Journal articles: 'Targeting tumorale'

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Dhani, Neesha, and Michael Milosevic. "Targeting tumoral hypoxia: finding opportunity in complexity." Future Oncology 8, no. 9 (September 2012): 1065–68. http://dx.doi.org/10.2217/fon.12.100.

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Raavé, René, Toin H. van Kuppevelt, and Willeke F. Daamen. "Chemotherapeutic drug delivery by tumoral extracellular matrix targeting." Journal of Controlled Release 274 (March 2018): 1–8. http://dx.doi.org/10.1016/j.jconrel.2018.01.029.

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He, Z., Z. Meng, P. Liang, L. Xing, X. Zheng, and G. Wang. "P13.15 Pre-clinical trial of T601 oncolytic virus for high grade glima via intra-tumoral injection." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii35—ii36. http://dx.doi.org/10.1093/neuonc/noab180.122.

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Abstract BACKGROUND An effective therapeutic method still hasn’t been devised for lethal high grade glioma. Thus, a method with high anti-tumoral efficiency, tumoral targeting, and acceptable side effect needs to be designed. Oncolytic virotherapy which can specifically lyse tumor cells via mass replication and deleting nucleotide metabolism related gene, like TK, required in viral replication and overexpressed in tumor cells, provides hope for patients. However, the virus only contained TK deletion is unable to show sufficient specificity of anti-tumoral response in tumor cells. Here, the adapted strain of vaccinia virus with high tumoral specificity due to TK and RR deletion and FUC1 insertion, named T601, is chosen in this project. In clinical application, intra-tumoral injection showed improved anti-tumoral efficiency and acceptable side effect. However, intra-tumoral viral injection in orthotropic glioma model is rare. In this project, various biosafety and antitumoral efficiency parameter would be tested for confirming the biosafety and reliability of intra-tumoral T601 viral injection for future clinical trials. MATERIAL AND METHODS For measuring the IC50 of T601, 10 different amounts of virus was tested in vitro via calculating cell viability with CCK-8(cell counting kit-8). For measuring the further antitumoral response of FCU1, different concentration of the 5-FC was added into the medium with IC50 viral amount. To ensure the biosafety of T601, MTD (maximum tolerance dose) was measured. Based on the MTD result, for evaluating the anti-tumoral efficiency, 106 pfu,105 pfu,104 pfu of virus was intra-tumoral injected in orthotopic GBM bearing mice. Tumor size was measured once a week through in vivo bioimaging system. RESULTS 0.022 MOI, the IC50 of T601, showed high cytotoxicity of T601. Moreover, the significantly decreased cell viability under the combined treatment of 5-FC and 0.22MOI T601 showed intact anti-tumoral function. In MTD assay, except for 107 group, no significant weight loss was found. However, in 107 pfu group, mean body weight decreased around 10% and animal fatality happened on day 9. According to the MTD result, certain amount of virus was intra-tumorally injected. In all treatment group, the tumor size was significantly shrined. At the same time, the survival rate of mice under viral treatment was significantly extended. CONCLUSION In summary, T601 exhibited efficient anti-tumoral function and acceptable side effect. T601 treatment prolonged the survival period of GBM mice with acceptable neurotoxicity, demonstrating that T601 contains necessary criterial for intra-tumoral injection. Ultimately, this project provided basic reference information of dose for future clinical trial.

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Halin, Cornelia, Luciano Zardi, and Dario Neri. "Antibody-Based Targeting of Angiogenesis." Physiology 16, no. 4 (August 2001): 191–94. http://dx.doi.org/10.1152/physiologyonline.2001.16.4.191.

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The selective targeting of neovasculature opens new avenues for the diagnosis and therapy of angiogenesis-related diseases such as cancer, blinding ocular disorders, and rheumatoid arthritis. Here we review recent advances in the identification of markers of angiogenesis as well as in the isolation and use of antibodies (and their derivatives) for the in vivo targeting of both tumoral and nontumoral neovasculature.

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Do, Manh-Hung, Phuong To, Young-Suk Cho, Se-Young Kwon, Eu Hwang, Chan Choi, Sang-Hee Cho, Sang-Jin Lee, Silvio Hemmi, and Chaeyong Jung. "Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer." International Journal of Molecular Sciences 19, no. 9 (September 10, 2018): 2694. http://dx.doi.org/10.3390/ijms19092694.

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CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

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Koltai, Tomas, Stephan Joel Reshkin, Tiago M. A. Carvalho, and Rosa A. Cardone. "Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer." International Journal of Molecular Sciences 22, no. 8 (April 12, 2021): 3953. http://dx.doi.org/10.3390/ijms22083953.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell’s proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.

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Muller, Alexander J., and Peggy A. Scherle. "Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors." Nature Reviews Cancer 6, no. 8 (August 1, 2006): 613–25. http://dx.doi.org/10.1038/nrc1929.

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Muller, Alexander J., and Peggy A. Scherle. "Erratum: Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors." Nature Reviews Cancer 6, no. 9 (August 17, 2006): 742. http://dx.doi.org/10.1038/nrc1979.

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Wu, Deyang, Xiaowei Liu, Jingtian Mu, Jin Yang, Fanglong Wu, and Hongmei Zhou. "Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers." Biomolecules 12, no. 3 (March 2, 2022): 392. http://dx.doi.org/10.3390/biom12030392.

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Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical protein markers, while simultaneously having unique transcriptional features, which makes the proteins expressed on TAMs promising targets during anti-tumor therapy. Herein, TAM-associated protein-dependent target strategies were developed with the aim of either reducing the numbers of TAMs or inhibiting the pro-tumoral functions of TAMs. Furthermore, the recent advances in TAMs associated with tumor metabolism and immunity were extensively exploited to repolarize these TAMs to become anti-tumor elements and reverse the immunosuppressive tumor microenvironment. In this review, we systematically summarize these current studies to fully illustrate the TAM-associated protein targets and their inhibitors, and we highlight the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-tumor therapy.

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Gisbert-Garzarán, Miguel, Daniel Lozano, and María Vallet-Regí. "Mesoporous Silica Nanoparticles for Targeting Subcellular Organelles." International Journal of Molecular Sciences 21, no. 24 (December 18, 2020): 9696. http://dx.doi.org/10.3390/ijms21249696.

