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1
Russo, Vincenzo, and Maria Pia Protti. "Tumor-derived factors affecting immune cells." Cytokine & Growth Factor Reviews 36 (August 2017): 79–87. http://dx.doi.org/10.1016/j.cytogfr.2017.06.005.
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Cao, Yihai, and Weide Zhong. "Tumor-derived lymphangiogenic factors and lymphatic metastasis." Biomedicine & Pharmacotherapy 61, no. 9 (October 2007): 534–39. http://dx.doi.org/10.1016/j.biopha.2007.08.009.
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Zong, Jinbao, Anton A. Keskinov, Galina V. Shurin, and Michael R. Shurin. "Tumor-derived factors modulating dendritic cell function." Cancer Immunology, Immunotherapy 65, no. 7 (March 16, 2016): 821–33. http://dx.doi.org/10.1007/s00262-016-1820-y.
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Hernandez-Guerrero, Tatiana, Bernard Doger, Jesus Garcia-Foncillas, Michael Jude Wick, and Victor Moreno. "Predictive factors for successful growth of patient derived xenografts (PDX)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e15069-e15069. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e15069.
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e15069 Background: PDXs have become a core component of translational cancer research. Developing these models can become challenging since little is known about which factors influence engraftment rates. We sought to determine which clinical, pathological, or molecular factors may predict better engraftment rates in PDXs. Methods: Between March 2017 and January 2021, biopsies obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. Statistical analyses were performed to identify factors that could correlate with final engraftment defined as achievement of at least three passes and sampling of PDXs tumors. We focused on clinical (patient factors) pathological (patients’ tumor samples) and molecular characteristics (patients’ tumor samples) analyzed either by immunohistochemistry (IHC) or next generation sequencing (NGS). Results: 585 tumor samples were collected and implanted. 21 failed to engraft due lack of malignant cells. Of 564 tumor-positive samples, 187 (33.2%) PDXs achieved successful growth at time of analysis (Feb, 21). The following clinical characteristics were correlated with engraftment: systemic antibiotics within 2 weeks of sampling: (38.1% (72/117) antibiotics- group vs 30.7% (115/260) no-antibiotics) (p = 0.048); systemic steroids within 2 weeks (41.5% (34/48) the steroids-receiving group vs 31.7% (153/329) no-steroids) (p: 0.05). For women, menopausal status was predictive: 34.9% (95/177) in postmenopausal achieved growth, Vs 20,4% (10/39) for premenopausal (p = 0.031). Baseline LDH levels: 74.9% (140/187) LDH levels above the upper limit of normality (ULN) against 25.1% (47/187) with normal LDH (p = 0.034). Tumor grade: Grade 1: 25.4% (47/187); grade 2: 34.8% (65/187) and grade 3: 40.1% (75/187) tumors achieved successful growth (p = 0.043). Similarly, higher ki67 levels were also correlated with better engraftment rates: (low (Ki67 < 15%): 8.9% (9/45) achieved growth, Vs high (Ki67 > 15%): 31% (35/113) (p:0.002). Presence of lymphovascular invasion in tumor sample was also predictive: 42.2% (97/230) with lymphovascular Vs 26.9% (90/334) of samples with no invasion (p = 0.0001). Likewise, 41.8% (59/141) of neural invasion-positive samples achieved growth against 30.3% (128/428) (p = 0.008). Mismatch repair deficient tumors showed better engraftment rates: 62.1% (18/29) achieved growth vs 40.8% (75/184) of proficient tumors (p = 0.026). 84 PDX were breast models, among which 57.9% (11/19) ER negative models grew, Vs 15.4% (10/65) of ER positive models (p = 0.0001). Conclusions: tumors with higher grade and Ki67, lymphovascular and/or perineural invasion, with dMMR and ER expression negative have higher chance of PDX development. Some clinical characteristics can also interfere with PDXs development such as use of steroids or antibiotics prior sampling.
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Pan, Ping-Ying, George X. Wang, Bingjiao Yin, Junko Ozao, Teresa Ku, Celia M. Divino, and Shu-Hsia Chen. "Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function." Blood 111, no. 1 (January 1, 2008): 219–28. http://dx.doi.org/10.1182/blood-2007-04-086835.
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Tumor growth induced a significant increase of myeloid-derived suppressor cells (MDSCs) in the tumor-bearing host. In our previous study, we showed that MDSCs induced tumor-specific T-cell tolerance and the development of T regulatory cells (Tregs). Tumor-derived factors have been implicated in the accumulation of MDSCs. We hypothesize that reduction of MDSC accumulation in tumor-bearing hosts, through the blockade of tumor factors, can prevent T-cell anergy and Treg development and thereby improve immune therapy for the treatment of advanced tumors. Several tumor-derived factors were identified by gene array analysis. Among the candidate factors, stem- cell factor (SCF) is expressed by various human and murine carcinomas and was selected for further study. Mice bearing tumor cells with SCF siRNA knockdown exhibited significantly reduced MDSC expansion and restored proliferative responses of tumor-infiltrating T cells. More importantly, blockade of SCF receptor (ckit)–SCF interaction by anti-ckit prevented tumor-specific T-cell anergy, Treg development, and tumor angiogenesis. Furthermore, the prevention of MDSC accumulation in conjunction with immune activation therapy showed synergistic therapeutic effect when treating mice bearing large tumors. This information supports the notion that modulation of MDSC development may be required to achieve effective immune-enhancing therapy for the treatment of advanced tumors.
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Preuss, Stephanie F., Denise Grieshober, and Hellmut G. Augustin. "Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia." Physiology 38, no. 4 (July 1, 2023): 000. http://dx.doi.org/10.1152/physiol.00001.2023.
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Proliferating cancer cells secrete a multitude of factors impacting metabolism, interorgan communication, and tumor progression. The distribution of tumor-derived factors to distant organs occurs via the circulation, which provides an extensive reactive surface lined by endothelial cells. Primary tumor-derived proteins impact cancer progression by modulating endothelial cell activation at the (pre-)metastatic niche, which affects tumor cell dissemination as well as the outgrowth of seeded metastatic cells into overt tumors. In addition, new insight indicates that endothelial cell signaling contributes to metabolic symptoms of cancer, including cancer-associated cachexia, opening a new field of vascular metabolism research. This review addresses how tumor-derived factors systemically affect endothelial cell signaling and activation and impact distant organs as well as tumor progression.
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Chen, Chuanzhi, Wu Lin, Yingying Huang, Xiangliu Chen, Haohao Wang, and Lisong Teng. "The Essential Factors of Establishing Patient-derived Tumor Model." Journal of Cancer 12, no. 1 (2021): 28–37. http://dx.doi.org/10.7150/jca.51749.
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Haimovitz-Friedman, A., DJ Falcone, A. Eldor, V. Schirrmacher, I. Vlodavsky, and Z. Fuks. "Activation of platelet heparitinase by tumor cell-derived factors." Blood 78, no. 3 (August 1, 1991): 789–96. http://dx.doi.org/10.1182/blood.v78.3.789.789.
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Abstract The nature of the cooperation between platelets and tumor cells during the process of blood-borne metastasis is essentially unknown. In previous in vitro studies we showed that platelets participated in the formation of gaps in the endothelial cell lining, and that concomitantly heparan sulfate glycosaminoglycans were degraded by the platelet heparitinase, released on activation of platelets. In the current study we show that the ability to degrade proteoheparan sulfate derived from endothelial extracellular matrix is gradually eliminated when the number of human platelets is decreased from 5 x 10(7) to 10(6) cells/mL. When aliquots of conditioned media or lysates of either Eb or heat-inactivated ESb mouse lymphoma cells (both of which showed no heparanase activity) were added to freeze-thawed lysates of 10(6) platelets, a reappearance of platelet heparitinase activity was observed. A similar activation was not elicited by lysates of several normal mammalian cells. These data suggest that in its native form, a fraction of the platelet heparitinase is stored in an inactive form that can be activated by a factor secreted by lymphoma, but not by normal cells. Partial characterization of the heparitinase-activating factor showed that it is a heat-stable polyanionic molecule, devoid of proteolytic activity and resistant to both proteolytic and chondroitinase digestions. Activation of platelet heparitinase was also observed on coincubation with chondroitinases ABC and AC, suggesting that the inactive form of platelet heparitinase could result from a complex formation with a chondroitinase-sensitive proteoglycan. The lymphoma-derived heparitinase activating factor itself is, however, not a chondroitinase, because activity of chondroitinase could not be detected in Eb and ESb cells. A possible mechanism by which tumor cells recruit and regulate the activity of platelet heparitinase, and its relevance to the progression of blood borne metastasis, is discussed.
