFkB(p65) translocation was not inhibited (mean of differences=0.63%, p=0.645) and NFAT-c2 translocation was minimally inhibited (mean of differences = -4%, p = 0.007) in activated CLL B Cells treated with CsA. The proportion of activated CLL CD4+ T cells expressing both CD69 and IFNΥ was reduced by 13.2% (p=0.003) in the presence of CsA whereas there was no inhibition of CD25(-1.5, p=0.16) and CD69(-1.4, p=0.5) expression in activated CLL B cells treated with CsA. In summary, CsA had a profound effect on CD4+ T cell activation in patients with CLL, as demonstrated by the reduction in NFkB (p65), NFAT-c2 nuclear translocation and CD69/IFNΥ expressing cells. In contrast, there was a minimal effect on NFAT-c2 translocation in activated CLL B cells and no impact on NFkB (p65) translocation or the expression of CD25 and CD69. These findings suggest that the previously documented activity of CsA in CLL is not due to a direct effect on the tumour but is instead indirect and mediated through inhibition of other microenvironment derived signals such as those provided by activated CD4+ T cells. Since it is likely that these co-stimulatory effects act in concert other signals, such as those induced by BCR activation, reexamination of CsA and similar agents in CLL would thus seem warranted. Disclosures: No relevant conflicts of interest to declare.
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Reidy, Mairead, Marianne VanDijk, Michael O'Neill, and Michael O'Dwyer. "The Dual PIM/PI3-K Inhibitor Ibl-202 Overcomes Microenvironmental Mediated Resistance in Multiple Myeloma and Prevents PIM1 Induced CXCR4 Upregulation." Blood 126, no. 23 (December 3, 2015): 5350. http://dx.doi.org/10.1182/blood.v126.23.5350.5350.
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Abstract Background: The interaction of multiple myeloma (MM) cells with bone marrow (BM) cells along with factors in the BM milieu such as chemokines and cytokines play a crucial role in both progression of MM and drug resistance. Activation of the PI3-K/Akt survival pathway is a characteristic of both human MM cell lines and patient samples. This activation can be linked to BM microenvironmental signalling and use of proteasome inhibitors in treatment, suggesting this as a crucial point of therapeutic intervention to abrogate growth and survival signals in MM. However, the efficacy of such therapeutics has been modest and is likely to be compromised by the stimulation of compensatory signalling pathways, such as the PIM kinases, which like the PI3-K/Akt pathway are also induced by BM microenvironmental influences and share similar downstream targets. These proto-oncogenic kinases are constitutively active and play an important role in proliferation and survival in MM. The influence of these kinases on homing and migration has been observed in other malignancies, this has yet to be reported in MM. Here we report the effects of a dual inhibitor of PIM/PI3-K, IBL-202, and provide novel insights into effects on cell survival, signaling and migration. Methods: We investigated the effect of IBL-202 against a panel of MM cell lines (MM.IS, NCI-H929s, KMS11 and RPMI-8226) and primary MM patient samples. The in vitro efficacy of IBL-202 was compared to that of single pan-PIM inhibitors pPIMi and AZD1208 and also the pan-PI3-K inhibitor GDC-0941. Apoptosis was measured with AnnexinV staining and cell cycle analysed with Edu/DAPI staining. To mimic BM microenvironmental conditions MM cells were cultured under hypoxic conditions (1% O2) and in co-culture with the human stromal cell line HS5. Surface expression of CXCR4 was assessed in MM cell lines by flow cytometry. PIM kinases, pCXCR4 and downstream targets of PIM/PI3-K were examined by western blot. Transwell migration assays were carried out in the presence of 50ng SDF-1α for 4h @ 37o C. Results: Simultaneous inhibition of PIM and PI3-K using IBL-202 in vitro was significantly more potent at inducing apoptosis than GDC-0941, pPIMi or AZD1208 in all MM cell lines tested. IC50 values were under 1μM for IBL-202 at 48h whilst in comparison the pan PIM inhibitors pPIMi and AZD1208 scored IC50 values between 5 and 10μM. The IC50 for GDC-0941 was on average 5μM (Figure 1). At the molecular level there was a notable decrease in phosphorylation of known PIM/PI3-K targets Akt (Ser473), Bad (Ser112) and the translational targets S6 (Ser235/236) and 4EBP1 (Thr37/46). The levels of total proteins were unchanged. Treatment with increasing doses of IBL-202 led to a marked reduction in cells in S phase of the cell cycle. These changes were paralled by down regulation of the cell cycle promoting proteins cyclin D1 and c-myc. IBL-202 was also effective in inducing apoptosis in primary MM patient samples (n=4) after just 24h as assessed by Annexin-V staining (Figure 2). To explore the role of the BM microenvironment we co-cultured MM cell lines with HS5s. This led to strong induction of PIM2 in MM cells. While MM cells in this setting were protected from Bortezomib-induced cell death, the apoptotic effect of IBL-202 was enhanced. In a further effort to mimic the tumour microenvironment we cultured MM cell lines in hypoxia. This may be of particular relevance as Pim-1 has been reported to be a pivotal regulator involved in hypoxia-induced chemoresistance. MM cells were further sensitised to IBL-202 in hypoxia. In addition, hypoxia increased the surface expression of CXCR4, a chemokine receptor critical for homing of MM cells to the bone marrow, with a concomitant increase in PIM1. Treatment of MM cell lines with IBL-202 reduced the level of PIM1 and CXCR4 Ser339 phosphorylation, along with down regulation of CXCR4 surface expression resulting in reduced migration of MM cells along an SDF-1 gradient. Conclusion: Together these data provide direct evidence of the potency of IBL-202 in MM in conditions that mimic the BM microenvironment. Moreover, they indicate a potential role for PIM kinases in facilitating dissemination and invasiveness of MM by CXCR4 and provide an added rationale for targeting PIM kinases in MM. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures O'Neill: Inflection Biosciences: Employment.
