Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions

Author(s): Altaf A. Shah, Mohammad A. Kamal, Salman Akhtar*

Journal Name: Current Drug Metabolism

Volume 22 , Issue 1 , 2021


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Abstract:

Background: Angiogenesis, involving the formation of new blood vessels from preexisting vessels, caters an important biological phenomenon for the growth and development of bodily structures in the human body. Regulation of angiogenesis in non-pathological conditions takes place through a well-defined balanced angiogenic-switch, which upon exposure to various pathological conditions may get altered. This makes the cells change their normal behavior resulting in uncontrolled division and angiogenesis.

Methods: The current review tries to present a brief framework of angiogenesis and tumor progression phenomenon along with the latest therapeutic interventions against VEGFR-2 and its future directions.

Results: The tumor angiogenic pathways functioning in diverse mechanisms via sprouting angiogenesis, intussusceptive angiogenesis, vascular co-option, vascular mimicry, and glomeruloid angiogenesis are normally activated by varied angiogenic stimulators and their receptors are interrelated to give rise to specialized signaling pathways. Amongst these receptors, VEGFR-2 is found as one of the key, critical mediators in tumor angiogenesis and is seen as a major therapeutic target for combating angiogenesis. Though a number of anti-angiogenic drugs like Ramucirumab, Sunitinib, Axitinib, Sorafenib, etc. showing good survival rates have been developed and approved by FDA against VEGFR-2, but these have also been found to be associated with serious health effects and adverse reactions.

Conclusion: An improved or alternative treatment is needed shortly that has a higher survival rate with the least side effects. Innovative strategies, including personalized medicine, nano-medicine, and cancer immunotherapy have also been outlined as an alternative treatment with a discussion on advancements and improvements required for their implementation methods.

Keywords: Tumor angiogenesis, Receptor tyrosine kinases, VEGFR-2, Personalized medicine, Nano-medicine, Sprouting angiogenesis.