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Haimovitz-Friedman, A., DJ Falcone, A. Eldor, V. Schirrmacher, I. Vlodavsky, and Z. Fuks. "Activation of platelet heparitinase by tumor cell-derived factors." Blood 78, no. 3 (August 1, 1991): 789–96. http://dx.doi.org/10.1182/blood.v78.3.789.bloodjournal783789.
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The nature of the cooperation between platelets and tumor cells during the process of blood-borne metastasis is essentially unknown. In previous in vitro studies we showed that platelets participated in the formation of gaps in the endothelial cell lining, and that concomitantly heparan sulfate glycosaminoglycans were degraded by the platelet heparitinase, released on activation of platelets. In the current study we show that the ability to degrade proteoheparan sulfate derived from endothelial extracellular matrix is gradually eliminated when the number of human platelets is decreased from 5 x 10(7) to 10(6) cells/mL. When aliquots of conditioned media or lysates of either Eb or heat-inactivated ESb mouse lymphoma cells (both of which showed no heparanase activity) were added to freeze-thawed lysates of 10(6) platelets, a reappearance of platelet heparitinase activity was observed. A similar activation was not elicited by lysates of several normal mammalian cells. These data suggest that in its native form, a fraction of the platelet heparitinase is stored in an inactive form that can be activated by a factor secreted by lymphoma, but not by normal cells. Partial characterization of the heparitinase-activating factor showed that it is a heat-stable polyanionic molecule, devoid of proteolytic activity and resistant to both proteolytic and chondroitinase digestions. Activation of platelet heparitinase was also observed on coincubation with chondroitinases ABC and AC, suggesting that the inactive form of platelet heparitinase could result from a complex formation with a chondroitinase-sensitive proteoglycan. The lymphoma-derived heparitinase activating factor itself is, however, not a chondroitinase, because activity of chondroitinase could not be detected in Eb and ESb cells. A possible mechanism by which tumor cells recruit and regulate the activity of platelet heparitinase, and its relevance to the progression of blood borne metastasis, is discussed.
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Hamburger, Anne W., Christine P. White, Karin Lurie, and Richard Kaplan. "Monocyte-Derived Growth Factors for Human Tumor Clonogenic Cells." Journal of Leukocyte Biology 40, no. 4 (October 1986): 381–92. http://dx.doi.org/10.1002/jlb.40.4.381.
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Shao, Xuejun, Shenghao Hua, Tao Feng, Dickson Kofi Wiredu Ocansey, and Lei Yin. "Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion." International Journal of Molecular Sciences 23, no. 19 (October 4, 2022): 11789. http://dx.doi.org/10.3390/ijms231911789.
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Tumor cells express a high quantity of exosomes packaged with unique cargos under hypoxia, an important characteristic feature in solid tumors. These hypoxic tumor-derived exosomes are, crucially, involved in the interaction of cancer cells with their microenvironment, facilitating not only immune evasion, but increased cell growth and survival, enhanced angiogenesis, epithelial–mesenchymal transition (EMT), therapeutic resistance, autophagy, pre-metastasis, and metastasis. This paper explores the tumor microenvironment (TME) remodeling effects of hypoxic tumor-derived exosome towards facilitating the tumor progression process, particularly, the modulatory role of these factors on tumor cell immune evasion through suppression of immune cells, expression of surface recognition molecules, and secretion of antitumor soluble factor. Tumor-expressed exosomes educate immune effector cells, including macrophages, monocytes, T cells, natural killer (NK) cells, dendritic cells (DCs), γδ T lymphocytes, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mast cells, and B cells, within the hypoxic TME through the release of factors that regulate their recruitment, phenotype, and function. Thus, both hypoxia and tumor-derived exosomes modulate immune cells, growth factors, cytokines, receptor molecules, and other soluble factors, which, together, collaborate to form the immune-suppressive milieu of the tumor environment. Exploring the contribution of exosomal cargos, such as RNAs and proteins, as indispensable players in the cross-talk within the hypoxic tumor microenvironmental provides a potential target for antitumor immunity or subverting immune evasion and enhancing tumor therapies.
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Irey, Emily A., Chelsea M. Lassiter, Nicholas J. Brady, Pavlina Chuntova, Ying Wang, Todd P. Knutson, Christine Henzler, et al. "JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors." Proceedings of the National Academy of Sciences 116, no. 25 (May 30, 2019): 12442–51. http://dx.doi.org/10.1073/pnas.1816410116.
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Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the protumorigenic factor cyclooxygenase-2 (COX-2), and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.
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P. R. "Carbohydrates, lymphokines, and tumor inducing and tumor derived factors affect NK-cell activity." Medical Oncology and Tumor Pharmacotherapy 2, no. 1 (March 1985): 65. http://dx.doi.org/10.1007/bf02934795.
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Cruz, Andrea, Abigail Locke, Katharine Halligan, Lauren Sanders, Allison Cheney, Ann-Catherine Jean Stanton, Robert Koncar, et al. "TMIC-54. THE ROLE OF TUMOR MICROENVIRONMENT DERIVED GROWTH FACTORS IN PEDIATRIC BRAIN TUMORS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii283. http://dx.doi.org/10.1093/neuonc/noac209.1098.
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Abstract BACKGROUND High-grade gliomas (HGGs) are the most common fatal intrinsic brain tumors in pediatric patients. H3K27-altered diffuse midline gliomas (H3K27-DMGs), a subgroup of HGGs defined by a histone 3 position 27 alteration, are especially aggressive and result in the poorest patient outcomes. Despite in-depth genomic characterization, the 5-year survival rate has yet to improve beyond 2% following diagnosis. A common feature of H3K27-DMGs is infiltration of microglia, macrophages, other myeloid cells, collectively referred to as GAMs, and a small population of T-cells. The contribution of non-tumor cells in the tumor microenvironment (TME) can both promote and or inhibit tumor growth, thus representing an opportunity in the pursuit of novel therapeutics. Using bioinformatic analysis on a human H3K37-DMG single cell-RNA sequencing dataset, we reveal several cell-to-cell communication signaling networks, mediated by ligand and receptor pairs, between GAMs and tumor cells, respectively. HYPOTHESIS Microglial-derived growth factors activate oncogenic signaling pathways via paracrine signaling axes, thus promoting H3K27-DMG tumor cell proliferation and growth. METHODS I will validate these findings and test their therapeutic potential using co-culture studies, CRISPR and shRNA gene silencing, and phospho-proteomics technology. RELEVANCE This research provides further insights on the contribution of non-tumor cells in the TME towards H3K27-DMG cell proliferation and growth and could potentially inform future therapy paradigms.
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Keskinov, A. A., M. R. Shurin, V. M. Bukhman, and Z. S. Shprakh. "IMPACT OF TUMOR-DERIVED FACTORS ON DENDRITIC CELLS IN CANCER." Russian Journal of Biotherapy 16, no. 1 (March 30, 2017): 12–23. http://dx.doi.org/10.17650/1726-9784-2017-16-1-12-23.