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Current chemotherapy treatments lack great selectivity towards tumoral cells, which leads to nonspecific drug distribution and subsequent side effects. In this regard, the use of nanoparticles able to encapsulate and release therapeutic agents has attracted growing attention. In this sense, mesoporous silica nanoparticles (MSNs) have been widely employed as drug carriers owing to their exquisite physico-chemical properties. Because MSNs present a surface full of silanol groups, they can be easily functionalized to endow the nanoparticles with many different functionalities, including the introduction of moieties with affinity for the cell membrane or relevant compartments within the cell, thus increasing the efficacy of the treatments. This review manuscript will provide the state-of-the-art on MSNs functionalized for targeting subcellular compartments, focusing on the cytoplasm, the mitochondria, and the nucleus.

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Niculae, Andrei Marian, Maria Dobre, Vlad Herlea, Florina Vasilescu, Laura Cristina Ceafalan, Bogdan Trandafir, Elena Milanesi, and Mihail Eugen Hinescu. "Lipid Handling Protein Gene Expression in Colorectal Cancer: CD36 and Targeting miRNAs." Life 12, no. 12 (December 16, 2022): 2127. http://dx.doi.org/10.3390/life12122127.

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The reprogramming of lipid metabolism has been highlighted in colorectal cancer (CRC) studies, suggesting a critical role for the scavenger receptor CD36 and fatty acid synthase (FASN) in this malignancy. In this study, we analyzed the gene expression levels of CD36, FASN, the cell surface glypican 4 (GPC4), and the two transporters SLC27A3 and SLC27A4 in 39 paired tumoral and peritumoral tissues from patients with CRC compared with 18 normal colonic mucosae. Moreover, the levels of seven miRNAs targeting CD36 and most of the analyzed genes were evaluated. We found a significant impairment of the expression of all the analyzed genes except GPC4 as well as the differential expression of miR-16-5p, miR-26b-5p, miR-107, miR-195-5p, and miR-27a-3p in the colonic mucosa of CRC patients. Interestingly, CD36 and miR-27a-3p were downregulated and upregulated, respectively, in tumoral tissues compared to peritumoral and control tissues, with a significant negative correlation in the group of patients developing lymph node metastasis. Our results sustain the relationship between CRC and fatty acid metabolism and emphasize the importance of related miRNAs in developing new therapeutic strategies.

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Fleur, Linnéa La, Johan Botling, Fei He, Catarina Pelicano, Giorgia Palano, Artur Mezheyeuski, Patrick Micke, Jeffrey Ravetch, Mikael Karlsson, and Dhifaf Sarhan. "720 Targeting MARCO and IL-37R on anti-inflammatory macrophages in lung cancer blocks regulatory T cells and shift balance to support cytotoxic lymphocyte function." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A762. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0720.

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BackgroundThe progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment (TME). In non-small cell lung cancer (NSCLC) accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Numerous clinical trials aiming to recover T cell anti-tumor activity have been failing due to the persistence immune suppression in TME. Thus, there is a clinical need for alternative treatments targeting the suppressive function of the TME. We have previously shown that antibodies targeting the scavenger receptor MARCO reprograms the pro-tumoral TAMs in murine cancer models. Here, we investigated the immune landscape of NSCLC in the presence of MARCO expressing TAMs. We tested targeting MARCO or the tumor mechanisms inducing MARCO on human TAMs and hypothesized that targeting these mechanisms will remodel the suppressive environment and relive the anti-tumor responses to increase the efficacy of immunotherapy.MethodsTo test our hypothesis, we first investigated the immune landscape of NSCLC in the presence of pro-tumoral MARCO+TAMs compared with tumors infiltrated by MARCO-TAMs. We next used RNAseq to analyze differential gene expression in NSCLC tumors infiltrated by MARCO positive or negative macrophages. In vitro, cytokine differentiated macrophages alternatively cultured with lung cancer cell lines were co-cultured with Natural Killer (NK) cells and T cells to mimic their interaction in the TME. Later, macrophages were treated with targeting antibodies and their phenotype and function were examined prior and following interaction with other immune cells.ResultsWe found that MARCO expressing TAM numbers correlated with increased occurrence of regulatory T cell and effector T cells and decreased NK cells in NSCLC infiltrated by MARCO+TAMs. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. Studies in vitro subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an anti-inflammatory phenotype through the release of IL-37. These human MARCO expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) repolarized TAMs resulted in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells.ConclusionsIn summary, our data demonstrate a novel immune therapeutic approach targeting human TAM immune suppression of NK and T cell anti-tumor activities and remodel immune suppression.Ethics ApprovalThe study was approved by Institutional Ethics Board, approval number Dnr 2013.977-31.1.

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Méry, Benoîte. "Targeting head and neck tumoral stem cells: From biological aspects to therapeutic perspectives." World Journal of Stem Cells 8, no. 1 (2016): 13. http://dx.doi.org/10.4252/wjsc.v8.i1.13.

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Finkel, Jemima, and Emmanuel A. Tsochatzis. "Targeting intra-tumoral lactic acidosis in hepatocellular carcinoma: a long way to go." Journal of Xiangya Medicine 2 (March 23, 2017): 32. http://dx.doi.org/10.21037/jxym.2017.03.01.

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Cano, Carla E., Christine Pasero, Aude De Gassart, René Hoet, Emmanuel Scotet, Erwan Mortier, Agnes Quemeneur, et al. "BTN2A, a New Immune-Checkpoint Targeting Vg9Vd2 T Cell Cytotoxicity." Blood 134, Supplement_1 (November 13, 2019): 1044. http://dx.doi.org/10.1182/blood-2019-128658.