[1]
Gordon, M.S.; Mendelson, D.S.; Kato, G. Tumor angiogenesis and novel antiangiogenic strategies. Int. J. Cancer, 2010, 126(8), 1777-1787.
[http://dx.doi.org/10.1002/ijc.25026] [PMID: 19904748]
[2]
Nussenbaum, F.; Herman, I.M. Tumor angiogenesis: insights and innovations. J. Oncol., 2010, 2010132641
[http://dx.doi.org/10.1155/2010/132641] [PMID: 20445741]
[3]
Rosen, E.S. Now and Then. J. Cataract Refract. Surg., 2004, 30(10), 2023-2024.
[http://dx.doi.org/10.1016/j.jcrs.2004.08.018]
[4]
Petrovic, N. Targeting angiogenesis in cancer treatments: Where do we Stand? J. Pharm. Pharm. Sci., 2016, 19(2), 226-238.
[http://dx.doi.org/10.18433/J30033] [PMID: 27518172]
[5]
Beckner, M.E. Encyclopedia of Cancer. Springer: New York; , 2011.
[http://dx.doi.org/10.1007/978-3-642-16483-5]
[6]
Muz, B.; de la Puente, P.; Azab, F.; Azab, A.K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl.), 2015, 3, 83-92.
[http://dx.doi.org/10.2147/HP.S93413] [PMID: 27774485]
[7]
Priya, S. K.; Nagare, R. P.; Sneha, V. S.; Sidhanth, C.; Bindhya, S.; Manasa, P.; Ganesan, T. S. Tumour angiogenesis - origin of blood vessels. 2016, 735, 729-735.
[http://dx.doi.org/10.1002/ijc.30067]
[8]
Ronca, R.; Benkheil, M.; Mitola, S.; Struyf, S.; Liekens, S. Tumor angiogenesis revisited: regulators and clinical implications. Med. Res. Rev., 2017, 37(6), 1231-1274.
[http://dx.doi.org/10.1002/med.21452] [PMID: 28643862]
[9]
Kolte, D.; Mcclung, J.A.; Aronow, W.S. Vasculogenesis and Angiogenesis. Elsevier Inc.: Netherlands; , 2016.
[http://dx.doi.org/10.1016/B978-0-12-802385-3.00006-1]
[10]
Siemann, D. W. Tumor Microenvironment Wiley: Germany; , 2010.
[http://dx.doi.org/10.1002/9780470669891]
[11]
De Spiegelaere, W.; Casteleyn, C.; Van den Broeck, W.; Plendl, J.; Bahramsoltani, M.; Simoens, P.; Djonov, V.; Cornillie, P. Intussusceptive angiogenesis: a biologically relevant form of angiogenesis. J. Vasc. Res., 2012, 49(5), 390-404.
[http://dx.doi.org/10.1159/000338278] [PMID: 22739226]
[12]
Mentzer, S.J.; Konerding, M.A. Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis, 2014, 17(3), 499-509.
[http://dx.doi.org/10.1007/s10456-014-9428-3] [PMID: 24668225]
[13]
Karthik, S.; Djukic, T.; Kim, J.D.; Zuber, B.; Makanya, A.; Odriozola, A.; Hlushchuk, R.; Filipovic, N.; Jin, S.W.; Djonov, V. Synergistic interaction of sprouting and intussusceptive angiogenesis during zebrafish caudal vein plexus development. Sci. Rep., 2018, 8(1), 9840.
[http://dx.doi.org/10.1038/s41598-018-27791-6] [PMID: 29959335]
[14]
Bridgeman, V.L.; Vermeulen, P.B.; Foo, S.; Bilecz, A.; Daley, F.; Kostaras, E.; Nathan, M. R.; Wan, E.; Frentzas, S.; Hegedus, B. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J. Pathol., 2017, 41(3), 362-374.
[15]
Kuczynski, E.A.; Vermeulen, P.B.; Pezzella, F.; Kerbel, R.S.; Reynolds, A.R. Vessel co-option in cancer. Nat. Rev. Clin. Oncol., 2019, 16(8), 469-493.
[http://dx.doi.org/10.1038/s41571-019-0181-9] [PMID: 30816337]
[16]
Voutouri, C.; Kirkpatrick, N.D.; Chung, E.; Mpekris, F.; Baish, J.W.; Munn, L.L.; Fukumura, D.; Stylianopoulos, T.; Jain, R.K. Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies. Proc. Natl. Acad. Sci. USA, 2019, 116(7), 2662-2671.
[http://dx.doi.org/10.1073/pnas.1818322116] [PMID: 30700544]
[17]
Kuczynski, E.A.; Reynolds, A.R. Vessel Co-option and resistance to anti-angiogenic therapy. Angiogenesis, 2020, 23(1), 55-74.
[http://dx.doi.org/10.1007/s10456-019-09698-6] [PMID: 31865479]
[18]
Zhang, J.G.; Zhou, H.M.; Zhang, X.; Mu, W.; Hu, J.N.; Liu, G.L.; Li, Q. Hypoxic induction of vasculogenic mimicry in hepatocellular carcinoma: role of HIF-1 α, RhoA/ROCK and Rac1/PAK signaling. BMC Cancer, 2020, 20(1), 32.