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Dendritic cells play key role during tumorigenesis and immune response to it. They are able to uptake and present antigens to T cells, resulting in specific T cell mediated immune response. Furthermore, interaction between dendritic cells and other types of immune cells may boost cell-mediated and humoral immune response to cancer. Contrary to that, numerous tumor-derived factors may attract dendritic cells to neoplastic sites, causing impairment of their maturation, differentiation, and functional activity, resulting in deficiency of anti-tumor immune response or dendritic cell-mediated tolerance. Various factors within tumor microenvironment may either stimulate or inhibit dendritic cells and therefore need to be determined for improving efficacy of biotherapy utilizing dendritic cells. Meanwhile, recovery of dendritic cells functions in cancer patients remains one of primary aims for cancer immunotherapy. This review outlines main types of tumor-derived factors and their impact on dendritic cells in cancer.
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Tang, Michael, Jun Diao, Jun Zhao, and Mark Cattral. "Tumor-derived factors promote differentiation of immunosuppressive Gr-1+cDC through TLR2. (127.25)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 127.25. http://dx.doi.org/10.4049/jimmunol.188.supp.127.25.
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Abstract Tumor cells secrete endogenous danger signals that modulate the tumor inflammatory microenvironment. We have found that the intra-tumor inflammatory milieu skews differentiation of DC precursors (pre-cDC) towards a novel immunosuppressive Gr-1+ subpopulation. Inhibition of this differentiation enhanced cytotoxic T cells expansion and suppressed tumor growth. We sought to identify signaling mechanisms that regulate Gr-1+DC development. Splenic Pre-cDC from wildtype and MyD88-/- mice were incubated with tumor-conditioned medium (TCM) derived from the Lewis lung carcinoma cell line or fibroblast control medium. Supernatants were collected to measure various cytokine levels and cell surface expression of Gr-1 was monitored by flow cytometry. We found that TCM, but not control medium induced IL-6, IL-10 & IL-1β production and Gr-1+DC development. These cells produced high amounts of IL-10 after secondary stimulation with LPS. MyD88-/- Pre-cDC stimulated with TCM did not produce cytokines or differentiate into Gr-1+DC. Tumors from MyD88-/- mice contained a significantly lower frequency of Gr-1+DC compared to wildtype mice (14.1% vs. 1.1%; p=0.001, n>5). To determine whether Toll-like receptor 2 (TLR2) was involved in Gr-1+DC development, we stimulated Pre-cDC with different TLR agonists. We found that both Pam3CSK4 (TLR2/TLR1) and FSL-1 (TLR2/TLR6), but not LPS (TLR4) mimicked the activity of TCM. Together these data suggest that MyD88 and TLR2 are involved in Gr-1+DC development.
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Chen, Qing, Kohei Suzuki, Luis Sifuentes-Dominguez, Naoteru Miyata, Jie Song, Adam Lopez, Petro Starokadomskyy, et al. "Paneth cell–derived growth factors support tumorigenesis in the small intestine." Life Science Alliance 4, no. 3 (December 28, 2020): e202000934. http://dx.doi.org/10.26508/lsa.202000934.
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Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit. PC depletion in ApcMin mice impaired adenoma development in the small intestine and led to decreased Wnt3 expression in small bowel adenomas. To determine if PC-derived Wnt3 was required for adenoma development, we examined tumor formation after PC-specific ablation of Wnt3. We found that this was sufficient to decrease small intestinal adenoma formation; moreover, organoids derived from these tumors displayed slower growth capacity. Overall, we report that PC-derived Wnt3 is required to sustain early tumorigenesis in the small bowel and identify a clear role for PC-derived Wnt production in intestinal pathology.
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Lopez, Diana M., Mayra Lopez-Cepero, Gordon A. Watson, Aruna Ganju, Eduardo Sotomayor, and Yang-Xin Fu. "Modulation of the Immune System by Mammary Tumor-Derived Factors." Cancer Investigation 9, no. 6 (January 1991): 643–53. http://dx.doi.org/10.3109/07357909109039876.
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Arpinati, Ludovica, Naomi Kaisar-Iluz, Merav E. Shaul, Christopher Groth, Viktor Umansky, and Zvi G. Fridlender. "Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils." Cancers 13, no. 20 (October 11, 2021): 5082. http://dx.doi.org/10.3390/cancers13205082.
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Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) and AB12 (mesothelioma) tumor models, we aimed to elucidate the source of TANs and to assess the mechanisms driving neutrophils’ plasticity in cancer. Both NDN and LDN were found to migrate in response to CXCL1 and CXCL2 exposure, and co-infiltrate the tumor site ex vivo and in vivo, although LDN migration into the tumor was higher than NDN. Tumor-derived factors and chemokines, particularly CXCL1, were found to drive neutrophil phenotypical plasticity, inducing NDN to transition towards a low-density state (LD-NDN). LD-NDN appeared to differ from NDN by displaying a phenotypical profile similar to LDN in terms of nuclear morphology, surface receptor markers, decreased phagocytic abilities, and increased ROS production. Interestingly, all three subpopulations displayed comparable cytotoxic abilities towards tumor cells. Our data suggest that TANs originate from both LDN and NDN, and that a portion of LDN derives from NDN undergoing phenotypical changes. NDN plasticity resulted in a change in surface marker expression and functional activity, gaining characteristics of LDN.
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Du, Shuanglong, and Yuqing Li. "Progress in tumor-derived exosome miRNA regulating tumor metastasis research." E3S Web of Conferences 292 (2021): 03089. http://dx.doi.org/10.1051/e3sconf/202129203089.
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Tumor metastasis is the most important biological feature of a malignant tumor. It is also a complex process involving multi-step, multi-gene, and multi-products. Tumor cell-derived exosomes are vesicles secreted by tumor cells, containing proteins, lipids, noncoding RNA, and other components. MicroRNA (miRNA) of tumor cell-derived exosomes affects the tumor cell microenvironment and participates in tumor metastasis by activating various signaling pathways. Here, we summarize the miRNA and its related pathways that affect many factors of tumor metastasis and discuss the role of tumor-derived miRNA in the treatment and prevention of tumor metastasis. We also conclude the targets of tumor-derived miRNA in recent years. This article can provide new ideas for the development of tumor metastasis targeting drugs in the future.
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Serpe, Carmela, Antonio Michelucci, Lucia Monaco, Arianna Rinaldi, Mariassunta De Luca, Pietro Familiari, Michela Relucenti, et al. "Astrocytes-Derived Small Extracellular Vesicles Hinder Glioma Growth." Biomedicines 10, no. 11 (November 17, 2022): 2952. http://dx.doi.org/10.3390/biomedicines10112952.
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All cells are capable of secreting extracellular vesicles (EVs), which are not a means to eliminate unneeded cellular compounds but represent a process to exchange material (nucleic acids, lipids and proteins) between different cells. This also happens in the brain, where EVs permit the crosstalk between neuronal and non-neuronal cells, functional to homeostatic processes or cellular responses to pathological stimuli. In brain tumors, EVs are responsible for the bidirectional crosstalk between glioblastoma cells and healthy cells, and among them, astrocytes, that assume a pro-tumoral or antitumoral role depending on the stage of the tumor progression. In this work, we show that astrocyte-derived small EVs (sEVs) exert a defensive mechanism against tumor cell growth and invasion. The effect is mediated by astrocyte-derived EVs (ADEVs) through the transfer to tumor cells of factors that hinder glioma growth. We identified one of these factors, enriched in ADEVs, that is miR124. It reduced both the expression and function of the volume-regulated anion channel (VRAC), that, in turn, decreased the cell migration and invasion of murine glioma GL261 cells.
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Malcolm, Joan E., Timothy M. Stearns, Susan D. Airhart, Joel H. Graber, and Carol J. Bult. "Factors that influence response classifications in chemotherapy treated patient-derived xenografts (PDX)." PeerJ 7 (March 28, 2019): e6586. http://dx.doi.org/10.7717/peerj.6586.