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Background: Anti-tumoral response of Vg9Vd2 T cells requires sensing of phosphoantigens accumulated in malignant cells through binding of butyrophilin 3A(BTN3A). Moreover, an unknown partner located in human Chr6 was shown to be mandatory to BTN3A-mediated Vg9Vd2 T cell activation in murine models. Here, we identified butyrophilin 2A (BTN2A), which is located to Chr6, as a requirement for BTN3A-mediated Vg9Vd2 T cell cytotoxicity against cancer cells. Methods: CRISPR-Cas9-mediated inactivation of BTN2A1/2A2 isoforms was performed in Daudi, K562 and HEK-293T cells. Vg9Vd2 T cells expanded from healthy PBMCs were co-cultured with wild-type or BTN2AKO cells +/- BrHPP (1 µM), HMBPP (0.1 µM) or zoledronate (45 µM), or anti-BTN2A mAb, and Vg9Vd2 T cell degranulation (%CD106ab+ cells), and intracellular TNFa and IFNg assessed after 4h. Mouse T cell hybridoma 53/4 expressing TCRVg9Vd2-MOP were co-cultured overnight with NIH3T3 murine fibroblasts transfected with BTN3A- and/or BTN2A-encoding plasmids +/-HMBPP(10 µM), or increasing doses of HMBPP or anti-BTN3 20.1 mAb. BTN2A transcript expression in normal vs. tumoral tissue was analyzed using GEPIA tool. Anti-BTN2A mAb staining was performed on human samples of primary AML, cervical and pancreatic carcinoma and assessed by flow cytometry. Results: Degranulation and intracellular IFNg/TNFa (n=6) were abolished in Vg9Vd2 T cells co-cultured with BTN2AKO Daudi, K562 and HEK-293T cells compared to wild-type, in all conditions tested including anti-BTN3 20.1. Murine cells do not express no BTN2A1 or BTN3A orthologs and are unable to activate human Vg9Vd2 T cells. Ectopic expression of BTN2A and BTN3A combination but neither BTN2A or BTN3A alone in murine NIH3T3 cells, allows triggering of IL-2 secretion in mouse 53/4-TCRVg9Vd2-MOP reporter cells in presence of HMBPP or 20.1 mAb in dose-dependent manner. Anti-BTN2A mAb was able to suppress Vg9Vd2 T cell degranulation/cytokine secretion against cancer cell lines and activation of mouse 53/4-TCRVg9Vd2-MOP reporter by BTN2A/BTN3A-expressing NIH3T3 in a dose-dependent manner. BTN2A transcript was significantly up-regulated in pancreatic, ovarian and cervical carcinoma vs. normal tissue. Extracellular BTN2A protein was detected in primary hematological and solid tumors. Conclusion: Here, we show that BTN2A is mandatory for BTN3A-mediated function in human Vg9Vd2 T cells. Moreover, concomitant BTN2A and BTN3A expression empowers murine T cells with activation through Vg9Vd2 TCR, opening new roads for mouse models of Vg9Vd2 T cell anti-tumoral responses. We describe an anti-BTN2A able to suppress Vg9Vd2 T cell function, and we show BTN2A expression in primary tumors. These results are relevant for understanding Vg9Vd2 T cell antitumoral immunity triggered by phosphoantigens and amino-bisphosphonates. Disclosures Olive: ImCheck Therapeutics: Consultancy, Equity Ownership, Patents & Royalties; GlaxoSmithKline: Patents & Royalties.

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Andrini, Laura, Gustavo H. Marin, Ana Maria Inda, Heriberto Bruzzoni-Giovanelli, Marcela Garcia, Jorge Errecalde, and Angelita Rebollo. "Anti-tumoral Effect of a Cell Penetrating and Interfering Peptide Targeting PP2A/SET Interaction." Folia Medica 62, no. 1 (March 31, 2020): 31–36. http://dx.doi.org/10.3897/folmed.62.e47737.

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Objective: To test cell penetrating and interfering peptide Mut3DPT-PP2A/SET in interaction between serine threonine phosphatase PP2A and its physiological inhibitor, the oncoprotein SET.Materials and methods: Adult male C3H/S-strain mice, 60 days old, were given a graft of breast adenocarcinoma cells (TN60) into subcutaneous tissue. Mut3DPT-PP2A/SET peptide was used to block PP2A and SET oncoprotein interaction. The graft-bearing animals were divided into a control group (injected with saline buffer), and an intervention group injected intraperitoneally with Mut3DPT-PP2A/SET peptide (5 mg/kg) every day from day 5 to day 37. The variables we used to compare the outcome in both groups were tumor size in mm (length×width) and histological changes. In the statistical analysis we used ANOVA and Student-Keuls multiple comparisons test and Tuckey for the post-test analysis.Results: 48 mice were grafted at day 0 with breast UNLP-C3H/S tumor cells, and after randomization, they were assigned to one of the two study groups. At day 5 all mice were injected either with placebo or with the peptide. The treated group showed significant tumor reduction (p<0.07). Histological changes showed presence of apoptosis and necrosis of tumor in treated group.Conclusion: The peptide Mut3DPT-PP2A/SET has demonstrated anti-tumor activity by reduction in vivo of tumor growth becoming a promising future in anticancer therapy. 

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Martinozzi, I., N. Rosso, C. Tiribelli, and D. Pascut. "Telomerase extratelomeric effects in hepatocellular carcinoma: Molecular targeting to impair tumoral networks in HCC." Digestive and Liver Disease 48 (February 2016): e22. http://dx.doi.org/10.1016/j.dld.2015.12.058.

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Everts, Anne, Melissa Bergeman, Grant McFadden, and Vera Kemp. "Simultaneous Tumor and Stroma Targeting by Oncolytic Viruses." Biomedicines 8, no. 11 (November 5, 2020): 474. http://dx.doi.org/10.3390/biomedicines8110474.

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Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their continuous complex interactions with tumor cells promote tumor progression and metastasis, emphasizing the challenges in tumor therapy development. Over the last decade, advances in oncolytic virotherapy have shown that oncolytic viruses (OVs) are a promising multi-faceted therapeutic platform for simultaneous tumor and stroma targeting. In addition to promoting tumor cell oncolysis and systemic anti-tumor immunity, accumulating data suggest that OVs can also directly target stromal components, facilitating OV replication and spread, as well as promoting anti-tumor activity. This review provides a comprehensive overview of the interactions between native and genetically modified OVs and the different targetable tumor stromal components, and outlines strategies to improve stroma targeting by OVs.

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Novio, Fernando. "Design of Targeted Nanostructured Coordination Polymers (NCPs) for Cancer Therapy." Molecules 25, no. 15 (July 29, 2020): 3449. http://dx.doi.org/10.3390/molecules25153449.