[http://dx.doi.org/10.1186/s12885-019-6501-8] [PMID: 31931758]
[19]
Haiaty, S.; Rashidi, M.R.; Akbarzadeh, M.; Maroufi, N.F.; Yousefi, B.; Nouri, M. Targeting vasculogenic mimicry by phytochemicals: a potential opportunity for cancer therapy. IUBMB Life, 2019, 2020(November), 1-17.
[http://dx.doi.org/10.1002/iub.2233] [PMID: 32026601]
[20]
Kim, H.S.; Won, Y.J.; Shim, J.H.; Kim, H.J.; Kim, J.; Hong, H.N.; Kim, B.S. Morphological characteristics of vasculogenic mimicry and its correlation with EphA2 expression in gastric adenocarcinoma. Sci. Rep., 2019, 9(1), 3414.
[http://dx.doi.org/10.1038/s41598-019-40265-7] [PMID: 30833656]
[21]
Brat, D.J.; Van Meir, E.G. Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. Am. J. Pathol., 2001, 158(3), 789-796.
[http://dx.doi.org/10.1016/S0002-9440(10)64025-4] [PMID: 11238026]
[22]
Sundberg, C.; Nagy, J.A.; Brown, L.F.; Feng, D.; Eckelhoefer, I.A.; Manseau, E.J.; Dvorak, A.M.; Dvorak, H.F. Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery. Am. J. Pathol., 2001, 158(3), 1145-1160.
[http://dx.doi.org/10.1016/S0002-9440(10)64062-X] [PMID: 11238063]
[23]
Liang, W.; Ferrara, N. The complex role of neutrophils in tumor angiogenesis and metastasis. Cancer Immunol. Res., 2016, 4(2), 83-91.
[http://dx.doi.org/10.1158/2326-6066.CIR-15-0313] [PMID: 26839309]
[24]
Qin, L.X.; Tang, Z.Y. The prognostic molecular markers in hepatocellular carcinoma. World J. Gastroenterol., 2002, 8(3), 385-392.
[http://dx.doi.org/10.3748/wjg.v8.i3.385] [PMID: 12046056]
[25]
Buonaguro, L.; Tagliamonte, M.; Petrizzo, A.; Damiano, E.; Tornesello, M.L.; Buonaguro, F.M. Cellular prognostic markers in hepatocellular carcinoma. Future Oncol., 2015, 11(11), 1591-1598.
[http://dx.doi.org/10.2217/fon.15.39] [PMID: 26043213]
[26]
Chung, A.S.; Ferrara, N. Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol., 2011, 27, 563-584.
[http://dx.doi.org/10.1146/annurev-cellbio-092910-154002] [PMID: 21756109]
[27]
Holmes, D.I.R.; Zachary, I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol., 2005, 6(2), 209.
[http://dx.doi.org/10.1186/gb-2005-6-2-209] [PMID: 15693956]
[28]
Cébe Suarez, S.; Pieren, M.; Cariolato, L.; Arn, S.; Hoffmann, U.; Bogucki, A.; Manlius, C.; Wood, J.; Ballmer-Hofer, K. A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell. Mol. Life Sci., 2006, 63(17), 2067-2077.
[http://dx.doi.org/10.1007/s00018-006-6254-9] [PMID: 16909199]
[29]
George, M.L.; Tutton, M.G.; Janssen, F.; Arnaout, A.; Abulafi, A.M.; Eccles, S.A.; Swift, R.I. VEGF-A, VEGF-C, and VEGF-D in Colorectal Cancer Progression. Neoplasia, 2001, 3(5), 420-427.
[30]
Shibuya, M.; Claesson-Welsh, L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res., 2006, 312(5), 549-560.
[http://dx.doi.org/10.1016/j.yexcr.2005.11.012] [PMID: 16336962]
[31]
Cross, M.J.; Dixelius, J.; Matsumoto, T.; Claesson-Welsh, L. VEGF-receptor signal transduction. Trends Biochem. Sci., 2003, 28(9), 488-494.
[http://dx.doi.org/10.1016/S0968-0004(03)00193-2] [PMID: 13678960]
[32]
Shibuya, M. Vascular endothelial growth factor (VEGF) and its receptor (vegfr) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer, 2011, 2(12), 1097-1105.
[http://dx.doi.org/10.1177/1947601911423031] [PMID: 22866201]
[33]
Macedo, F.; Ladeira, K.; Longatto-Filho, A.; Martins, S.F. Gastric cancer and angiogenesis: Is VEGF a useful biomarker to assess progression and remission? J. Gastric Cancer, 2017, 17(1), 1-10.
[http://dx.doi.org/10.5230/jgc.2017.17.e1] [PMID: 28337358]
[34]
Yonemura, Y.; Endo, Y.; Tabata, K.; Kawamura, T.; Etsurou, H. Y. Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer. In: Int. J. Clin. Oncol; 318-327.
