The Influence of Tumor Microenvironment on Tumor Progression; and Anticancer Therapies
DOI:
https://doi.org/10.30683/1929-2279.2020.09.08Keywords:
Tumor microenvironment, inflammation, hypoxia, metastasis, apoptosis, angiogenesis, oncogene, immunotherapy, catecholamine, necrosis, IL-1, IL-6.Abstract
All tumors are surrounded by complex environmental components including blood and lymph vessels; cellular components like fibroblasts, endothelial cells, immune cells; and non-cellular stromal cytokines, extracellular vesicles, and extracellular matrix. All of these along with the tumor cells constitute the tumor microenvironment (TME). Also the physical and chemical factors within this tumor microenvironment including extracellular pH, hypoxia, elevated interstitial fluid pressure, and fibrosis closely associate with the tumor progression at local site, its metastasis to remote areas of the body, immunosuppression, and drug resistance exhibited by the tumor. These cellular and extracellular components of TME primarily contribute to the process of carcinogenesis. This review focuses on multiple factors that alter the microenvironment to make it favorable for tumor growth at primary site and its metastasis to secondary sites. Also some of the natural products that may help to treat the tumor conditions via alteration of this microenvironment are mentioned which may provide new venues for development of newer drugs halting the progression of the tumors.
References
Lorusso G, Rüegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol 2008; 130: 1091-1103. https://doi.org/10.1007/s00418-008-0530-8 DOI: https://doi.org/10.1007/s00418-008-0530-8
Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27: 5904-5912. https://doi.org/10.1038/onc.2008.271 DOI: https://doi.org/10.1038/onc.2008.271
Ireland L, Luckett T, Schmid MC, et al. Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis. bioRxiv 2019; 732149. https://doi.org/10.1101/732149 DOI: https://doi.org/10.1101/732149
Ireland L, Santos A, Ahmed MS, et al. Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. Cancer Res 2016; 76: 6851-6863. https://doi.org/10.1158/0008-5472.CAN-16-1201 DOI: https://doi.org/10.1158/0008-5472.CAN-16-1201
Ireland L, Santos A, Campbell F, et al. Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer. Oncogene 2018; 37: 2022-2036. https://doi.org/10.1038/s41388-017-0115-x DOI: https://doi.org/10.1038/s41388-017-0115-x
Quaranta V, Rainer C, Nielsen SR, et al. Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer. Cancer Res 2018; 78: 4253-4269. https://doi.org/10.1158/0008-5472.CAN-17-3876 DOI: https://doi.org/10.1158/0008-5472.CAN-17-3876
Figueiredo CR, Azevedo RA, Mousdell S, et al. Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma. Front Immunol 2018; 9: 1132. https://doi.org/10.3389/fimmu.2018.01132 DOI: https://doi.org/10.3389/fimmu.2018.01132
Nielsen SR, Quaranta V, Linford A, et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol 2016; 18: 549-560. https://doi.org/10.1038/ncb3340 DOI: https://doi.org/10.1038/ncb3340
Boudreau A, van't Veer LJ, Bissell MJ. An “elite hacker”: breast tumors exploit the normal microenvironment program to instruct their progression and biological diversity. Cell Adhes Migr 2012; 6: 236-2489. https://doi.org/10.4161/cam.20880 DOI: https://doi.org/10.4161/cam.20880
Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012; 196: 395-406. https://doi.org/10.1083/jcb.201102147 DOI: https://doi.org/10.1083/jcb.201102147
Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Canc 2002; 2: 38-47. https://doi.org/10.1038/nrc704 DOI: https://doi.org/10.1038/nrc704
Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 2012; 33: 207. https://doi.org/10.1016/j.tips.2012.01.005 DOI: https://doi.org/10.1016/j.tips.2012.01.005
Casazza A, Di Conza G, Wenes M, et al. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 2014; 33: 1743-54. https://doi.org/10.1038/onc.2013.121 DOI: https://doi.org/10.1038/onc.2013.121
Bellone M, Calcinotto A. Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes. Front Oncol 2013; 3: 231. https://doi.org/10.3389/fonc.2013.00231 DOI: https://doi.org/10.3389/fonc.2013.00231
Lee N, Barthel SR, Schatton T. Melanoma stem cells and metastasis: mimicking hematopoietic cell trafficking? Lab Invest 2014; 94: 13-30. https://doi.org/10.1038/labinvest.2013.116 DOI: https://doi.org/10.1038/labinvest.2013.116
Robbins PF, Kawakami Y. Human tumor antigens recognized by T cells. Curr Opin Immunol 1996; 8: 628-636. https://doi.org/10.1016/S0952-7915(96)80078-1 DOI: https://doi.org/10.1016/S0952-7915(96)80078-1
Noonan KA, Ghosh N, Rudraraju L, et al. Targeting Immune Suppression with PDE5 Inhibition in EndStage Multiple Myeloma, Marilyn Bui, and Ivan Borrello; Cancer Immunol Res 2014; 2(8): 725-31. https://doi.org/10.1158/2326-6066.CIR-13-0213 DOI: https://doi.org/10.1158/2326-6066.CIR-13-0213
Henkart PA. Mechanism of lymphocyte-mediated cytotoxicity. Annu Rev Immunol 1985; 3: 31-58. https://doi.org/10.1146/annurev.iy.03.040185.000335 DOI: https://doi.org/10.1146/annurev.iy.03.040185.000335
Anikeeva N, Sykulev Y. Mechanisms controlling granule-mediated cytolytic activity of cytotoxic T lymphocytes. Immunol Res 2011; 51: 183-194. https://doi.org/10.1007/s12026-011-8252-8 DOI: https://doi.org/10.1007/s12026-011-8252-8
Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006; 6(5): 392-401. https://doi.org/10.1038/nrc1877 DOI: https://doi.org/10.1038/nrc1877
Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed) 2010; 15: 166-79. https://doi.org/10.2741/3613 DOI: https://doi.org/10.2741/3613
Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost 2004; 30: 95-108. https://doi.org/10.1055/s-2004-822974 DOI: https://doi.org/10.1055/s-2004-822974
Prisco D, et al. Platelet activation and platelet lipid composition in pulmonary cancer Prostaglandins Leukot. Essent Fatty Acids 1995; 53: 65-68. https://doi.org/10.1016/0952-3278(95)90085-3 DOI: https://doi.org/10.1016/0952-3278(95)90085-3
Blann AD, et al. Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coagul Fibrinolysis 2001; 12: 43-50. https://doi.org/10.1097/00001721-200101000-00007 DOI: https://doi.org/10.1097/00001721-200101000-00007
Verheul HMW, et al. Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin Cancer Res 2000; 6: 166-171.
Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11(2): 123-134. https://doi.org/10.1038/nrc3004 DOI: https://doi.org/10.1038/nrc3004
Erdogan B, Webb DJ. Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans 2017; 45(1): 229-236. https://doi.org/10.1042/BST20160387 DOI: https://doi.org/10.1042/BST20160387
Estrella V, Chen T, Lloyd M, Wojtkowiak J, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 2013; 73(5): 1524-35. https://doi.org/10.1158/0008-5472.CAN-12-2796 DOI: https://doi.org/10.1158/0008-5472.CAN-12-2796
Li X, Yu X, Dai D, et al. The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters. Oncotarget 2016; 7(17): 23141-55. https://doi.org/10.18632/oncotarget.8153 DOI: https://doi.org/10.18632/oncotarget.8153
Lamszus K, Ulbricht U, Matschke J, et al. Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 2003; 9: 1399-1405.