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Conventional cancer chemotherapy presents notable drug side effects due to non-selective action of the chemotherapeutics to normal cells. Nanoparticles decorated with receptor-specific ligands on the surface have shown an important role in improving site-selective binding, retention, and drug delivery to the cancer cells. This review summarizes the recent reported achievements using nanostructured coordination polymers (NCPs) with active targeting properties for cancer treatment in vitro and in vivo. Despite the controversy surrounding the effectivity of active targeting nanoparticles, several studies suggest that active targeting nanoparticles notably increase the selectivity and the cytotoxic effect in tumoral cells over the conventional anticancer drugs and non-targeted nanoparticle platform, which enhances drug efficacy and safety. In most cases, the nanocarriers have been endowed with remarkable capabilities such as stimuli-responsive properties, targeting abilities, or the possibility to be monitored by imaging techniques. Unfortunately, the lack of preclinical studies impedes the evaluation of these unique and promising findings for the translation of NCPs into clinical trials.

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Giordano, Frank, Barbara Link, Martin Glas, Ulrich Herrlinger, Frederik Wenz, Viktor Umansky, J. Brown, and Carsten Herskind. "Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12." Cancers 11, no. 3 (February 26, 2019): 272. http://dx.doi.org/10.3390/cancers11030272.

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Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of this cascade is overexpression of the CXC-motive chemokine ligand 12 (CXCL12), formerly known as stromal-cell derived factor 1 (SDF-1). We here review the role of CXCL12 in recruitment of pro-vasculogenic and immunosuppressive cells and give an overview on future and current drugs that target this axis.

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Clemente, Sofia M., Oscar H. Martínez-Costa, Maria Monsalve, and Alejandro K. Samhan-Arias. "Targeting Lipid Peroxidation for Cancer Treatment." Molecules 25, no. 21 (November 5, 2020): 5144. http://dx.doi.org/10.3390/molecules25215144.

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Cancer is one of the highest prevalent diseases in humans. The chances of surviving cancer and its prognosis are very dependent on the affected tissue, body location, and stage at which the disease is diagnosed. Researchers and pharmaceutical companies worldwide are pursuing many attempts to look for compounds to treat this malignancy. Most of the current strategies to fight cancer implicate the use of compounds acting on DNA damage checkpoints, non-receptor tyrosine kinases activities, regulators of the hedgehog signaling pathways, and metabolic adaptations placed in cancer. In the last decade, the finding of a lipid peroxidation increase linked to 15-lipoxygenases isoform 1 (15-LOX-1) activity stimulation has been found in specific successful treatments against cancer. This discovery contrasts with the production of other lipid oxidation signatures generated by stimulation of other lipoxygenases such as 5-LOX and 12-LOX, and cyclooxygenase (COX-2) activities, which have been suggested as cancer biomarkers and which inhibitors present anti-tumoral and antiproliferative activities. These findings support the previously proposed role of lipid hydroperoxides and their metabolites as cancer cell mediators. Depletion or promotion of lipid peroxidation is generally related to a specific production source associated with a cancer stage or tissue in which cancer originates. This review highlights the potential therapeutical use of chemical derivatives to stimulate or block specific cellular routes to generate lipid hydroperoxides to treat this disease.

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Allen, Nicholas C., Rajat Chauhan, Paula J. Bates, and Martin G. O’Toole. "Optimization of Tumor Targeting Gold Nanoparticles for Glioblastoma Applications." Nanomaterials 12, no. 21 (November 2, 2022): 3869. http://dx.doi.org/10.3390/nano12213869.

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Glioblastoma brain tumors represent an aggressive form of gliomas that is hallmarked by being extremely invasive and aggressive due to intra and inter-tumoral heterogeneity. This complex tumor microenvironment makes even the newer advancements in glioblastoma treatment less effective long term. In developing newer treatment technologies against glioblastoma, one should tailor the treatment to the tumor microenvironment, thus allowing for a more robust and sustained anti-glioblastoma effect. Here, we present a novel gold nanoparticle therapy explicitly designed for bioactivity against glioblastoma representing U87MG cell lines. We employ standard conjugation techniques to create oligonucleotide-coated gold nanoparticles exhibiting strong anti-glioblastoma behavior and optimize their design to maximize bioactivity against glioblastoma. Resulting nanotherapies are therapy specific and show upwards of 75% inhibition in metabolic and proliferative activity with stark effects on cellular morphology. Ultimately, these gold nanotherapies are a good base for designing more multi-targeted approaches to fighting against glioblastoma.

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Diego-González, Lara, Andrea Fernández-Carrera, Ana Igea, Amparo Martínez-Pérez, M. Elisabete C. D. Real Oliveira, Andreia C. Gomes, Carmen Guerra, Mariano Barbacid, África González-Fernández, and Rosana Simón-Vázquez. "Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor." Cancers 14, no. 13 (June 24, 2022): 3102. http://dx.doi.org/10.3390/cancers14133102.

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Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the combined expression of FOSL-1 and YAP, two signaling proteins related with tumor cell proliferation and survival. To improve the efficacy of cell transfection, DODAB:MO (1:2) liposomes were used as siRNA nanocarriers, forming a complex denominated siRNA-lipoplexes. Liposomes and lipoplexes (carrying two siRNA for each targeted protein, or the combination of four siRNAs) were physico-chemically and biologically characterized. They showed very good biocompatibility and stability. The efficient targeting of FOSL-1 and YAP expression at both mRNA and protein levels was first proved in vitro using mouse pancreatic tumoral cell lines (KRASG12V and p53 knockout), followed by in vivo studies using subcutaneous allografts on mice. The peri-tumoral injection of lipoplexes lead to a significant decrease in the tumor growth in both Athymic Nude-Foxn1nu and C57BL/6 mice, mainly in those receiving the combination of four siRNAs, targeting both YAP and FOSL-1. These results open a new perspective to overcome the fast tumor progression in pancreatic cancer.

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Furgiuele, Sonia, Géraldine Descamps, Lorena Cascarano, Ambre Boucq, Christine Dubois, Fabrice Journe, and Sven Saussez. "Dealing with Macrophage Plasticity to Address Therapeutic Challenges in Head and Neck Cancers." International Journal of Molecular Sciences 23, no. 12 (June 7, 2022): 6385. http://dx.doi.org/10.3390/ijms23126385.