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Kovács, Dávid, Nóra Igaz, Annamária Marton, Andrea Rónavári, Péter Bélteky, László Bodai, Gabriella Spengler, et al. "Core–shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts." Journal of Nanobiotechnology 18, no. 1 (January 21, 2020). http://dx.doi.org/10.1186/s12951-020-0576-x.
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Abstract Background Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. Results We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. Conclusions Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.
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Han, Xuexiang, Yiye Li, Ying Xu, Xiao Zhao, Yinlong Zhang, Xiao Yang, Yongwei Wang, et al. "Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem." Nature Communications 9, no. 1 (August 23, 2018). http://dx.doi.org/10.1038/s41467-018-05906-x.
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AbstractPancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.
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Chen, Jing-Yi, Chien-Feng Li, You-Syuan Lai, and Wen-Chun Hung. "Lysine demethylase 2A expression in cancer-associated fibroblasts promotes breast tumour growth." British Journal of Cancer, October 7, 2020. http://dx.doi.org/10.1038/s41416-020-01112-z.
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Abstract Background Our previous study demonstrated that lysine demethylase 2A (KDM2A) enhances stemness in breast cancer cells. This demethylase is also highly expressed in cancer-associated fibroblasts (CAFs). However, its clinical significance is unclear. Methods The expression of KDM2A in CAFs was studied using immunohistochemical staining and its association with clinicopathological features and patient’s survival was tested. Overexpression and knockdown strategies were used to investigate KDM2A-regulated genes in fibroblasts. Senescent cells were detected by using β-galactosidase staining. The in vivo tumour-promoting activity of stromal KDM2A was confirmed by animal study. Results Increase of stromal KDM2A is associated with advanced tumour stage and poor clinical outcome in breast cancer patients. Cancer-derived cytokines stimulated KDM2A expression in normal fibroblasts and transformed them into CAFs. Upregulation of KDM2A induced p53-dependent senescence in fibroblasts and enhanced the release of cytokines, which reciprocally promoted cancer cell proliferation. Additionally, KDM2A upregulated programmed death-ligand 1 (PD-L1) expression via transcriptional activation in fibroblasts. Knockdown of KDM2A completely abolished the tumour-promoting activity of CAFs on breast tumour growth in vivo and diminished PD-L1 expression in the stroma of tumour tissues. Conclusions Stromal KDM2A plays an oncogenic role in breast cancer and inhibition of KDM2A reduces fibroblast senescence and suppresses tumour growth.
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Murphy, Kendelle J., Jessie Zhu, Michael Trpceski, Brooke A. Pereira, Paul Timpson, and David Herrmann. "Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy." Biochemical Society Transactions, August 5, 2022. http://dx.doi.org/10.1042/bst20220162.
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The dense desmoplastic and fibrotic stroma is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC), regulating disease progression, metastasis and response to treatment. Reciprocal interactions between the tumour and stroma are mediated by bidirectional integrin-mediated signalling, in particular by Focal Adhesion Kinase (FAK). FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. Therapeutic targeting of the PDAC stroma is an evolving area of interest for pre-clinical and clinical research, where a subtle reshaping of the stromal architecture prior to chemotherapy may prove promising in the clinical management of disease and overall patient survival. Here, we describe how transient stromal manipulation (or ‘priming’) via short-term FAK inhibition, rather than chronic treatment, can render PDAC cells exquisitely vulnerable to subsequent standard-of-care chemotherapy. We assess how our priming publication fits with the recent literature and describe in this perspective how this could impact future cancer treatment. This highlights the significance of treatment timing and warrants further consideration of anti-fibrotic therapies in the clinical management of PDAC and other fibrotic diseases.