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In this study, we investigated the impact of initial tumor volume, rate of tumor growth, cohort size, study duration, and data analysis method on chemotherapy treatment response classifications in patient-derived xenografts (PDXs). The analyses were conducted on cisplatin treatment response data for 70 PDX models representing ten cancer types with up to 28-day study duration and cohort sizes of 3–10 tumor-bearing mice. The results demonstrated that a 21-day dosing study using a cohort size of eight was necessary to reliably detect responsive models (i.e., tumor volume ratio of treated animals to control between 0.1 and 0.42)—independent of analysis method. A cohort of three tumor-bearing animals led to a reliable classification of models that were both highly responsive and highly nonresponsive to cisplatin (i.e., tumor volume ratio of treated animals to control animals less than 0.10). In our set of PDXs, we found that tumor growth rate in the control group impacted treatment response classification more than initial tumor volume. We repeated the study design factors using docetaxel treated PDXs with consistent results. Our results highlight the importance of defining endpoints for PDX dosing studies when deciding the size of cohorts to use in dosing studies and illustrate that response classifications for a study do not differ significantly across the commonly used analysis methods that are based on tumor volume changes in treatment versus control groups.
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Gluszko, Alicja, Shafaq M. Mirza, Katarzyna Piszczatowska, Ireneusz Kantor, Marta Struga, and Miroslaw J. Szczepanski. "The role of tumor-derived exosomes in tumor angiogenesis and tumor progression." Current Issues in Pharmacy and Medical Sciences 32, no. 4 (December 1, 2019): 193–202. http://dx.doi.org/10.2478/cipms-2019-0034.
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Abstract Exosomes, belonging to the group of extracellular bodies, are released by healthy as well as cancerous cells and serve as a communication pathway. Tumor-derived exosomes (TEX) possess the capacity to reprogram the function of normal cells owing to their genetic and molecular cargo. Such exosomes target endothelial cells (among others) in the tumor microenvironment to promote angiogenesis. Blood supply is essential in solid tumor growth and metastasis. The potential of pro-angiogenic changes is enhanced by an increased amount of circulating tumor-derived exosomes in the body fluids of cancer patients. A vascular network is important, since the proliferation, as well as the metastatic spread of cancer cells depends on an adequate supply of oxygen and nutrients, and the removal of waste products. New blood vessels and lymphatic vessels are formed through processes called angiogenesis and lymphangiogenesis, respectively. Angiogenesis is regulated by both activator and inhibitor molecules. Thousands of patients have received anti-angiogenic therapy to date. Despite their theoretical efficacy, anti-angiogenic treatments have not proved beneficial in terms of long-term survival. Tumor-derived exosomes carrying pro-angiogenic factors might be a target for new anti-cancer therapy.
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Joki, Tatsuhiro, Rona S. Carroll, Ian F. Dunn, Jianping Zhang, Toshiaki Abe, and Peter McL Black. "Assessment of Alterations in Gene Expression in Recurrent Malignant Glioma after Radiotherapy Using Complementary Deoxyribonucleic Acid Microarrays." Neurosurgery 48, no. 1 (January 1, 2001): 195–202. http://dx.doi.org/10.1097/00006123-200101000-00035.
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Abstract OBJECTIVE We used complementary deoxyribonucleic acid expression microarrays to assess the effects of radiotherapy on gene expression in glioblastoma multiforme. We hypothesized that postradiation recurrent tumors may demonstrate alterations in gene expression from the primary tumor specimen. METHODS Patients were diagnosed with glioblastoma multiforme at resection of the initial tumor, and they received 60 Gy of fractionated radiotherapy before recurrence. Ribonucleic acid samples from both the primary and the postradiation recurrent tumor in each patient were screened and compared using complementary deoxyribonucleic acid expression arrays and Northern blot analysis. RESULTS Messenger ribonucleic acid levels of growth factors participating in paracrine loops, such as vascular endothelial growth factor and platelet-derived growth factor receptor β, were decreased in postradiation recurrent tumors as compared with primary tumors in three of four patients. However, messenger ribonucleic acid levels of growth factors involved in autocrine loops, such as epidermal growth factor receptor, platelet-derived growth factor α, platelet-derived growth factor A, and basic fibroblast growth factor, were decreased in two of four, two of four, three of four, and three of four patients' recurrent tumors, respectively. Microvessel counts demonstrated that blood vessel growth was decreased significantly in postradiation recurrent tumor specimens. CONCLUSION After radiotherapy of glioblastoma multiforme, levels of paracrine-acting growth factors are diminished in correspondence with the reduction in vascular density. In contrast, growth factors that participate in autocrine loops demonstrate elevated levels of gene expression. These results suggest that maintenance of autocrine loops may be important in tumor regrowth after radiotherapy.
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Gerbec, Zachary J., Antonio Serapio-Palacios, Sarah E. Woodword, Jorge Pena Diaz, Brett Finlay, and Shoukat Dedhar. "Abstract A047: Tumor-derived bacteria drive breast cancer metastasis." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): A047. http://dx.doi.org/10.1158/1538-7445.metastasis22-a047.
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Abstract Metastasis is a major barrier to long-term survival and therapeutic options for aggressive, metastatic forms of breast cancer remain limited. Studies using patient samples have identified tumor-resident bacteria that preferentially associate with specific breast cancer types including highly aggressive TNBC. However, it is not yet understood how intratumoral bacteria directly contributes to disease progression and metastatic propensity independent of other prognostic factors. It is therefore the goal of the Dedhar and Finlay labs to identify how specific bacteria within metastatic breast cancer control immune and tumor cell functions to regulate metastatic potential and determine the outcome of disease progression. Using the syngenic, immunocompetent 4T1 and 67NR breast cancer models of metastatic and non-metastatic disease, we found microbiome depletion significantly reduces primary tumor growth highly metastatic 4T1 tumors specifically. We also found bacterial depletion reduces metastatic burden and extends survival time compared to microbiome-replete controls. Along with alterations in disease progression, microbiome depletion induces changes in immune cell function that occur specifically in the metastatic 4T1 tumors, revealing differential microbial-based regulation of metastatic versus non-metastatic disease. To identify bacteria that control metastasis in microbiome-replete controls, we plated surgically resected tumor suspensions on bacterial growth media and compared bacteria from the 4T1 and 67NR primary tumors. We identified several species of the Bacillus genus that were unique to 4T1 tumors and were present both within the primary tumor as well as metastatic nodules. To determine how these bacteria effect disease progression, we designed several in vivo model systems to directly test the ability of the isolated bacteria to promote metastasis. Using an orthotopic inoculation model with 4T1 or EMT6 cells, we found that following intratumoral injection, the 4T1- derived Bacillus species was actually able to augment metastasis when introduced directly back into primary tumors. To determine the specificity of this phenomenon, we then compared the effects of the 4T1 and 67NR-isolated bacteria on metastasis by injecting 4T1 cells that had been co-cultured with either bacteria prior to injection. Interestingly, we found that while the 67NR-derived bacteria had little effect on metastasis, the 4T1-derived Bacillus species significantly enhanced metastatic tumor burden compared to all other groups including those cultured with the 67NR-derived bacteria. These data demonstrate the ability of certain bacteria to promote metastatic disease. Based on these findings, we hypothesize specific bacteria play a causative role in augmenting metastatic propensity, and seek to determine functional differences between intratumoral bacteria to identify mechanistic targets for prevention of metastasis. We also seek to expand this work into clinical models to identify potential prognostic factors as well as mechanistic targets for disease treatment. Citation Format: Zachary J. Gerbec, Antonio Serapio-Palacios, Sarah E. Woodword, Jorge Pena Diaz, Brett Finlay, Shoukat Dedhar. Tumor-derived bacteria drive breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A047.
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Gerbec, Zachary J., Antonio Serapio-Palacios, Sarah Woodward, Jorge Pena-Diaz, B. Brett Finlay, and Shoukat Dedhar. "Abstract 5897: Tumor-derived bacteria drive breast cancer metastasis." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5897. http://dx.doi.org/10.1158/1538-7445.am2023-5897.