Gacche RN. Compensatory angiogenesis and tumor refractoriness. Oncogenesis 2015; 4(6): e153. https://doi.org/10.1038/oncsis.2015.14 DOI: https://doi.org/10.1038/oncsis.2015.14
Casadei C, Dizman N, Schepisi G, et al. Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors. Ther Adv Med Oncol 2019; 11: 1758835919890285. https://doi.org/10.1177/1758835919890285 DOI: https://doi.org/10.1177/1758835919890285
Sakai K, Nakamura T, Kinoshita T, et al. HGF-Antagonists: Structure, Activities, and Anti-cancer Approach. Current Signal Transduction Therapy 2011; 6: 191. https://doi.org/10.2174/157436211795659964 DOI: https://doi.org/10.2174/157436211795659964
Cochin V, Gross-Goupil M, Ravaud A, et al. Cabozantinib: Mechanism of action, efficacy and indications. Bulletin du Cancer 2017; 104(5): 393-401. https://doi.org/10.1016/j.bulcan.2017.03.013 DOI: https://doi.org/10.1016/j.bulcan.2017.03.013
Girard JP, Moussion C, Forster R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 2012; 12: 762-773. https://doi.org/10.1038/nri3298 DOI: https://doi.org/10.1038/nri3298
Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol 2012; 23(Suppl 8): viii6-9. https://doi.org/10.1093/annonc/mds256 DOI: https://doi.org/10.1093/annonc/mds256
Chung YR, Kim HJ, Jang MH, et al. Prognostic value of tumor infiltrating lymphocyte subsets in breast cancer depends on hormone receptor status. Breast Cancer Res Treat 2017; 161(3): 409-420. https://doi.org/10.1007/s10549-016-4072-9 DOI: https://doi.org/10.1007/s10549-016-4072-9
Wiedemann GM, Knott MML, Vetter VK, et al. Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells. OncoImmunology 2016; 5: 9. https://doi.org/10.1080/2162402X.2016.1175794 DOI: https://doi.org/10.1080/2162402X.2016.1175794
Beano A, Signorino E, Evangelista A, et al. Correlation between NK function and response to trastuzumab in metastatic breast cancer patients. J Transl Med 2008; 6: 25. https://doi.org/10.1186/1479-5876-6-25 DOI: https://doi.org/10.1186/1479-5876-6-25
Leischner C, Burkard M, Pfeiffer MM, et al. Nutritional immunology: function of natural killer cells and their modulation by resveratrol for cancer prevention and treatment. Nutr J 2015; 15: 47. https://doi.org/10.1186/s12937-016-0167-8 DOI: https://doi.org/10.1186/s12937-016-0167-8
Lam W, Bussom S, Guan F, et al. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med 2010; 2: 45ra59. https://doi.org/10.1126/scitranslmed.3001270 DOI: https://doi.org/10.1126/scitranslmed.3001270
Liu S-H, Cheng Y-C. Old formula, new Rx: The journey of PHY906 as cancer adjuvant therapy. Journal of Ethnopharmacology 2012; 140(3): 614-623. https://doi.org/10.1016/j.jep.2012.01.047 DOI: https://doi.org/10.1016/j.jep.2012.01.047
Lam W, Jiang Z, Guan F, et al. PHY906 (KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment. Sci Rep 2015; 5: 9384. https://doi.org/10.1038/srep09384 DOI: https://doi.org/10.1038/srep09384
Mukherjee S, Hussaini R, White R, et al. TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors. Cancer Immunol Immunother 2018; 67(5): 761-774. https://doi.org/10.1007/s00262-018-2130-3 DOI: https://doi.org/10.1007/s00262-018-2130-3
de la Cruz-López, Karen G, et al. Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches. Frontiers in Oncology 2019; 9: 1143. https://doi.org/10.3389/fonc.2019.01143 DOI: https://doi.org/10.3389/fonc.2019.01143
Zhang Y, Yang JM. Altered energy metabolism in cancer: a unique opportunity for therapeutic intervention. Cancer Biol Ther 2013; 14(2): 81-89. https://doi.org/10.4161/cbt.22958 DOI: https://doi.org/10.4161/cbt.22958
McCarty MF, Whitaker J. Manipulating tumor acidification as a cancer treatment strategy. Altern Med Rev 2010; 15(3): 264-72.
Fais S, Venturi G, Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev 2014; 33(4): 1095-1108. https://doi.org/10.1007/s10555-014-9531-3 DOI: https://doi.org/10.1007/s10555-014-9531-3
Faubert B, Li KY, Cai L, et al. Lactate Metabolism in Human Lung Tumors Cell 2017; 171(2): 358-371.e9. https://doi.org/10.1016/j.cell.2017.09.019 DOI: https://doi.org/10.1016/j.cell.2017.09.019
Ribeiro MD, Silva AS, Bailey KM, et al. Buffer Therapy for Cancer. J Nutr Food Sci 2012; 2: 6. https://doi.org/10.4172/2155-9600.S2-006 DOI: https://doi.org/10.4172/2155-9600.S2-006
Pötzl J, Roser D, Bankel L, Hömberg N, et al. Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN‐γ and induces NK cell‐dependent lymphoma control without other immunotherapies. Int J Cancer 2017; 140(9): 2125-2133. https://doi.org/10.1002/ijc.30646 DOI: https://doi.org/10.1002/ijc.30646
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