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Kay, Emily J., Grigorios Koulouras, and Sara Zanivan. "Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis." Frontiers in Oncology 11 (August 27, 2021). http://dx.doi.org/10.3389/fonc.2021.719922.
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Cancer associated fibroblasts (CAFs) are a major component of the tumour microenvironment in most tumours, and are key mediators of the response to tissue damage caused by tumour growth and invasion, contributing to the observation that tumours behave as ‘wounds that do not heal’. CAFs have been shown to play a supporting role in all stages of tumour progression, and this is dependent on the highly secretory phenotype CAFs develop upon activation, of which extracellular matrix (ECM) production is a key element. A collagen rich, stromal ECM has been shown to influence tumour growth and metastasis, exclude immune cells and impede drug delivery, and is associated with poor prognosis in many cancers. CAFs also extensively remodel their metabolism to support cancer cells, however, it is becoming clear that metabolic rewiring also supports intrinsic functions of activated fibroblasts, such as increased ECM production. In this review, we summarise how fibroblasts metabolically regulate ECM production, focussing on collagen production, at the transcriptional, translational and post-translational level, and discuss how this can provide possible strategies for effectively targeting CAF activation and formation of a tumour-promoting stroma.
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Shams, Anwar. "Re-evaluation of the myoepithelial cells roles in the breast cancer progression." Cancer Cell International 22, no. 1 (December 12, 2022). http://dx.doi.org/10.1186/s12935-022-02829-y.
Full textAbstract:
AbstractOver the past decades, luminal epithelial cell lineage has gained considerable attraction as the functionally milk-secreting units and as the most fruitful acreage for breast cancer launching. Recognition of the effective involvement of the myoepithelial cells in mammary gland development and in hampering tumorigenesis has renewed the interest in investigating the biological roles of this second main mammary lineage. The human breast is made up of an extensively branching ductal system intervening by copious lobular units. The ductal system is coated by a chain of luminal epithelial cells (LECs) situated on a layer of myoepithelial cells (MECs) and encompassed by a distinguished basement membrane. Ductal contractility during lactation is a well-known function delivered by the MECs however this is not the only assignment mediated by these cellular populations. It has been well appreciated that the MECs exhibit a natural paracrine power in defeating cancer development and advancement. MECs were found to express numerous proteinase inhibitors, anti-angiogenic factors, and tumour suppressors proteins. Additionally, MECs contributed effectively to maintaining the right luminal cells' polarization and further separating them from the adjacent stroma by making an integrated fence. Indeed, disruption of the MECs layer was reported to facilitate the invasion of the cancer cells to the surrounding stroma. Nonetheless, MECs were also found to exhibit cancer-promoting effects and provoke tumour invasion and dissemination by displaying distinct cancer chemokines. Herein in this review, we aimed to address the roles delivered by MECs in breast cancer progression and decipher the molecular mechanisms regulating proper MECs’ physiology, integrity, and terminal differentiation. Graphical Abstract
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Takahashi, Masahide, Hiroki Kobayashi, Yasuyuki Mizutani, Akitoshi Hara, Tadashi Iida, Yuki Miyai, Naoya Asai, and Atsushi Enomoto. "Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin/Islr in Cancer Fibrosis." Frontiers in Cell and Developmental Biology 9 (October 5, 2021). http://dx.doi.org/10.3389/fcell.2021.749924.
Full textAbstract:
Fibroblasts synthesise the extracellular matrix (ECM) such as collagen and elastin, the excessive accumulation of which can lead to fibrosis and organ dysfunction under pathological conditions. Cancer-associated fibroblasts (CAFs) are major constituents of the tumour microenvironment (TME) that accompany the desmoplastic reaction responsible for anti-cancer treatment resistance. Thus, it is important to dissect the roles of CAFs in the TME to develop new therapeutic strategies for refractory cancers. Recent progress in the studies of CAF biology suggests that the functions of CAFs are complicated and that they are composed of functionally distinct populations, including cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). We recently identified a new cell surface marker for rCAFs in pancreatic and colon cancers, designated as Meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue)/Islr (immunoglobulin super family containing leucine-rich repeat). Based on the distribution of Meflin/Islr-positive cells, we also considered it a specific candidate marker for mesenchymal stroma/stem cells. Meflin/Islr-positive CAFs have been shown to suppress cancer progression by being involved in regulating collagen structures and BMP signalling in the TME. This review describes the function of Meflin/Islr in cancer fibrosis as well as in cardiac and lung fibrosis and its potential in the development of new cancer therapeutics.