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Abstract Metastasis is a major barrier to long-term survival and therapeutic options for aggressive, metastatic forms of breast cancer remain limited. Studies using patient samples have identified tumor-resident bacteria that preferentially associate with specific breast cancer types, however, it is not yet understood how intratumoral bacteria directly contributes to disease progression and metastatic propensity independent of other prognostic factors. It is therefore the goal of the Dedhar and Finlay labs to identify how specific bacteria within metastatic breast cancer control immune and tumor cell functions to regulate metastatic potential and determine the outcome of disease progression. Using the syngenic, immunocompetent 4T1 and 67NR breast cancer models of metastatic and non-metastatic disease, we found microbiome depletion significantly reduces primary tumor growth of highly metastatic 4T1 tumors specifically. We also found bacterial depletion reduces metastatic burden and extends survival time compared to microbiome-replete controls. Microbiome depletion also induces changes in immune cell function that occur specifically in the metastatic 4T1 tumors, revealing differential microbial-based regulation of metastatic versus non-metastatic disease. To identify bacteria that control metastasis in microbiome-replete controls, we plated surgically resected tumor suspensions on bacterial growth media and compared bacteria from the 4T1 and 67NR primary tumors. We identified several species of the Bacillus genus that were unique to 4T1 tumors and were present both within the primary tumor as well as metastatic nodules. We then designed several in vivo model systems to directly test the ability of the isolated bacteria to promote metastasis. Using an orthotopic inoculation model with 4T1 or EMT6 cells, we found that following intratumoral injection, the 4T1-derived Bacillus species was actually able to augment metastasis when introduced directly back into primary tumors. To determine the specificity of this phenomenon, we then compared the effects of the 4T1 and 67NR-isolated bacteria on metastasis by injecting 4T1 cells that had been co-cultured with either bacteria prior to injection. Interestingly, we found that while the 67NR-derived bacteria had little effect on metastasis, the 4T1-derived Bacillus species significantly enhanced metastatic tumor burden compared to all other groups including those cultured with the 67NR-derived bacteria. These data demonstrate the ability of certain bacteria to promote metastatic disease. Based on these findings, we hypothesize specific bacteria play a causative role in augmenting metastatic propensity, and seek to determine functional differences between intratumoral bacteria to identify mechanistic targets for prevention of metastasis. We also seek to expand this work into clinical models to identify potential prognostic factors as well as mechanistic targets for disease treatment. Citation Format: Zachary J. Gerbec, Antonio Serapio-Palacios, Sarah Woodward, Jorge Pena-Diaz, B Brett Finlay, Shoukat Dedhar. Tumor-derived bacteria drive breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5897.
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Rosa-Caldwell, Megan E., Jacob L. Brown, David E. Lee, Tyrone A. Washington, and Nicholas P. Greene. "Tumor Derived Factors Induce Muscle Mitochondria Hyperpolarization And Subsequent Superoxide Production." Medicine & Science in Sports & Exercise 50, no. 5S (May 2018): 148. http://dx.doi.org/10.1249/01.mss.0000535572.42104.0f.
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Sugihara, Eiji, Takatsune Shimizu, Kensuke Kojima, Jo Ishizawa, Michael Andreeff, and Hideyuki Saya. "Arf and Ink4a Are Critical Factors Determining the Cell of Origin and Therapeutic Sensitivity in Myc-Induced Mouse Lymphoid Tumor." Blood 118, no. 21 (November 18, 2011): 2448. http://dx.doi.org/10.1182/blood.v118.21.2448.2448.
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Abstract Abstract 2448 Understanding the cell of origin of tumors is important not only for elucidating detailed mechanisms of tumorigenesis but also for characterizing the context in which tumor cells develop, both of which provide valuable information that can inform preventive therapy and therapeutic strategies in the clinical setting. However, the cell of origin and the factors determining the cell of origin remain unclear. In this study, a mouse model of precursor-B acute lymphoblastic leukemia/lymphoma (pre-B ALL/LBL: B220+CD19+CD43+/–IgM−) was established by retroviral transduction of Myc oncogenes (N-Myc or c-Myc) into mouse bone marrow mononuclear cells. To identify the cell of origin of this tumor, we fractionated N-Myc-transduced hematopoietic stem cells (HSCs), common lymphoid progenitors (CLPs), myeloid progenitors (MPs) and committed progenitor B cells, and then transplanted into recipient mice in a limiting dilution manner. As a result, HSCs showed the highest susceptibility to N-Myc-induced pre-B ALL/LBL versus CLPs and MPs. Frequencies of tumor-initiating cells originated from HSCs, CLPs and MPs were 1/184, 1/558 and 1/9286, respectively. Although N-Myc was unable to induce any tumor directly from committed progenitor B cells, N-Myc was able to induce pre-B ALL/LBL directly from those cells in the absence of Ink4a and Arf genes whose expression is normally maintained at low levels for endowing self-renewal capacity to HSCs. Furthermore, we found that N-Myc induced pre-B ALL/LBL directly from Arf deficient progenitor B cells. Since Arf was expressed significantly higher in progenitor B cells than Ink4a, Arf might play a predominant role in the determination of the cell of origin. In our mouse model, there is no significant difference between two types of Myc oncogenes, N-Myc and c-Myc, in respect to tumorigenic activities of the induced tumors, suggesting similar impacts of Myc family genes on lymphoid tumor. Next, we analyzed chemotherapeutic sensitivities of tumor cells derived from distinct cells of origin, wild-type HSCs and Ink4a/Arf−/− progenitor B cells. Tumor cells derived from Ink4a/Arf−/− progenitor B cells were significantly more resistant to Ara-C treatment than those derived from wild-type HSCs in vivo and in vitro. To eradicate Ink4a/Arf−/−-derived tumor cells, the Mdm2 inhibitor Nutlin-3 was used because Nultin-3 was assumed to be able to replace the role of Arf which inhibits Mdm2 to block p53 degradation. As a result, Nutlin-3 restored p53 and thereby induced massive apoptosis in tumor cells derived from Ink4a/Arf−/− progenitor B cells. In contrast, Nutlin-3 did not induce apoptosis in tumor cells derived from wild-type HSCs due to p53 mutations. Furthermore, Nutlin-3 effectively induced apoptosis in human B-ALL cell lines with wild-type p53 and lacking Ink4a and Arf expression. In addition, tumor cells derived from Ink4a/Arf−/− cells were more sensitive to Nutlin-3 treatment than normal bone marrow mononuclear cells. Therefore, Mdm2 inhibition can be a novel and promising therapeutic approach to the treatment of Ink4a/Arf deficient pre-B ALL/LBL, such as is frequently found in Ph+ B-ALL and relapsed B-ALL. Collectively these findings suggest that Ink4a and Arf are critical determining factors of the cell of origin of pre-B ALL/LBL, and that tumor cells derived from distinct cells of origin showed different drug sensitivities to Ara-C and Nutlin-3, which provides a novel insight into preventive therapy and different therapeutic approaches depending on genetic background of tumor cells. Disclosures: Saya: Kyowa Hakko Kirin, Co., Ltd.: Research Funding.
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Broggi, Maria A. S., Lea Maillat, Cristina C. Clement, Natacha Bordry, Patricia Corthésy, Aymeric Auger, Maurice Matter, et al. "Tumor-associated factors are enriched in lymphatic exudate compared to plasma in metastatic melanoma patients." Journal of Experimental Medicine 216, no. 5 (April 11, 2019): 1091–107. http://dx.doi.org/10.1084/jem.20181618.
