Targeting Angiogenesis and Growth Factor Pathways: Implications for Cancer Therapy and Tumor Microenvironment Regulation
Ibrahim D. Al deeb1*, Enas M. Daoud1
Journal of Angiotherapy 8(11) 1-8 https://doi.org/10.25163/angiotherapy.8115316
Submitted: 01 September 2024 Revised: 07 November 2024 Published: 09 November 2024
Abstract
Angiogenesis is a critical process in tumor development, involving the formation of new blood vessels from pre-existing ones. Tumor vasculature, unlike normal vasculature, exhibits structural abnormalities, including leaky and poorly organized vessels. These features create a hypoxic and acidic microenvironment, significantly impacting the efficacy of chemotherapeutic interventions and altering endothelial cell physiology. This review synthesizes recent findings on the roles of endothelial cells and tumor vasculature in angiogenesis. It highlights key mechanisms such as endothelial cell migration, proliferation, and the involvement of angiogenic regulators like vascular endothelial growth factor receptor-2 (VEGFR-2) and Delta-like ligand 4 (Dll4)/NOTCH signaling pathways. Endothelial cells play pivotal roles in vascular sprouting, tube formation, and stabilization during angiogenesis. Activation of VEGFR-2 by vascular endothelial growth factor (VEGF) determines endothelial cell fate, orchestrating tip and stalk cell differentiation through Dll4/NOTCH signaling. Additionally, tumor vasculature abnormalities, such as deficient pericyte coverage and elevated interstitial pressure, create challenges for effective drug delivery and promote tumor progression. Despite significant progress in understanding angiogenesis, several unanswered questions remain. Key challenges include identifying the most impactful angiogenic factors, understanding their regulatory mechanisms, and determining whether targeting tumor cells, stromal cells, or endothelial cells is most effective. The interplay between angiogenic factors suggests a complex network that requires further exploration to unravel tumor pathogenesis. Targeting angiogenesis holds promise as a therapeutic strategy. However, the current focus on VEGF pathways has limited the development of alternative anti-angiogenic agents. Future research should prioritize the discovery of novel angiogenic regulators and their interactions to expand therapeutic options.
Keywords: Angiogenesis, Tumor Vasculature, Endothelial Cells, Vegfr-2, Dll4/Notch Signaling, Hypoxic Microenvironment, Anti-Angiogenic Therapy
References
Abraham, J. A., Mergia, A., Whang, J. L., Tumolo, A., Friedman, J., Hjerrild, K. A., Gospodarowicz, D., & Fiddes, J. C. (1986). Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. Science, 233(4763), 545–548.
Adams, R. H., & Alitalo, K. (2007). Molecular regulation of angiogenesis and lymphangiogenesis. Nature Reviews Molecular Cell Biology, 8(6), 464.
Afonina, I. S., Zhong, Z., Karin, M., & Beyaert, R. (2017). Limiting inflammation—the negative regulation of NF-κB and the NLRP3 inflammasome. Nature Immunology, 18(8), 861.
Albini, A., Tosetti, F., Li, V. W., Noonan, D. M., & Li, W. W. (2012). Cancer prevention by targeting angiogenesis. Nature Reviews Clinical Oncology, 9(9), 498.
Andrae, J., Gallini, R., & Betsholtz, C. (2008). Role of platelet-derived growth factors in physiology and medicine. Genes & Development, 22(10), 1276–1312.
Augustin, H. G., Koh, G. Y., Thurston, G., & Alitalo, K. (2009). Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nature Reviews Molecular Cell Biology, 10(3), 165–177.
Bernabeu, C., Lopez-Novoa, J. M., & Quintanilla, M. (2009). The emerging role of TGF-β superfamily coreceptors in cancer. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1792(10), 954–973.
Bierie, B., & Moses, H. L. (2006). TGF-β and cancer. Cytokine & Growth Factor Reviews, 17(1–2), 29–40.
Blancher, C., Moore, J. W., Robertson, N., & Harris, A. L. (2001). Effects of Ras and von Hippel-Lindau gene mutations on hypoxia-inducible factor-1α, HIF-2α, and VEGF expression. Cancer Research, 61(19), 7349–7356.
Blobe, G. C., Schiemann, W. P., & Lodish, H. F. (2000). Role of transforming growth factor β in human disease. The New England Journal of Medicine, 342(18), 1350–1358.
Blood, C. H., & Zetter, B. R. (1990). Tumor interactions with the vasculature: Angiogenesis and tumor metastasis. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1032(1), 89–118.
Carmeliet, P. (2003). Angiogenesis in health and disease. Nature Medicine, 9(6), 653–660.
Carmeliet, P., & Jain, R. K. (2000). Angiogenesis in cancer and other diseases. Nature, 407(6801), 249.
Carmeliet, P., & Jain, R. K. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature, 473(7347), 298.
Charpentier, M. S., & Conlon, F. L. (2014). Cellular and molecular mechanisms underlying blood vessel lumen formation. BioEssays, 36(3), 251–259.
Colavitti, R., Pani, G., Bedogni, B., Anzevino, R., Borrello, S., Waltenberger, J., & Galeotti, T. (2002). Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. The Journal of Biological Chemistry, 277(3), 2075–2083.
Dabrow, M. B., Francesco, M. R., McBrearty, F. X., & Caradonna, S. (1998). The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. Gynecologic Oncology, 71(1), 29–37.
De Luca, A., Carotenuto, A., Rachiglio, A., Gallo, M., Maiello, M. R., Aldinucci, D., Pinto, A., & Normanno, N. (2008). The role of the EGFR signaling in tumor microenvironment. Journal of Cellular Physiology, 214(3), 559–567.
De Palma, M., Biziato, D., & Petrova, T. V. (2017). Microenvironmental regulation of tumour angiogenesis. Nature Reviews Cancer, 17(8), 457–474.
Doyle, S. L., Ozaki, E., Brennan, K., Humphries, M. M., Mulfaul, K., Keaney, J., Kenna, P. F., Maminishkis, A., Kiang, A.-S., & Saunders, S. P. (2014). IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration. Science Translational Medicine, 6(230), 230ra44–230ra44.
Dvorak, H. F., Brown, L. F., Detmar, M., & Dvorak, A. M. (1995). Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. The American Journal of Pathology, 146(5), 1029.
Eikesdal, H. P., Sugimoto, H., Birrane, G., Maeshima, Y., Cooke, V. G., Kieran, M., & Kalluri, R. (2008). Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity. Proceedings of the National Academy of Sciences, 105(39), 15040–15045.
Ferrara, N. (2010). Pathways mediating VEGF-independent tumor angiogenesis. Cytokine & Growth Factor Reviews, 21(1), 21–26.
Gavard, J., & Gutkind, J. S. (2006). VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin. Nature Cell Biology, 8(11), 1223.
Gazzaniga, P., Gandini, O., Gradilone, A., Silvestri, I., Giuliani, L., Magnanti, M., Gallucci, M., Saccani, G., Frati, L., & Agliano, A. M. (1999). Detection of basic fibroblast growth factor mRNA in urinary bladder cancer: Correlation with local relapses. International Journal of Oncology, 14(6), 1123–1130.
Gebala, V., Collins, R., Geudens, I., Phng, L.-K., & Gerhardt, H. (2016). Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo. Nature Cell Biology, 18(4), 443.
Gille, H., Kowalski, J., Li, B., et al. (2001). Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). Journal of Biological Chemistry, 276(5), 3222–3230.
Hanahan, D., & Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86(3), 353–364.
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674.
Hellwig-Bürgel, T., Rutkowski, K., Metzen, E., Fandrey, J., & Jelkmann, W. (1999). Interleukin-1β and tumor necrosis factor-α stimulate
Holash, J., Maisonpierre, P. C., Compton, D., et al. (1999). Vessel co-option, regression, and growth in tumors mediated by angiopoietins and VEGF. Science, 284(5422), 1994–1998.
Holmqvist, K., Cross, M. J., Rolny, C., et al. (2004). The adaptor protein Shb binds to tyrosine 1175 in VEGFR-2. Journal of Biological Chemistry, 279(21), 22267–22275.
Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H., Ramchandran, R., Torre, A., Maeshima, Y., Mier, J. W., Sukhatme, V. P., & Kalluri, R. (2000). Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth. The Journal of Biological Chemistry, 275(2), 1209–1217.
Korc, M., & Friesel, R. E. (2009). The role of fibroblast growth factors in tumor growth. Current Cancer Drug Targets, 9(5), 639–651.
Lindahl, P., Johansson, B. R., Levéen, P., & Betsholtz, C. (1997). Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science, 277(5323), 242–245.
Lindner, V., Majack, R. A., & Reidy, M. A. (1990). Basic fibroblast growth factor stimulates endothelial regrowth and proliferation in denuded arteries. The Journal of Clinical Investigation, 85(6), 2004–2008.
Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK–Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18(5), 516–523.
Oliner, J., Min, H., Leal, J., Yu, D., Rao, S., You, E., Tang, X., Kim, H., Meyer, S., & Han, S. J. (2004). Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell, 6(5), 507–515.
Petit, A. M., Rak, J., Hung, M.-C., et al. (1997). Neutralizing antibodies against EGF and ErbB-2/Neu receptor tyrosine kinases downregulate VEGF production. The American Journal of Pathology, 151(6), 1523.
Rafii, S., Lyden, D., Benezra, R., et al. (2002). Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy? Nature Reviews Cancer, 2(11), 826.
Rathinavelu, A., Alhazzani, K., Dhandayuthapani, S., & Kanagasabai, T. (2017). Anti-cancer effects of F16: A novel VEGFR-specific inhibitor. Tumor Biology. https://doi.org/10.1177/1010428317726841
Reinmuth, N., Liu, W., Jung, Y. D., et al. (2001). Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB Journal, 15(7), 1239–1241.
Ribatti, D., & Crivellato, E. (2012). “Sprouting angiogenesis”, a reappraisal. Developmental Biology, 372(2), 157–165.
Seppinen, L., Sormunen, R., Soini, Y., et al. (2008). Lack of collagen XVIII accelerates cutaneous wound healing. Matrix Biology, 27(6), 535–546.
Shibuya, M., & Claesson-Welsh, L. (2006). Signal transduction by VEGF receptors in regulation of angiogenesis. Experimental Cell Research, 312(5), 549–556.
Winkler, F., Kozin, S. V., Tong, R. T., Chae, S.-S., Booth, M. F., Garkavtsev, I., Xu, L., Hicklin, D. J., Fukumura, D., & di Tomaso, E. (2004). Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell, 6(6), 553–563.
Yarden, Y., & Sliwkowski, M. X. (2001). Untangling the ErbB signalling network. Nature Reviews Molecular Cell Biology, 2(2), 127–137.
View Dimensions
View Altmetric
Save
Citation
View
Share