Mechanisms of Tumor Angiogenesis and Resulting Therapy Resistance
DOI:
https://doi.org/10.58445/rars.3058Keywords:
cancer, angiogenesis, treatment, therapy resistance, tumor, VEGF, anti-angiogenic, anti-VEGF, hypoxia, neovascularization, blood vessels, drugsAbstract
In 2021, over 10 million people died of cancer worldwide. Although recent technology and innovations have saved the lives of many, a large portion of cancer cells continue to avoid these treatments; a key part of this is due to the formation of new blood capillaries, known as angiogenesis. Typically, angiogenesis occurs in tissue repair, embryonic development, the menstrual cycle, muscle growth, and organ-lining development.1 However, tumor angiogenesis is uncontrolled and rapid, giving tumor cells the nutrient and oxygen supply they need to sustain themselves and spread through the bloodstream. Several treatments have been attempted to disrupt this process, including angiogenesis inhibitors, but more widespread therapies, such as chemotherapy, are often affected by both angiogenesis and its inhibition. To effectively administer treatments, it is essential that the mechanisms, including pro-angiogenic growth factors, signalling pathways, and oxygen levels, of this self-sustaining aspect of cancer cells is evaluated and taken into consideration. In this study, I aim to analyze the extent to which tumor angiogenesis allows these malignant cells to resist cancer treatments.
References
Gupta MK, Qin RY. Mechanism and its regulation of tumor-induced angiogenesis. World journal of gastroenterology. 2003;9(6):1144-1155. doi:https://doi.org/10.3748/wjg.v9.i6.1144
Cleveland Clinic. Tumor: What Is It, Types, Symptoms, Treatment & Prevention. Cleveland Clinic. Published October 5, 2021. https://my.clevelandclinic.org/health/diseases/21881-tumor
Folkman J. Tumor Angiogenesis: Therapeutic Implications. New England Journal of Medicine. 1971;285(21):1182-1186. doi:https://doi.org/10.1056/nejm197111182852108
Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, Challenges and Opportunities. Cellular and Molecular Life Sciences. 2019;77(9):1745-1770. doi:https://doi.org/10.1007/s00018-019-03351-7
Pozzi A, Yurchenco PD, Iozzo RV. The nature and biology of basement membranes. Matrix biology : journal of the International Society for Matrix Biology. 2017;57-58:1-11. doi:https://doi.org/10.1016/j.matbio.2016.12.009
López-Otín C, Bond JS. Proteases: Multifunctional Enzymes in Life and Disease. Journal of Biological Chemistry. 2008;283(45):30433-30437. doi:https://doi.org/10.1074/jbc.r800035200
Nishida N. Angiogenesis in Cancer. Taylor & Francis Online. Published December 24, 2022. https://www.tandfonline.com/doi/full/10.2147/vhrm.s23213
Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduction and Targeted Therapy. 2023;8(1). doi:https://doi.org/10.1038/s41392-023-01460-1
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8(4):299-309. doi:https://doi.org/10.1016/j.ccr.2005.09.005
Beyer C, Distler J. Tyrosine Kinase - an overview | ScienceDirect Topics. www.sciencedirect.com. Published 2013. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/tyrosine-kinase
Todd VM, Johnson RW. Hypoxia in bone metastasis and osteolysis. Cancer Letters. 2020;489:144-154. doi:https://doi.org/10.1016/j.canlet.2020.06.004
Wautier JL, Wautier MP. Vascular Permeability in Diseases. ProQuest. 2022;23(7):3645. doi:https://doi.org/10.3390/ijms23073645
Shibuya M, Claessonwelsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Experimental Cell Research. 2006;312(5):549-560. doi:https://doi.org/10.1016/j.yexcr.2005.11.012
Molhoek KR, Erdag G, Rasamny J, et al. VEGFR-2 expression in human melanoma: Revised assessment. International Journal of Cancer. 2011;129(12):2807-2815. doi:https://doi.org/10.1002/ijc.25963
Spannuth WA, Nick AM, Jennings NB, et al. Functional Significance of VEGFR-2 on Ovarian Cancer Cells. International journal of cancer Journal international du cancer. 2009;124(5):1045-1053. doi:https://doi.org/10.1002/ijc.24028
Capp C, Wajner SM, Siqueira DR, Brasil BA, Meurer L, Maia AL. Increased Expression of Vascular Endothelial Growth Factor and Its Receptors, VEGFR-1 and VEGFR-2, in Medullary Thyroid Carcinoma. Thyroid. 2010;20(8):863-871. doi:https://doi.org/10.1089/thy.2009.0417
Padró T, Bieker R, Ruiz S, et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia. 2002;16(7):1302-1310. doi:https://doi.org/10.1038/sj.leu.2402534
Cenciarelli C, Marei HE, Felsani A, et al. PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals. Oncotarget. 2016;7(33):53047-53063. doi:https://doi.org/10.18632/oncotarget.10132