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Liquid biopsies allow monitoring of cancer progression and detection of relapse, but reliable biomarkers in melanoma are lacking. Because secreted factors preferentially drain to lymphatic vessels before dilution in the blood, we hypothesized that lymph should be vastly enriched in cancer biomarkers. We characterized postoperative lymphatic exudate and plasma of metastatic melanoma patients after lymphadenectomy and found a dramatic enrichment in lymphatic exudate of tumor-derived factors and especially extracellular vesicles containing melanoma-associated proteins and miRNAs, with unique protein signatures reflecting early versus advanced metastatic spread. Furthermore, lymphatic exudate was enriched in memory T cells, including tumor-reactive CD137+ and stem cell–like types. In mice, lymph vessels were the major route of extracellular vesicle transport from tumors to the systemic circulation. We suggest that lymphatic exudate provides a rich source of tumor-derived factors for enabling the discovery of novel biomarkers that may reflect disease stage and therapeutic response.
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Scioli, Maria Giovanna, Gabriele Storti, Federico D’Amico, Pietro Gentile, Bong-Sung Kim, Valerio Cervelli, and Augusto Orlandi. "Adipose-Derived Stem Cells in Cancer Progression: New Perspectives and Opportunities." International Journal of Molecular Sciences 20, no. 13 (July 4, 2019): 3296. http://dx.doi.org/10.3390/ijms20133296.
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Growing importance has been attributed to interactions between tumors, the stromal microenvironment and adult mesenchymal stem cells. Adipose-derived stem cells (ASCs) are routinely employed in regenerative medicine and in autologous fat transfer procedures. To date, clinical trials have failed to demonstrate the potential pro-oncogenic role of ASC enrichment. Nevertheless, some pre-clinical studies from in vitro and in vivo models have suggested that ASCs act as a potential tumor promoter for different cancer cell types, and support tumor progression and invasiveness through the activation of several intracellular signals. Interaction with the tumor microenvironment and extracellular matrix remodeling, the exosomal release of pro-oncogenic factors as well as the induction of epithelial-mesenchymal transitions are the most investigated mechanisms. Moreover, ASCs have also demonstrated an elective tumor homing capacity and this tumor-targeting capacity makes them a suitable carrier for anti-cancer drug delivery. New genetic and applied nanotechnologies may help to design promising anti-cancer cell-based approaches through the release of loaded intracellular nanoparticles. These new anti-cancer therapies can more effectively target tumor cells, reaching higher local concentrations even in pharmacological sanctuaries, and thus minimizing systemic adverse drug effects. The potential interplay between ASCs and tumors and potential ASCs-based therapeutic approaches are discussed.
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Kitadai, Yasuhiko. "Angiogenesis and Lymphangiogenesis of Gastric Cancer." Journal of Oncology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/468725.
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Tumor angiogenesis is the result of an imbalance between positive and negative angiogenic factors released by tumor and host cells into the microenvironment of the neoplastic tissue. The stroma constitutes a large part of most solid tumors, and cancer-stromal cell interactions contribute functionally to tumor growth and metastasis. Activated fibroblasts and macrophages in tumor stroma play important roles in angiogenesis and tumor progression. In gastric cancer, tumor cells and stromal cells produce various angiogenic factors, including vascular endothelial growth factor, interleukin-8, platelet-derived endothelial cell growth factor, and angiopoietin. In addition,Helicobacter pyloriinfection increases tumor cell expression of metastasis-related genes including those encoding several angiogenic factors. We review the current understanding of molecular mechanisms involved in angiogenesis and lymphangiogenesis of human gastric cancer.
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Olejarz, Wioletta, Agnieszka Dominiak, Aleksandra Żołnierzak, Grażyna Kubiak-Tomaszewska, and Tomasz Lorenc. "Tumor-Derived Exosomes in Immunosuppression and Immunotherapy." Journal of Immunology Research 2020 (May 22, 2020): 1–11. http://dx.doi.org/10.1155/2020/6272498.
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Tumor-derived exosomes (TEX) are involved in cancer development, metastasis, and disease progression. They can modulate angiogenesis to elevate the malignant degree of tumor cells. TEX carry immunosuppressive factors affecting the antitumor activities of immune cells. Tumor cells as well as immune cells secrete immunologically active exosomes which affect intercellular communication, antigen presentation, activation of immune cells, and immune surveillance. Cell proliferation and immune response suppression create a favorable microenvironment for tumor. TEX can inhibit immune cell proliferation, induce apoptosis of activated CD8+ Teffs, suppress NK cell activity, interfere with monocyte differentiation, and promote Treg as well as MDSC expansion. Exosomes of microenvironment cells may also contribute to the development of drug resistance in cancer therapy. An important role of TEX in modulating the sensitivity of tumor cells to immunotherapy is a promising area of research to make the cancer therapy more successful.
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Dow, Alexa M., Michelle D. Rojo, Scout M. Treadwell, and Heather L. Machado. "Abstract 933: Macrophage-derived C/EBPb promotes breast tumorigenesis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 933. http://dx.doi.org/10.1158/1538-7445.am2022-933.
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Abstract Breast cancer growth and progression relies on complex interactions between tumor cells and surrounding stromal cells, including immune cells. Infiltrating immune cells, including macrophages, have been shown to promote tumor progression and metastasis, and efforts have aimed at the tumor microenvironment as a therapeutic strategy. Although tumor-promoting roles of macrophages are well-established, the specific macrophage factors and transcription factor-mediated regulatory programs that drive breast cancer progression are less understood. Using a p53-/- syngeneic model of premalignant progression to invasive cancer, we identified distinct subpopulations of macrophages that resemble both normal tissue resident macrophages and tumor-associated macrophages. Interestingly, most of these macrophage subsets highly express C/EBPβ, suggesting a global function of C/EBPβ in macrophages. C/EBPβ is a transcription factor that is overexpressed in breast cancer tissues and is important for monocyte differentiation and myeloid-derived suppressor cell function. To address the function of macrophage C/EBPβ during tumorigenesis, Cebpb-floxed mice were bred to iCsf1r-Cre mice to generate mice (CebpbΔM) where Cebpb is selectively deleted in macrophages (CSF1R-expressing myeloid cells). Genetic ablation of macrophage C/EBPβ in premalignant lesions results in a significant decrease in progression to invasive cancer. In established claudin-low tumors, deletion of macrophage C/EBPβ results in decreased tumor latency and the re-expression of cytokeratin 8+E-cadherin+ cells, reminiscent of luminal-like tumors. This phenoytpe was recapitulated in an ex vivo 3D co-culture model, where uniformly round structures that lack mesenchymal projections form in the presence of CebpbΔM BMDMs. These data suggest that macrophage C/EBPβ may help maintain a mesenchymal phenotype in claudin-low tumors. Ongoing studies are aimed at identifying the Cebpb-induced gene networks in macrophages that mediate tumor progression. These studies will have critical implications for whether inhibition of C/EBPβ-regulated genes may revert claudin-low tumors to a luminal-like phenotype, rendering tumors responsive to current therapies. This work is supported by NIH R01CA212518 (H.L.M.). Citation Format: Alexa M. Dow, Michelle D. Rojo, Scout M. Treadwell, Heather L. Machado. Macrophage-derived C/EBPb promotes breast tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 933.
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Liu, Jianguo, and Xiaojing Ma. "Host-derived CCL5 is critical for mammary tumor growth and metastasis (50.30)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S96. http://dx.doi.org/10.4049/jimmunol.178.supp.50.30.