[http://dx.doi.org/10.1007/s10147-005-0508-7]
[35]
Morin, E.; Sjöberg, E.; Tjomsland, V.; Testini, C.; Lindskog, C.; Franklin, O.; Sund, M.; Öhlund, D.; Kiflemariam, S.; Sjöblom, T.; Claesson-Welsh, L. VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. J. Pathol., 2018, 246(3), 311-322.
[http://dx.doi.org/10.1002/path.5141] [PMID: 30027561]
[36]
Stuttfeld, E.; Ballmer-Hofer, K. Structure and function of VEGF receptors. IUBMB Life, 2009, 61(9), 915-922.
[http://dx.doi.org/10.1002/iub.234] [PMID: 19658168]
[37]
Robinson, D.R.; Wu, Y.M.; Lin, S.F. The protein tyrosine kinase family of the human genome. Oncogene, 2000, 19(49), 5548-5557.
[http://dx.doi.org/10.1038/sj.onc.1203957] [PMID: 11114734]
[38]
Sorrelle, N.; Brekken, R. KDR (kinase insert domain receptor)/vascular endothelial growth factor receptor 2 (VEGFR2). Atlas Genet. Cytogenet. Oncol. Haematol., 2018, 20(7), 392-402.
[http://dx.doi.org/10.4267/2042/66055]
[39]
Park, S.A.; Jeong, M.S.; Ha, K.T.; Jang, S.B. Structure and function of vascular endothelial growth factor and its receptor system. BMB Rep., 2018, 51(2), 73-78.
[http://dx.doi.org/10.5483/BMBRep.2018.51.2.233] [PMID: 29397867]
[40]
Holmes, K.; Roberts, O.L.; Thomas, A.M.; Cross, M.J. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell. Signal., 2007, 19(10), 2003-2012.
[http://dx.doi.org/10.1016/j.cellsig.2007.05.013] [PMID: 17658244]
[41]
Kowanetz, M.; Ferrara, N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin. Cancer Res., 2006, 12(17), 5018-5022.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1520] [PMID: 16951216]
[42]
Apte, R.S.; Chen, D.S.; Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6), 1248-1264.
[http://dx.doi.org/10.1016/j.cell.2019.01.021] [PMID: 30849371]
[43]
Napione, L.; Alvaro, M.; Alvaro, M.; Bussolino, F. VEGF-mediated signal transduction in tumor angiogenesis., In: Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy, IntechOpen: Croatia, 2017 10.5772/66764.
[44]
Cattaneo, F.; Castaldo, M.; Parisi, M.; Faraonio, R.; Esposito, G.; Ammendola, R. Formyl peptide receptor 1 modulates endothelial cell functions by NADPH Oxidase-dependent VEGFR2 transactivation. Oxid. Med. Cell. Longev., 2018, 2018, 2609847.
[http://dx.doi.org/10.1155/2018/2609847] [PMID: 29743977]
[45]
Abhinand, C.S.; Raju, R.; Soumya, S.J.; Arya, P.S.; Sudhakaran, P.R. VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J. Cell Commun. Signal., 2016, 10(4), 347-354.
[http://dx.doi.org/10.1007/s12079-016-0352-8] [PMID: 27619687]
[46]
Takahashi, T.; Yamaguchi, S.; Chida, K.; Shibuya, M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells. EMBO J., 2001, 20(11), 2768-2778.
[http://dx.doi.org/10.1093/emboj/20.11.2768] [PMID: 11387210]
[47]
Shibuya, M. VEGFR and type-V RTK activation and signaling. Cold Spring Harb. Perspect. Biol., 2013, 5(10)a009092
[http://dx.doi.org/10.1101/cshperspect.a009092] [PMID: 24086040]
[48]
Bazzazi, H.; Isenberg, J.S.; Popel, A.S. Inhibition of VEGFR2 activation and its downstream signaling to ERK1/2 and calcium by thrombospondin-1 (TSP1): in silico investigation. Front. Physiol., 2017, 8, 48.
[http://dx.doi.org/10.3389/fphys.2017.00048] [PMID: 28220078]
[49]
Fearnley, G.W.; Bruns, A.F.; Wheatcroft, S.B.; Ponnambalam, S. VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration. Biol. Open, 2015, 4(6), 731-742.
[http://dx.doi.org/10.1242/bio.201410884] [PMID: 25910937]
[50]
Crespo, S.; Kind, M.; Arcaro, A. The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis. J. Cancer Metastasis Treat., 2016, 2, 80-89.
[http://dx.doi.org/10.20517/2394-4722.2015.72]
[51]
Porta, C.; Paglino, C.; Mosca, A. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol., 2014, 4, 64.