Cavalcanti E, Ignazzi A, Michele FD, Caruso ML. PDGFRα expression as a novel therapeutic marker in well-differentiated neuroendocrine tumors. Cancer Biology & Therapy. 2018;20(4):423-430. doi:https://doi.org/10.1080/15384047.2018.1529114
Burger RA. Overview of anti-angiogenic agents in development for ovarian cancer. Gynecologic Oncology. 2011;121(1):230-238. doi:https://doi.org/10.1016/j.ygyno.2010.11.035
Heindryckx F. Targeting the tumor stroma in hepatocellular carcinoma. World Journal of Hepatology. 2014;7(2):165. doi:https://doi.org/10.4254/wjh.v7.i2.165
HIF1A hypoxia inducible factor 1 subunit alpha [Homo sapiens (human)] - Gene - NCBI. Nih.gov. Published 2019. https://www.ncbi.nlm.nih.gov/gene/3091
Ellis LM. Epidermal growth factor receptor in tumor angiogenesis. Hematology-oncology Clinics of North America. 2004;18(5):1007-1021. doi:https://doi.org/10.1016/j.hoc.2004.06.002
Frantz C, Stewart KM, Weaver VM. The Extracellular Matrix at a Glance. Journal of Cell Science. 2010;123(24):4195-4200. doi:https://doi.org/10.1242/jcs.023820
Joao Incio, Ligibel JA, McManus D, et al. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci Transl Med. 2018;10(432). doi:https://doi.org/10.1126/scitranslmed.aag0945
Tanaka K. The proteasome: Overview of Structure and Functions. Proceedings of the Japan Academy, Series B. 2009;85(1):12-36. doi:https://doi.org/10.2183/pjab.85.12
Pezzella F. Pharmacogenetics implementation in the clinics: information and guidelines for germline variants. Cancer Drug Resistance. Published online 2019. doi:https://doi.org/10.20517/cdr.2019.39
Valyi-Nagy K, Kormos B, Ali M, Shukla D, Valyi-Nagy T. Stem cell marker CD271 is expressed by vasculogenic mimicry-forming uveal melanoma cells in three-dimensional cultures. Molecular vision. 2012;18:588-592. https://pubmed.ncbi.nlm.nih.gov/22419851/
Kuczynski EA, Yin M, Bar-Zion A, et al. Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma. Journal of the National Cancer Institute. 2016;108(8):djw030. doi:https://doi.org/10.1093/jnci/djw030
Rohwer N, Cramer T. Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways. Drug Resistance Updates. 2011;14(3):191-201. doi:https://doi.org/10.1016/j.drup.2011.03.001
Chantrain CF, Shimada H, Jodele S, et al. Stromal Matrix Metalloproteinase-9 Regulates the Vascular Architecture in Neuroblastoma by Promoting Pericyte Recruitment. Cancer Research. 2004;64(5):1675-1686. doi:https://doi.org/10.1158/0008-5472.can-03-0160
Itoh T. FTO. Cas.org. Published 2025. https://chemport-n.cas.org//chemport-n/?APP=ftslink&action=reflink&origin=npg&version=1.0&coi=1%3ACAS%3A528%3ADyaK1cXhsFersLo%3D&md5=85f031f2efaf463cdc99fb8d8a7217a6
Shaaban S, Alsulami M, Arbab SA, et al. Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma. International journal of cancer research. 2016;12(2):69-81. doi:https://doi.org/10.3923/ijcr.2016.69.81
Cleveland Clinic. What Are Cytokines? Types and Function. Cleveland Clinic. Published March 1, 2023. https://my.clevelandclinic.org/health/body/24585-cytokines
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nature Medicine. 2001;7(9):987-989. doi:https://doi.org/10.1038/nm0901-987
Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews. 2011;91(3):1071-1121. doi:https://doi.org/10.1152/physrev.00038.2010
de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. The Lancet Oncology. 2012;13(12):1225-1233. doi:https://doi.org/10.1016/S1470-2045(12)70509-0
Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. The New England Journal of Medicine. 2007;356(2):125-134. doi:https://doi.org/10.1056/NEJMoa060655
Kamal MA, Mandour YM, Mostafa, Stein U, H.M. El Tayebi. Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges. Molecules. 2022;27(17):5537-5537. doi:https://doi.org/10.3390/molecules27175537
Georganaki M, van Hooren L, Dimberg A. Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer. Frontiers in Immunology. 2018;9. doi:https://doi.org/10.3389/fimmu.2018.03081
Mokhtari RB, Homayouni TS, Baluch N, et al. Combination Therapy in Combating Cancer. Oncotarget. 2017;8(23). doi:https://doi.org/10.18632/oncotarget.16723
Cleveland Clinic. Embolization Procedure: Definition, Purpose & Types. Cleveland Clinic. Published July 14, 2022. https://my.clevelandclinic.org/health/treatments/23512-embolization-procedure
Zhou C, Shi Q, Liu J, Huang S, Yang C, Xiong B. Effect of Inhibiting Tumor Angiogenesis After Embolization in the Treatment of HCC with Apatinib-Loaded p(N-Isopropyl-Acrylamide-co-Butyl Methyl Acrylate) Temperature-Sensitive Nanogel. Journal of Hepatocellular Carcinoma. 2020;Volume 7:447-456. doi:https://doi.org/10.2147/jhc.s282209
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