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Abstract CCL5 is a chemokine produced by a variety of human cells under stress. It plays an important role in inflammation by recruiting T cells, macrophages and eosinophils to inflammatory sites. It has been shown in animal studies that tumor-derived CCL5 is able to help tumors to form new blood vessels (angiogenesis), thus fostering their growth. Tumor-derived CCL5 can also inhibit the T cell response and enhance the growth of breast cancer. Human studies have shown high incidence of CCL5 expression in tissue sections of breast carcinomas. Furthermore, in stage II breast cancer patients, the expression of CCL5 increased significantly the risk for disease progression. However, the mechanisms of CCL5 promote the tumor growth and metastasis is still unknown. Using a syngeneic 4T1 mammary tumor model that closely resembles human breast cancer in primary tumor growth characteristics and metastatic properties, we have observed that, compared to control wild type mice of identical background, mice that are genetically deficient in CCL5 (CCL5-ko) are highly resistant to 4T1 tumor growth and to tumor-induced death. In addition, the remaining tumors in CCL5-ko mice developed little lung metastasis after 60 days. The CCL5-ko mice that regressed the tumor promptly and strongly rejected rechallenge with 4T1 tumor, indicating establishment of protective immunity. Furthermore, mAb-mediated neutralization of CCL5 in vivo prevented 4T1 tumor growth and lung metastasis. Our data also indicate that 4T1 tumor cells spontaneously produce high levels of CCL5 driven by highly active NF-kB and other yet to be characterized transcription factors. In conclusion, CCL5 plays a critical role in the growth and metastasis of mammary tumors, and that CCL5 represents a desirable and accessible target in breast cancer therapy.
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Jotzu, Constantin, Eckhard Alt, Gabriel Welte, Jie Li, Bryan T. Hennessy, Eswaran Devarajan, Srinivasalu Krishnappa, Severin Pinilla, Lilly Droll, and Yao-Hua Song. "Adipose Tissue-Derived Stem Cells Differentiate into Carcinoma-Associated Fibroblast-Like Cells under the Influence of Tumor-Derived Factors." Analytical Cellular Pathology 33, no. 2 (2010): 61–79. http://dx.doi.org/10.1155/2010/695162.
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Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue-derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g., expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factor-beta 1 (TGFβ1) and the differentiation of hASCs towards CAFs is dependent on TGFβ1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFβ1 as well as by pretreatment of the hASCs with SB431542, a TGFβ1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in anin vitroinvasion assay, as well as increased expression of stromal-cell-derived factor 1 (SDF-1) and CCL5. Taken together, these data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.
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Deepak, Praveen, and Arbind Acharya. "Anti-tumor Immunity and Mechanism of Immunosuppression Mediated by Tumor Cells: Role of Tumor-Derived Soluble Factors and Cytokines." International Reviews of Immunology 29, no. 4 (July 2010): 421–58. http://dx.doi.org/10.3109/08830185.2010.483027.
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Mullins, David W., Ryan S. Martins, and Klaus D. Elgert. "Tumor-Derived Cytokines Dysregulate Macrophage Interferon-γ Responsiveness and Interferon Regulatory Factor-8 Expression." Experimental Biology and Medicine 228, no. 3 (March 2003): 270–77. http://dx.doi.org/10.1177/153537020322800305.
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Tumors can evade immune responses through suppressor signals that dysregulate host effector cell function. In this study we demonstrate that tumor-derived suppressor molecules impede host antitumor immune activity through dysregulation of multiple macrophage (MΦ) pathways, including suppressed production of cytotoxic and immunostimulatory agents and impaired expression of the interferon regulatory factor-8 (IRF-8) protein, a critical transducer of interferon-γ-mediated activation pathways. The tumor-derived immunosuppressive cytokines interieukin-10 and transforming growth factor-β, constrain IRF-8 production by normal MΦs, regardless of priming, and IRF-8 is also dysregulated in primary MΦs from tumorburdened hosts. Collectively, these data describe a new mechanism by which tumors disrupt immune function and suggest that abrogation of tumor-derived immunoregulatory factors in situ can restore immune function and enhance antitumor efficacy.
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Otero, Jacklyn, Kathryn J. Russell, DongTao Fu, Wenyin Shi, Marda L. Jorgensen, Steven M. Guthrie, Dietmar Siemann, Edward W. Scott, and Christopher R. Cogle. "Tumor Vasculogenesis Can Be Derived from the Hematopoietic Stem Cell." Blood 108, no. 11 (November 16, 2006): 1806. http://dx.doi.org/10.1182/blood.v108.11.1806.1806.
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Abstract Blood vessel development is essential to cancer growth and metastasis. Based on our recent findings that the hematopoietic stem cell (HSC) provides functional hemangioblast activity in repairing the ischemic retina, we questioned if the HSC also acts as a pathologic hemangioblast - contributing to tumor vasculogenesis. Using a transplant model of green fluorescent protein (GFP) marrow into wild-type C57BL/6 mice, we injected lung cancer (LLC) and allowed the tumor to grow for 14 days. All tumor specimens demonstrated tumor vessels with marrow-derived endothelial cells. Approximately 25% of tumor vessels contained marrow-derived endothelial cells as demonstrated by GFP, CD31 and vWF expression. Confocal microscopy was used to identify true marrow-derived endothelial cells lining the vascular lumen versus marrow-derived pericytes juxtaposed to endothelial cells. We further questioned whether the tumor neovasculogenesis is from a clonal, self-renewing HSC. Lung cancers grown in recipients of single cell and serially transplanted hematopoietic stem cells (n=9) demonstrate clonal, donor-derived endothelial cells in 5% of tumor vasculature, matching hematopoietic engraftment. Our results indicate that the self-renewing, clonal adult hematopoietic stem cell exhibits pathologic hemangioblast activity, capable of producing both blood and blood vessels within tumors. Given that the HSC and its EPC progeny can contribute to tumor vasculogenesis, we further hypothesized that factors that affect leukocyte trafficking likely affect the pathologic hemangioblast activity of HSC. Thus, we made slight modifications to our transplant and tumor inoculation model by administering GCSF and SCF to mobilize marrow derived EPC. Over the ensuing 14 days, the tumors in the cytokine treated group grew at a much faster rate and to a much larger size than tumors in the control mice. After 14 days of cytokine treatment and tumor growth, microvessel density was not different between cytokine treated mice (n=4) and control mice (n=4); however, marrow-derived tumor vasculogenesis was markedly elevated in the cytokine treated compared to controls (63% vs. 26%). In conclusion, the HSC contributes to blood vessels within lung cancer and strategies targeting HSC/EPC mobilization (such as during the recovery phase of chemotherapy) potentially represent excellent ant-neoplastic opportunities.
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Owen, Jennifer L., Diana M. Lopez, Joseph F. Grosso, Kathleen M. Guthrie, Lynn M. Herbert, Marta Torroella-Kouri, and Vijaya Iragavarapu-Charyulu. "The expression of CCL2 by T lymphocytes of mammary tumor bearers: Role of tumor-derived factors." Cellular Immunology 235, no. 2 (June 2005): 122–35. http://dx.doi.org/10.1016/j.cellimm.2005.08.032.
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Giurini, Eileena F., Mary Beth Madonna, Andrew Zloza, and Kajal H. Gupta. "Microbial-Derived Toll-like Receptor Agonism in Cancer Treatment and Progression." Cancers 14, no. 12 (June 14, 2022): 2923. http://dx.doi.org/10.3390/cancers14122923.
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Toll-like receptors (TLRs) are typical transmembrane proteins, which are essential pattern recognition receptors in mediating the effects of innate immunity. TLRs recognize structurally conserved molecules derived from microbes and damage-associated molecular pattern molecules that play an important role in inflammation. Since the first discovery of the Toll receptor by the team of J. Hoffmann in 1996, in Drosophila melanogaster, numerous TLRs have been identified across a wide range of invertebrate and vertebrate species. TLR stimulation leads to NF-κB activation and the subsequent production of pro-inflammatory cytokines and chemokines, growth factors and anti-apoptotic proteins. The expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. The anti-tumoral effects can result from the activation of anti-tumoral immune responses and/or the direct induction of tumor cell death. The pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment. The aim of this review is to draw attention to the effects of TLR stimulation in cancer, the activation of various TLRs by microbes in different types of tumors, and, finally, the role of TLRs in anti-cancer immunity and tumor rejection.