[http://dx.doi.org/10.3389/fonc.2014.00064] [PMID: 24782981]
[52]
Ruggero, D.; Sonenberg, N. The Akt of translational control. Oncogene, 2005, 24(50), 7426-7434.
[http://dx.doi.org/10.1038/sj.onc.1209098] [PMID: 16288289]
[53]
Liu, H.; Zhang, L.; Zhang, X.; Cui, Z. PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy. OncoTargets Ther., 2017, 10, 2865-2871.
[http://dx.doi.org/10.2147/OTT.S95267] [PMID: 28652768]
[54]
Cells, R. Vojtechová, M.; Turecková, J.; Kucerová, D.; Sloncová, E.; Vachtenheim, J.; Tuhácková, Z. Regulation of mTORC1 signaling by Src kinase activity is Akt1-independent in RSV-transformed cells. Neoplasia, 2008, 10(2), 99-107.
[55]
Chamcheu, J.C.; Roy, T.; Uddin, M.B.; Banang-mbeumi, S.; Chamcheu, R. N.; Walker, A. L.; Liu, Y.; Huang, S. Role and therapeutic targeting of the PI3K/Akt/mTOR signaling pathway in skin cancer: a review of current status and future trends on natural and synthetic agents therapy. Cells, 2019, 8(8) , 803.
[56]
Fontanella, C.; Ongaro, E.; Bolzonello, S.; Guardascione, M.; Fasola, G.; Aprile, G. Clinical advances in the development of novel VEGFR2 inhibitors. Ann. Transl. Med., 2014, 2(12) , 123.
[57]
Ferrara, N.; Adamis, A.P. Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov., 2016, 15(6), 385-403.
[http://dx.doi.org/10.1038/nrd.2015.17] [PMID: 26775688]
[58]
Peng, F.W.; Liu, D.K.; Zhang, Q.W.; Xu, Y.G.; Shi, L. VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016). Expert Opin. Ther. Pat., 2017, 27(9), 287-1004.
[http://dx.doi.org/10.1080/13543776.2017.1344215]
[59]
Zhang, H.; Chen, J. Current status and future directions of cancer immunotherapy. J. Cancer, 2018, 9(10), 1773-1781.
[http://dx.doi.org/10.7150/jca.24577] [PMID: 29805703]
[60]
Yang, Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J. Clin. Invest., 2015, 125(9), 3335-3337.
[http://dx.doi.org/10.1172/JCI83871] [PMID: 26325031]
[61]
Barbee, M.S.; Ogunniyi, A.; Horvat, T.Z.; Dang, T.O. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann. Pharmacother., 2015, 49(8), 907-937.
[http://dx.doi.org/10.1177/1060028015586218] [PMID: 25991832]
[62]
Sambi, M.; Bagheri, L.; Szewczuk, M.R. Current challenges in cancer immunotherapy: multimodal approaches to improve efficacy and patient response rates. J. Oncol., 2019, 20194508794
[http://dx.doi.org/10.1155/2019/4508794] [PMID: 30941175]
[63]
Patel, M.; White, C.; Lowe, C.; Sherba, J.J. Cancer Treatment., 2019, 6, 79-100.
[http://dx.doi.org/10.1142/S2339547818300020.The]
[64]
Sultan, G. Zubair, S. Bioinformatics approaches for big data analytics in precision medicine: an overview. J. Anal. Comut., 2019, 10.
[65]
Mukherjee, S. Recent progress toward antiangiogenesis application of nanomedicine in cancer therapy. Future Sci OA., 2018, 4(7), 9. FSO318.
[http://dx.doi.org/10.4155/fsoa-2018-0051]
[66]
Darweesh, R.S.; Ayoub, N.M.; Nazzal, S. Gold nanoparticles and angiogenesis: molecular mechanisms and biomedical applications. Int. J. Nanomedicine, 2019, 14, 7643-7663.
[67]
Sadoughi, F. The potential role of chitosan-based nanoparticles as drug delivery systems in pancreatic cancer. IUBMB Life, 2020, 72(5), 872-883.
[68]
Kriegman, S.; Blackiston, D.; Levin, M.; Bongard, J. A scalable pipeline for designing reconfigurable organisms. Proc. Natl. Acad. Sci. USA, 2020, 117(4), 1853-1859.
[http://dx.doi.org/10.1073/pnas.1910837117] [PMID: 31932426]


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VOLUME: 22
ISSUE: 1
Year: 2021
Published on: 19 October, 2020
Page: [50 - 59]
Pages: 10
DOI: 10.2174/1389200221666201019143252
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