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The head and neck tumor microenvironment (TME) is highly infiltrated with macrophages. More specifically, tumor-associated macrophages (TAM/M2-like) are one of the most critical components associated with poor overall survival in head and neck cancers (HNC). Two extreme states of macrophage phenotypes are described as conducting pro-inflammatory/anti-tumoral (M1) or anti-inflammatory/pro-tumoral (M2) activities. Moreover, specific metabolic pathways as well as oxidative stress responses are tightly associated with their phenotypes and functions. Hence, due to their plasticity, targeting M2 macrophages to repolarize in the M1 phenotype would be a promising cancer treatment. In this context, we evaluated macrophage infiltration in 60 HNC patients and demonstrated the high infiltration of CD68+ cells that were mainly related to CD163+ M2 macrophages. We then optimized a polarization protocol from THP1 monocytes, validated by specific gene and protein expression levels. In addition, specific actors of glutamine pathway and oxidative stress were quantified to indicate the use of glutaminolysis by M2 and the production of reactive oxygen species by M1. Finally, we evaluated and confirmed the plasticity of our model using M1 activators to repolarize M2 in M1. Overall, our study provides a complete reversible polarization protocol allowing us to further evaluate various reprogramming effectors targeting glutaminolysis and/or oxidative stress in macrophages.

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Albaret, Marie, Claudine Vermot-Desroches, Arnaud Paré, Jean-Xavier Roca-Martinez, Lucie Malet, Jad Esseily, Laetitia Gerossier, et al. "Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells." Cancers 10, no. 11 (November 16, 2018): 452. http://dx.doi.org/10.3390/cancers10110452.

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Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which they impact cancer biology remain largely unexplored. The aim of this study was to expose an externalized form of cytokeratin 8 (eK8) as a key player of colorectal tumorigenesis and characterize its mode of action. To achieve this, we generated a unique antagonist monoclonal antibody (D-A10 MAb) targeting an eight-amino-acid-long domain of eK8, which enabled us to ascertain the pro-tumoral activity of eK8 in both KRAS-mutant and wild-type colorectal cancers (CRC). We showed that this pro-tumoral activity involves a bidirectional eK8-dependent control of caspase-mediated apoptosis in vivo and of the plasminogen-induced invasion process in cellulo. Furthermore, we demonstrated that eK8 is anchored at the plasma membrane supporting this dual function. We, therefore, identified eK8 as an innovative therapeutic target in CRC and provided a unique MAb targeting eK8 that displays anti-neoplastic activities that could be useful to treat CRC, including those harboring KRAS mutations.

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Belgiovine, Cristina, Elisabeth Digifico, Clément Anfray, Aldo Ummarino, and Fernando Torres Andón. "Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing." Journal of Clinical Medicine 9, no. 10 (October 8, 2020): 3226. http://dx.doi.org/10.3390/jcm9103226.

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In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

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Penny, Hweixian Leong, Je Lin Sieow, Sin Yee Gun, Mai Chan Lau, Bernett Lee, Jasmine Tan, Cindy Phua, et al. "Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma." International Journal of Molecular Sciences 22, no. 12 (June 14, 2021): 6350. http://dx.doi.org/10.3390/ijms22126350.

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Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

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Proietti, Ilaria, Nevena Skroza, Simone Michelini, Alessandra Mambrin, Veronica Balduzzi, Nicoletta Bernardini, Anna Marchesiello, et al. "BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions." Cancers 12, no. 7 (July 7, 2020): 1823. http://dx.doi.org/10.3390/cancers12071823.

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The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects. The MAPK pathway is involved in T-cell receptor signalling, and interference in the pathway by BRAF inhibitors has beneficial effects on the tumour microenvironment and anti-tumour immune response in BRAF-mutant melanoma, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced melanoma differentiation antigen expression and presentation of tumour antigens by HLA 1, and increased intra-tumoral T-cell infiltration and activity. These effects promote recognition of the tumour by the immune system and enhance anti-tumour T-cell responses. Combining BRAF inhibitors with MEK inhibitors provides more complete blockade of the MAPK pathway. The immunomodulatory effects of BRAF inhibition alone or in combination with MEK inhibition provide a rationale for combining these targeted therapies with immune checkpoint inhibitors. Available data support the synergy between these treatment approaches, indicating such combinations provide an additional beneficial effect on the tumour microenvironment and immune response in BRAF-mutant melanoma.

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Ponzo, Matteo, Anais Debesset, Mélissande Cossutta, Mounira Chalabi-Dchar, Claire Houppe, Caroline Pilon, Alba Nicolas-Boluda, et al. "Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression." Cancers 14, no. 17 (August 31, 2022): 4265. http://dx.doi.org/10.3390/cancers14174265.

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Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.

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Revel, Margot, Marie V. Daugan, Catherine Sautés-Fridman, Wolf H. Fridman, and Lubka T. Roumenina. "Complement System: Promoter or Suppressor of Cancer Progression?" Antibodies 9, no. 4 (October 25, 2020): 57. http://dx.doi.org/10.3390/antib9040057.

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Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.

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Vincent, Marie, Géraldine Teppaz, Véronique Solé, Anne Bessard, Séverine Loisel, Hervé Watier, Béatrice Clémenceau, et al. "CS14-6. Development of two IL15 immunocytokines targeting either GD2- or CD20- tumoral bearing cells." Cytokine 56, no. 1 (October 2011): 102. http://dx.doi.org/10.1016/j.cyto.2011.07.396.

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Min, Kyung Hyun, Jong-Ho Kim, Sang Mun Bae, Hyeri Shin, Min Sang Kim, Sangjin Park, Hyejung Lee, et al. "Tumoral acidic pH-responsive MPEG-poly(β-amino ester) polymeric micelles for cancer targeting therapy." Journal of Controlled Release 144, no. 2 (June 2010): 259–66. http://dx.doi.org/10.1016/j.jconrel.2010.02.024.

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Lee, H. K., R. Maharjan, Y. Jeon, J. U. Choi, and Y. Byun. "OP01 Prion-like protein doppel as a novel marker for tumoral angiogenesis and tumor targeting." ESMO Open 7, no. 6 (December 2022): 100674. http://dx.doi.org/10.1016/j.esmoop.2022.100674.

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Fung, Kimberly, Delphine Vivier, Outi Keinänen, Elaheh Khozeimeh Sarbisheh, Eric W. Price, and Brian M. Zeglis. "89Zr-Labeled AR20.5: A MUC1-Targeting ImmunoPET Probe." Molecules 25, no. 10 (May 15, 2020): 2315. http://dx.doi.org/10.3390/molecules25102315.

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High expression levels of the tumor-associated antigen MUC1 have been correlated with tumor aggressiveness, poor response to therapy, and poor survival in several tumor types, including breast, pancreatic, and epithelial ovarian cancer. Herein, we report the synthesis, characterization, and in vivo evaluation of a novel radioimmunoconjugate for the immuno-positron emission tomography (immunoPET) imaging of MUC1 expression based on the AR20.5 antibody. To this end, we modified AR20.5 with the chelator desferrioxamine (DFO) and labeled it with the positron-emitting radiometal zirconium-89 (t1/2 ~3.3 d) to produce [89Zr]Zr-DFO-AR20.5. In subsequent in vivo experiments in athymic nude mice bearing subcutaneous MUC1-expressing ovarian cancer xenografts, [89Zr]Zr-DFO-AR20.5 clearly delineated tumor tissue, producing a tumoral activity concentration of 19.1 ± 6.4 percent injected dose per gram (%ID/g) at 120 h post-injection and a tumor-to-muscle activity concentration ratio of 42.4 ± 10.6 at the same time point. Additional PET imaging experiments in mice bearing orthotopic MUC1-expressing ovarian cancer xenografts likewise demonstrated that [89Zr]Zr-DFO-AR20.5 enables the visualization of tumor tissue—including metastatic lesions—with promising tumor-to-background contrast.

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Li, Zihai, Joseph H. Azar, and Mark P. Rubinstein. "Converting Tumoral PD-L1 into a 4-1BB Agonist for Safer and More Effective Cancer Immunotherapy." Cancer Discovery 12, no. 5 (May 2, 2022): 1184–86. http://dx.doi.org/10.1158/2159-8290.cd-22-0219.

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Summary: Dose-limiting toxicities are thought to temper the efficacy of single-agent 4-1BB agonists. To overcome this hurdle, in this issue of Cancer Discovery, Muik and colleagues report preclinical and clinical studies describing a first-in-class bispecific fusion protein targeting 4-1BB and PD-L1. See related article by Muik et al., p. 1248 (9).

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Raue, Rebecca, Ann-Christin Frank, Shahzad Nawaz Syed, and Bernhard Brüne. "Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 4 (February 23, 2021): 2210. http://dx.doi.org/10.3390/ijms22042210.

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The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.

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Coletta, Sara, Silvia Lonardi, Francesca Sensi, Edoardo D’Angelo, Matteo Fassan, Salvatore Pucciarelli, Arianna Valzelli, et al. "Tumor Cells and the Extracellular Matrix Dictate the Pro-Tumoral Profile of Macrophages in CRC." Cancers 13, no. 20 (October 16, 2021): 5199. http://dx.doi.org/10.3390/cancers13205199.

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Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. In colorectal cancer (CRC), a strong infiltration of TAMs is accompanied by a decrease in effector T cells and an increase in the metastatic potential of CRC. We investigated the functional profile of TAMs infiltrating CRC tissue by immunohistochemistry, flow cytometry, ELISA, and qRT-PCR and their involvement in impairing the activation of effector T cells. In CRC biopsies, we evidenced a high percentage of macrophages with low expression of the antigen-presenting complex MHC-II and high expression of CD206. Monocytes co-cultured with tumor cells or a decellularized tumor matrix differentiated toward a pro-tumoral macrophage phenotype characterized by decreased expression of MHC-II and CD86 and increased expression of CD206 and an abundant release of pro-tumoral cytokines and chemokines. We demonstrated that the hampered expression of MHC-II in macrophages is due to the downregulation of the MHC-II transactivator CIITA and that this effect relies on increased expression of miRNAs targeting CIITA. As a result, macrophages become unable to present antigens to CD4 T lymphocytes. Our data suggest that the tumor microenvironment contributes to defining a pro-tumoral profile of macrophages infiltrating CRC tissue with impaired capacity to activate T cell effector functions.

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Fiani, Maria Luisa, Valeria Barreca, Massimo Sargiacomo, Flavia Ferrantelli, Francesco Manfredi, and Maurizio Federico. "Exploiting Manipulated Small Extracellular Vesicles to Subvert Immunosuppression at the Tumor Microenvironment through Mannose Receptor/CD206 Targeting." International Journal of Molecular Sciences 21, no. 17 (August 31, 2020): 6318. http://dx.doi.org/10.3390/ijms21176318.

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Immunosuppression at tumor microenvironment (TME) is one of the major obstacles to be overcome for an effective therapeutic intervention against solid tumors. Tumor-associated macrophages (TAMs) comprise a sub-population that plays multiple pro-tumoral roles in tumor development including general immunosuppression, which can be identified in terms of high expression of mannose receptor (MR or CD206). Immunosuppressive TAMs, like other macrophage sub-populations, display functional plasticity that allows them to be re-programmed to inflammatory macrophages. In order to mitigate immunosuppression at the TME, several efforts are ongoing to effectively re-educate pro-tumoral TAMs. Extracellular vesicles (EVs), released by both normal and tumor cells types, are emerging as key mediators of the cell to cell communication and have been shown to have a role in the modulation of immune responses in the TME. Recent studies demonstrated the enrichment of high mannose glycans on the surface of small EVs (sEVs), a subtype of EVs of endosomal origin of 30–150 nm in diameter. This characteristic renders sEVs an ideal tool for the delivery of therapeutic molecules into MR/CD206-expressing TAMs. In this review, we report the most recent literature data highlighting the critical role of TAMs in tumor development, as well as the experimental evidences that has emerged from the biochemical characterization of sEV membranes. In addition, we propose an original way to target immunosuppressive TAMs at the TME by endogenously engineered sEVs for a new therapeutic approach against solid tumors.

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Crescence, Lydie, Evelyne Beraud, Veronique Sbarra, Jean-Paul Bernard, Dominique Lombardo, and Eric Mas. "Targeting a Novel Onco-glycoprotein Antigen at Tumoral Pancreatic Cell Surface by mAb16D10 Induces Cell Death." Journal of Immunology 189, no. 7 (September 5, 2012): 3386–96. http://dx.doi.org/10.4049/jimmunol.1102647.

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Mitou, Géraldine, Julie Frentzel, Aurore Desquesnes, Sophie Le Gonidec, Talal AlSaati, Isabelle Beau, Laurence Lamant, et al. "Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma." Oncotarget 6, no. 30 (August 17, 2015): 30149–64. http://dx.doi.org/10.18632/oncotarget.4999.

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Schellens, Jan H. M., Josep Tabernero, Ulrik Niels Lassen, Ignacio Melero, Krisztian Homicsko, Guillem Argilés, Jose Luis Perez Gracia, et al. "CEA-targeted engineered IL2: Clinical confirmation of tumor targeting and evidence of intra-tumoral immune activation." Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015): 3016. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.3016.

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Miyake, Makito, Steve Goodison, Evan Gomes, Wasia Rizwani, Shanti Ross, Ge Zhang, and Charles Joel Rosser. "Induction of endothelial proliferation and angiogenesis through activating the ERK1/2/EGF pathway mediate by CXC chemokine receptor 2 by chemokine (C-X-C motif) ligand 1." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 138. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.138.

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138 Background: Endothelial cell growth and proliferation are critical for tumoral angiogenesis. We report here that blockade of Chemokine (C-X-C motif) ligand 1 (CXCL1) results in reduction of human endothelial cell proliferation and its ability to induce angiogenesis. Methods: Two human endothelial cell lines, HUVEC and HDMEC, were used in the in vitro assays. Proliferation assay and matrigel tube formation assay were performed to test the inhibitory effect of anti-CXCL antibody on the activity of endothelial cells in vitro. Matrigel plug assay in nude mice was performed to test the in vivo angiogenic activity of CXCL1. Results: CXCL1 interacts with its receptor CXC chemokine Receptor 2 and induces endothelial cell proliferation, whereas blockade of CXCL1 is associated with reduction in cellular proliferation through a decrease in levels of cyclin D and cdk4 and inhibition of angiogenesis through EGF and ERK 1/2. Targeting CXCL1 inhibits neoangiogenesis but has no effect on disrupting established vasculature. Furthermore targeting CXCL1 is associated with reduction in migration of human endothelial cells in an in vitro model. Additionally, neutralizing antibody against CXCL1 in a xenograft angiogenesis model resulted in inhibition of angiogenesis. Conclusions: CXCL1-induced regulation of angiogenesis has not been studied extensively in human cancers, thus these findings illustrate a novel contribution of CXCL1 interactions in pathological angiogenesis. Therefore, the ability to selectively modulate CXCL1, specifically in tumoral angiogenesis, may promote the development of novel oncologic therapeutic strategies.

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Fleischmann, A. M., B. Waser, and J. C. Reubi. "Gastrin-releasing peptide receptors in the tumor vascular bed of various human cancers: high incidence in urinary tract cancers." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14575-e14575. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14575.

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e14575 Background: Tumoral Gastrin-releasing peptide (GRP) receptors are potential targets for diagnosis and therapy using radiolabeled or cytotoxic GRP analogs. GRP-receptor overexpression has been detected in cancer cells and, more recently, also in the vascular bed of selected tumors. More information on vascular GRP-receptors in cancer is required to asses their potential for vascular targeting applications. Methods: Frequent human cancers from the breast (n=134), lung (n=57), prostate (n=50), kidney (n=32), colon (n=46), urinary tract (n=26) and biliary tract (n=23) were analyzed using in vitro GRP-receptor autoradiography on tissue sections with the 125I-[Tyr4]-bombesin radioligand and/or the universal radioligand 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]-bombesin(6–14). GRP-receptor expressing tumoral vessels were evaluated in each tumor group for prevalence, quantity (vascular score) and GRP-receptor density. Results: Prevalence of vascular GRP-receptors is variable, ranging from 13% (prostate cancer) to 92% (urinary tract cancer). Different tumor-types within a given site may have divergent prevalence of vascular GRP-receptors (e.g. lung: small cell cancer: 0%; adenocarcinoma: 59%; squamous carcinoma: 83%). Also the vascular score varies widely, with highest score in urinary tract cancer (1.69), moderate scores in lung (0.91), colon (0.88), kidney (0.84) and biliary tract (0.69) cancers and low scores in breast (0.39) and prostate (0.14) cancers. Vascular GRP-receptors are expressed in the muscular vessel wall in moderate to high densities. Normal non- neoplastic control tissues from these organs lack vascular GRP-receptors. Conclusions: Tumoral vessels in all evaluated sites overexpress GRP-receptors, suggesting a major biological function of GRP-receptors in the tumor vascular bed. Vascular GRP-receptor expression varies between the tumor-types indicating tumor-specific mechanisms in their regulation. Urinary tract cancers express vascular GRP-receptors so abundantly, that they are promising candidates for vascular targeting applications. No significant financial relationships to disclose.

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Sathiyanadan, Karthik, Florian Alonso, Sonia Domingos-Pereira, Tania Santoro, Lauriane Hamard, Valérie Cesson, Paolo Meda, Denise Nardelli-Haefliger, and Jacques-Antoine Haefliger. "Targeting Endothelial Connexin37 Reduces Angiogenesis and Decreases Tumor Growth." International Journal of Molecular Sciences 23, no. 6 (March 8, 2022): 2930. http://dx.doi.org/10.3390/ijms23062930.

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Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37−/− mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37−/− mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments.

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Baeza, Alejandro. "Tumor Targeted Nanocarriers for Immunotherapy." Molecules 25, no. 7 (March 26, 2020): 1508. http://dx.doi.org/10.3390/molecules25071508.

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The paramount discovery of passive accumulation of nanoparticles in tumoral tissues triggered the development of a wide number of different nanoparticles capable of transporting therapeutic agents to tumoral tissues in a controlled and selective way. These nanocarriers have been endowed with important capacities such as stimuli-responsive properties, targeting abilities, or the capacity to be monitored by imaging techniques. However, after decades of intense research efforts, only a few nanomedicines have reached the market. The reasons for this disappointing outcome are varied, from the high tumor-type dependence of enhanced permeation and retention (EPR) effect to the poor penetration capacity of nanocarriers within the cancerous tissue, among others. The rapid nanoparticle clearance by immune cells, considered another important barrier, which compromises the efficacy of nanomedicines, would become an important ally in the fight against cancer. In the last years, the fine-tuned ability of immune cells to recognize and engulf nanoparticles have been exploited to deliver immunoregulating agents to specific immune cell populations selectively. In this work, the recent advances carried out in the development of nanocarriers capable of operating with immune and tumoral cells in order to orchestrate an efficient antitumoral response will be presented. The combination of nanoparticles and immunotherapy would deliver powerful weapons to the clinicians that offer safer and more efficient antitumoral treatments for the patients.

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Leshem, Yasmin, Emily King, Ronit Mazor, Yoram Reiter, and Ira Pastan. "SS1P Immunotoxin Induces Markers of Immunogenic Cell Death and Enhances the Effect of the CTLA-4 Blockade in AE17M Mouse Mesothelioma Tumors." Toxins 10, no. 11 (November 14, 2018): 470. http://dx.doi.org/10.3390/toxins10110470.

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SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced. The goal of this study is to evaluate if SS1P therapy renders mesothelioma tumors more sensitive to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade. We evaluated the ability of SS1P to induce adenosine triphosphate (ATP) secretion and calreticulin expression on the surface of AE17M mouse mesothelioma cells. Both properties are associated with immunogenic cell death. Furthermore, we treated these tumors with intra-tumoral SS1P and systemic CTLA-4. We found that SS1P increased the release of ATP from AE17M cells in a dose and time-dependent manner. In addition, SS1P induced calreticulin expression on the surface of AE17M cells. These results suggest that SS1P promotes immunogenic cell death and could sensitize tumors to anti-CTLA-4 based therapy. In mouse studies, we found that the combination of anti-CTLA-4 with intra-tumoral SS1P induced complete regressions in most mice and provided a statistically significant survival benefit compared to monotherapy. The surviving mice were protected from tumor re-challenge, indicating the development of anti-tumor immunity. These findings support the use of intra-tumoral SS1P in combination with anti-CTLA-4.

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Villaverde, Gonzalo, and Alejandro Baeza. "Targeting strategies for improving the efficacy of nanomedicine in oncology." Beilstein Journal of Nanotechnology 10 (January 14, 2019): 168–81. http://dx.doi.org/10.3762/bjnano.10.16.

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The use of nanoparticles as drug carriers has provided a powerful weapon in the fight against cancer. These nanocarriers are able to transport drugs that exhibit very different nature such as lipophilic or hydrophilic drugs and big macromolecules as proteins or RNA. Moreover, the external surface of these carriers can be decorated with different moieties with high affinity for specific membrane receptors of the tumoral cells to direct their action specifically to the malignant cells. The selectivity improvement yielded by these nanocarriers provided a significative enhancement in the efficacy of the transported drug, while the apparition of side effects in the host was reduced. Additionally, it is possible to incorporate targeting moieties selective for organelles of the cell, which improves even more the effect of the transported agents. In the last years, more sophisticated strategies such as the use of switchable, hierarchical or double targeting strategies have been proposed for overcoming some of the limitations of conventional targeting strategies. In this review, recent advances in the development of targeted nanoparticles will be described with the aim to present the current state of the art of this technology and its huge potential in the oncological field.

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Bova, Valentina, Alessia Filippone, Giovanna Casili, Marika Lanza, Michela Campolo, Anna Paola Capra, Alberto Repici, et al. "Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness." Cancers 14, no. 16 (August 20, 2022): 4032. http://dx.doi.org/10.3390/cancers14164032.

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Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.

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Allegra, Alessandro, Mario Di Gioacchino, Alessandro Tonacci, Claudia Petrarca, and Sebastiano Gangemi. "Nanomedicine for Immunotherapy Targeting Hematological Malignancies: Current Approaches and Perspective." Nanomaterials 11, no. 11 (October 21, 2021): 2792. http://dx.doi.org/10.3390/nano11112792.

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Conventional chemotherapy has partial therapeutic effects against hematological malignancies and is correlated with serious side effects and great risk of relapse. Recently, immunotherapeutic drugs have provided encouraging results in the treatment of hematological malignancies. Several immunotherapeutic antibodies and cell therapeutics are in dynamic development such as immune checkpoint blockades and CAR-T treatment. However, numerous problems restrain the therapeutic effectiveness of tumor immunotherapy as an insufficient anti-tumor immune response, the interference of an immune-suppressive bone marrow, or tumoral milieu with the discharge of immunosuppressive components, access of myeloid-derived suppressor cells, monocyte intrusion, macrophage modifications, all factors facilitating the tumor to escape the anti-cancer immune response, finally reducing the efficiency of the immunotherapy. Nanotechnology can be employed to overcome each of these aspects, therefore having the possibility to successfully produce anti-cancer immune responses. Here, we review recent findings on the use of biomaterial-based nanoparticles in hematological malignancies immunotherapy. In the future, a deeper understanding of tumor immunology and of the implications of nanomedicine will allow nanoparticles to revolutionize tumor immunotherapy, and nanomedicine approaches will reveal their great potential for clinical translation.

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Viel, Thomas, Estelle Dransart, Fariba Nemati, Emilie Henry, Benoit Thézé, Didier Decaudin, Daniel Lewandowski, Raphael Boisgard, Ludger Johannes, and Bertrand Tavitian. "In Vivo Tumor Targeting by the B-Subunit of Shiga Toxin." Molecular Imaging 7, no. 6 (November 1, 2008): 7290.2008.00022. http://dx.doi.org/10.2310/7290.2008.00022.

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Delivery of drugs to the appropriate target cells would improve efficacy and reduce potential side effects. The nontoxic B-subunit of the intestinal pathogen-produced Shiga toxin (STxB) binds specifically to the glycosphingolipid Gb3, overex-pressed in membranes of certain tumor cells, and enters these cells through the retrograde pathway. Therefore, STxB binding to Gb3 receptors may be useful for cell-specific vectorization or imaging purposes. Here we labeled STxB with a fluorophore to evaluate its potential as an in vivo cell-specific targeting reagent in two different models of human colorectal carcinoma. Fluorescent STxB was administered systemically to xenografted nude mice, and its biodistribution was studied by optical imaging. The use of fluorescent STxB allowed the combination of the macroscopic observations with analyses at the cellular level using confocal microscopy. After administration, the fluorescent STxB was slowly eliminated by renal excretion. However, it accumulated in the tumor area. Furthermore, STxB was demonstrated to enter the Gb3-expressing tumoral cells, as well as the epithelial cells of the neovascularization and the monocytes and macrophages surrounding the xenografts.

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Journal articles on the topic 'Targeting tumorale'

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