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Szatanek, Rafał, and Monika Baj-Krzyworzeka. "CD44 and Tumor-Derived Extracellular Vesicles (TEVs). Possible Gateway to Cancer Metastasis." International Journal of Molecular Sciences 22, no. 3 (February 2, 2021): 1463. http://dx.doi.org/10.3390/ijms22031463.
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Cancer metastasis, the final stage of tumor progression, is a complex process governed by the interplay of multiple types of cells and the tumor microenvironment. One of the aspects of this interplay involves the release of various factors by the tumor cells alone or by forcing other cells to do so. As a consequence of these actions, tumor cells are prepared in favorable conditions for their dissemination and spread to other sites/organs, which guarantees their escape from immunosurveillance and further progression. Tumor-derived extracellular vesicles (TEVs) represent a heterogeneous population of membrane-bound vesicles that are being actively released by different tumors. The array of proteins (i.e., receptors, cytokines, chemokines, etc.) and nucleic acids (i.e., mRNA, miR, etc.) that TEVs can transfer to other cells is often considered beneficial for the tumor’s survival and proliferation. One of the proteins that is associated with many different tumors as well as their TEVs is a cluster of differentiation 44 in its standard (CD44s) and variant (CD44v) form. This review covers the present information regarding the TEVs-mediated CD44s/CD44v transfer/interaction in the context of cancer metastasis. The content and the impact of the transferred cargo by this type of TEVs also are discussed with regards to tumor cell dissemination.
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Zhao, Xia, Zhihao Yu, and Ku Zang. "Platelet-Derived Growth Factors Affect Clinical Features and Prognosis of Gastric Cancer." Journal of Oncology 2022 (August 18, 2022): 1–6. http://dx.doi.org/10.1155/2022/2108368.
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Purpose. To investigate the association of platelet-derived growth factors (PDGFs), clinicopathological features, and prognosis in gastric cancer patients. Methods. Tumor specimens of 180 individuals with gastric cancer treated between 2016 and 2020 were collected. Immunohistochemical staining and Western blot (WB) were used to detect the expression of PDGF-B and PDGF-D. The relationship between the expression of PDGF-B and PDGF-D and relapse-free subsistence (RFS) time was assessed using Kaplan–Meier curves. Univariate and multivariate Cox proportional hazards regression models were used to evaluate the relationship between the expression of PDGF-B and PDGF-D and the prognosis and clinicopathological features in gastric cancer patients. Results. High expression of PDGF-B and PDGF-D was detected in 108 (60%) and 137 (76%) tumor specimens, respectively. The expressions of PDGF-B and PDGF-D were independent predictive indicators in multivariate analysis when compared to tumor depth, tumor stage, lymph node metastasis, and RFS ( P < 0.01 ). Conclusion. The high expression of PDGF-B and PDGF-D in gastric cancer tissues is associated with poor prognosis and poor survival rate of the patients. The expression of PDGF-B and PDGF-D can be used as important indicators to evaluate the biological behavior and prognosis of gastric cancer.
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Oldham, R. K., J. R. Maleckar, C. S. Friddell, W. M. Lewko, W. H. West, and J. R. Yannelli. "Tumor-derived activated cells: preliminary laboratory and clinical results." Clinical Chemistry 35, no. 8 (August 1, 1989): 1576–80. http://dx.doi.org/10.1093/clinchem/35.8.1576.
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Abstract It is well known that T lymphocytes can mediate significant anti-tumor responses. A limiting factor has always been the ability to expand T cells, whether from the peripheral blood, spleen, or tumor. The recent availability of recombinant interleukin-2 (r-IL2) has demonstrated the feasibility of expanding T cells and the clinical efficacy of these cells as anti-tumor effectors in murine models. Concomitantly, researchers discovered that lymphokine-activated killer cells--peripheral blood cells functionally distinct from T cells--could be cultured, expanded, and re-infused in patients, with significant clinical effects. For many years, the infiltrating lymphocytes have been recognized in tumor biopsies and known to be cytolytically active. Major limiting factors were the ability to culture large numbers of these infiltrating cells and the limited understanding of the tumor antigens involved for T-cell stimulation. Restimulation by antigen (tumor cells) appears to provide the ongoing antigen stimulation needed to maintain selective killing of tumor cells. By defining various factors in the medium that support and enhance T-cell growth and activation, the components are becoming available to develop a broad attack on advanced cancer by using this laboratory-based technology of stimulation and expansion of tumor-derived activated cells.
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Riedel, Angela, Moutaz Helal, Luisa Pedro, Jonathan J. Swietlik, David Shorthouse, Werner Schmitz, Lisa Haas, et al. "Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma." Cancer Immunology Research 10, no. 4 (March 9, 2022): 482–97. http://dx.doi.org/10.1158/2326-6066.cir-21-0778.
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Abstract Communication between tumors and the stroma of tumor-draining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization.
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Wang, Bing, Jiusong Sun, Shiro Kitamoto, Min Yang, Anders Grubb, Harold A. Chapman, Raghu Kalluri, and Guo-Ping Shi. "Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors." Journal of Biological Chemistry 281, no. 9 (December 19, 2005): 6020–29. http://dx.doi.org/10.1074/jbc.m509134200.
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Yu, Zhixian, Kevin P. Mouillesseaux, Erich J. Kushner, and Victoria L. Bautch. "Tumor-Derived Factors and Reduced p53 Promote Endothelial Cell Centrosome Over-Duplication." PLOS ONE 11, no. 12 (December 15, 2016): e0168334. http://dx.doi.org/10.1371/journal.pone.0168334.
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Presta, Marco, and Daniel B. Rifkin. "New Aspects of Blood Vessel Growth: Tumor and Tissue-Derived Angiogenesis Factors." Pathophysiology of Haemostasis and Thrombosis 18, no. 1 (1988): 6–17. http://dx.doi.org/10.1159/000215778.
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Hoagland, J. G., S. Scoggin, R. Giavazzi, D. Campbell, K. Kanellopoulos, and J. M. Jessup. "Tumor-derived suppressor factors (TDSFs) in normal and neoplastic colon and rectum." Journal of Surgical Research 40, no. 5 (May 1986): 467–74. http://dx.doi.org/10.1016/0022-4804(86)90217-9.
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Kuang, Dong-Ming, Yan Wu, Nini Chen, Jiasen Cheng, Shi-Mei Zhuang, and Limin Zheng. "Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes." Blood 110, no. 2 (July 15, 2007): 587–95. http://dx.doi.org/10.1182/blood-2007-01-068031.
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Abstract Macrophages (Mφ) in most solid tumors exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow tumor microenvironments to “educate” Mφ are incompletely understood. Here, we report that culture supernatants (TSNs) from several types of tumor cell lines can drive monocytes to become immunosuppressive Mφ. Kinetic experiments revealed that soon after exposure to these TSNs, monocytes began to provoke transient proinflammatory responses and then became refractory to subsequent stimulation. Other TSNs that failed to cause such temporary preactivation did not alter Mφ polarization. Consistent with these results, we observed that the monocytes/Mφ in different areas of human tumor samples exhibited distinct activation patterns. Moreover, we found that hyaluronan fragments constitute a common factor produced by various tumors to induce the formation of immunosuppressive Mφ, and also that upregulation of hyaluronan synthase-2 in tumor cells is correlated with the ability of the cells to cause Mφ dysfunction. These results indicate that soluble factors derived from tumor cells, including hyaluronan fragments, co-opt the normal development of Mφ to dynamically educate the recruited blood monocytes in different niches of a tumor. The malignant cells can thereby avoid initiation of potentially dangerous Mφ functions and create favorable conditions for tumor progression.
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Filiberti, Serena, Mariapia Russo, Silvia Lonardi, Mattia Bugatti, William Vermi, Cathy Tournier, and Emanuele Giurisato. "Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways." Biomedicines 10, no. 11 (October 26, 2022): 2709. http://dx.doi.org/10.3390/biomedicines10112709.
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Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal.