Targeting Angiogenesis: New Horizons in Ocular Tumor Therapy

Authors

  • Prof Dr. Ammar A. Razzak Mahmood Dept of Pharmaceutical Chemistry, College of of Pharmacy-Bab- Al-mouadam, University of Baghdad, Baghdad
  • Dr. Anand Mohan Jha Post Graduate Department of Chemistry, M. L. S. M. College, Darbhanga (Lalit Narayan Mithila University, Darbhanga, Bihar)
  • Dr. John Abraham Assistant Professor, Department of Family Medicine, St. Johns National Academy of Health Sciences, Bangalore, India- 560034
  • Dr. Laishram Elizabeth Devi Assistant Professor, Department of Pharmacology, Shija Academy of Health Sciences, Langol, Imphal, Manipur

DOI:

https://doi.org/10.22376/ijtos.2025.3.1.13-20

Keywords:

Ocular Tumor, retinal cancer, Von-Hippel-Lindau, Vasculogenesis and Tumor Therapy

Abstract

Angiogenesis, the formation of new blood vessels within malignant tumors, is essential for cancer growth, sustenance, and metastasis. This complex process is regulated by a variety of molecular factors and pathways, as explored in a recent comprehensive review on angiogenesis. The review highlights the regulatory mechanisms that unlock therapeutic potential, focusing on hypoxia and its role in inducing vascular endothelial growth factor (VEGF) expression, a key driver of angiogenesis. It examines the interplay between angiopoietins, fibroblast growth factors (FGFs), and endogenous inhibitors of angiogenesis, as well as the role of transmembrane adhesion proteins, such as integrins, in mediating cellular responses critical to vascular development. The review also discusses the critical role of angiogenesis in tumor growth, emphasizing how the "angiogenic switch" enables tumors to acquire an aggressive phenotype. In this context, anti-angiogenic (AAG) therapies targeting these pathways are being investigated for various cancers, including ocular malignancies. Despite the widespread use of angiogenesis inhibitors in non-malignant ocular diseases, reports of their application in ocular tumors remain limited. Evidence supports the involvement of angiogenesis in the progression and metastasis of ocular malignancies, including retinoblastoma, ocular melanoma, and Von Hippel-Lindau (VHL) disease. Preliminary studies of AAG therapies for ocular tumors, such as ocular melanoma and VHL, show promising results. However, their efficacy needs to be confirmed through well-designed, controlled clinical trials. By providing a detailed overview of the molecular underpinnings of angiogenesis and its implications for tumor growth, this review underscores the potential of targeting angiogenic pathways as a therapeutic strategy for ocular tumors and other malignancies.

References

Eichmann A, Pardanaud L, Yuan L, Moyon D. Vasculogenesis and the search for the hemangioblast. Journal of hematotherapy & stem cell research. 2002 Apr 1;11(2):207-14.

Hendrikx G, Voo S, Bauwens M, Post MJ, Mottaghy FM. SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease. European Journal of Nuclear Medicine and Molecular Imaging. 2016 Dec;43:2433-47.

Kazerounian S, Lawler J. Integration of pro-and anti-angiogenic signals by endothelial cells. Journal of Cell Communication and Signaling. 2018 Mar;12:171-9.

Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. cell. 1996 Aug 9;86(3):353-64.

Josko J, Mazurek M. Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. Med Sci Monit. 2004 Apr 1;10(4):RA89-98.

Zafar MI, Zheng J, Kong W, Ye X, Gou L, Regmi A, Chen LL. The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence. Bioscience reports. 2017 Aug 31;37(4):BSR20171089.

Mahmudabadi AZ, Karimi MM, Bahabadi M, Hoseinabadi ZB, JafariSani M, Ahmadi R. Inhibition of AGS cancer cell proliferation following siRNA-mediated downregulation of VEGFR2. Cell Journal (Yakhteh). 2016;18(3):381.

Kliche S, Waltenberger J. VEGF receptor signaling and endothelial function. IUBMB life. 2001 Jul 1;52(1):61-6.

Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE. Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer research. 2013 Mar 15;73(6):1649-57.

Jamali N, Sorenson CM, Sheibani N. Vitamin D receptor expression is essential for the antiangiogenic activity of vitamin D. The FASEB Journal. 2016 Apr;30:1211-6.

Shojaei F. Anti-angiogenesis therapy in cancer: current challenges and future perspectives. Cancer letters. 2012 Jul 28;320(2):130-7.

Means JC, Passarelli AL. Viral fibroblast growth factor, matrix metalloproteases, and caspases are associated with enhancing systemic infection by baculoviruses. Proceedings of the National Academy of Sciences. 2010 May 25;107(21):9825-30.

Rössler J, Dietrich T, Pavlakovic H, Schweigerer L, Havers W, Schüler A, Bornfeld N, Schilling H. Higher vessel densities in retinoblastoma with local invasive growth and metastasis. The American journal of pathology. 2004 Feb 1;164(2):391-4.

Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. Journal of enzyme inhibition and medicinal chemistry. 2016 Nov 1;31(sup1):177-83.

Lalmanach G, Naudin C, Lecaille F, Fritz H. Kininogens: more than cysteine protease inhibitors and kinin precursors. Biochimie. 2010 Nov 1;92(11):1568-79.

Rusnati M, Presta M. Angiogenic growth factors interactome and drug discovery: The contribution of surface plasmon resonance. Cytokine & growth factor reviews. 2015 Jun 1;26(3):293-310.

Hindle LN. Investigating the effect of the KSHV vIRF2 and vIRF4 proteins on the interferon response (Doctoral dissertation, University of Birmingham).

Shibuya M. Vascular endothelial growth factor-dependent and-independent regulation of angiogenesis. BMB reports. 2008;41(4):278-86.

Retter AS, Figg WD, Dahut WL. The combination of antiangiogenic and cytotoxic agents in the treatment of prostate cancer. Clinical prostate cancer. 2003 Dec 1;2(3):153-9.

Mohamed MO, Adam EA, Abdlla BM, Abdelghani S, Bashier L. Vascular Endothelial Growth Factor (VEGF) as biological markers expressed in ovarian cancer using the immuno-histochemical technique. J Med Sci. 2021;25(112):1311-137.

Selvakumaran M, Amaravadi RK, Vasilevskaya IA, O'Dwyer PJ. Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clinical cancer research. 2013 Jun 1;19(11):2995-3007.

Gourley M, Williamson JS. Angiogenesis new targets for the development of anticancer chemotherapies. Current pharmaceutical design. 2000 Mar 1;6(4):417-39.

Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer—alterations to anti-VEGF pathway. International journal of molecular sciences. 2018 Apr 18;19(4):1232.

Spoerri PE, Afzal A, Li Calzi S, Shaw LC, Cai J, Pan H, Boulton M, Grant MB. Effects of VEGFR-1, VEGFR-2, and IGF-IR hammerhead ribozymes on glucose-mediated tight junction expression in cultured human retinal endothelial cells. Mol Vis. 2006 Jan 12;12(12):32-42.

Mauriz JL, González-Gallego J. Antiangiogenic drugs: current knowledge and new approaches to cancer therapy. Journal of pharmaceutical sciences. 2008 Oct 1;97(10):4129-54.

Handsley MM, Edwards DR. Metalloproteinases and their inhibitors in tumor angiogenesis. International Journal of Cancer. 2005 Jul 20;115(6):849-60.

Sund M, Nyberg P, Eikesdal HP. Endogenous matrix-derived inhibitors of angiogenesis. Pharmaceuticals. 2010 Sep 28;3(10):3021-39.

Majeski HE, Yang J. The 2016 John J. Abel award lecture: targeting the mechanical microenvironment in cancer. Molecular Pharmacology. 2016 Dec 1;90(6):744-54.

Wang N, Xu P, Liu Y, Zhao P, Ruan J, Zheng Y, Jin J, Wang S, Yao J, Xiang D, Zhang D. Efficacy and safety of thalidomide for chemotherapy-induced nausea and vomiting. Journal of Cancer. 2020;11(15):4560.

Prasad G, Wang H, Hill DL, Zhang R. Recent advances in experimental molecular therapeutics for malignant gliomas. Current Medicinal Chemistry-Anti-Cancer Agents. 2004 Jul 1;4(4):347-61.

Riccardi C, Napolitano E, Platella C, Musumeci D, Melone MA, Montesarchio D. Anti‐VEGF DNA‐based aptamers in cancer therapeutics and diagnostics. Medicinal Research Reviews. 2021 Jan;41(1):464-506.

Tapper D, Langer R, Bellows AR, Folkman J. Angiogenesis capacity as a diagnostic marker for human eye tumors. Surgery. 1979 Jul 1;86(1):36-40.

Boyd SR, Tan D, Bunce C, Gittos A, Neale MH, Hungerford JL, Charnock-Jones S, Cree IA. Vascular endothelial growth factor is elevated in ocular fluids of eyes harbouring uveal melanoma: identification of a potential therapeutic window. British Journal of Ophthalmology. 2002 Apr 1;86(4):448-52.

Soni S, Lee DS, DiVito Jr J, Bui AH, DeRaffele G, Radel E, Kaufman HL. Treatment of pediatric ocular melanoma with high-dose interleukin-2 and thalidomide. Journal of pediatric hematology/oncology. 2002 Aug 1;24(6):488-91.

Bielenberg DR, Zetter BR. The contribution of angiogenesis to the process of metastasis. The Cancer Journal. 2015 Jul 1;21(4):267-73.

Tapper D, Langer R, Bellows AR, Folkman J. Angiogenesis capacity as a diagnostic marker for human eye tumors. Surgery. 1979 Jul 1;86(1):36-40.

Pina Y, Boutrid H, Schefler A, Dubovy S, Feuer W, Jockovich ME, Murray TG. Blood vessel maturation in retinoblastoma tumors: spatial distribution of neovessels and mature vessels and its impact on ocular treatment. Investigative ophthalmology & visual science. 2009 Mar 1;50(3):1020-4.

Aldughayfiq B, Ashfaq F, Jhanjhi NZ, Humayun M. Explainable AI for retinoblastoma diagnosis: interpreting deep learning models with LIME and SHAP. Diagnostics. 2023 Jun 1;13(11):1932.

Lokken DM, Kumar A, Strugnell SA, Darjatmoko SR, Albert JM, Lindstrom MJ, Patel S. Effectiveness of vitamin d analogues in treating large tumors and duringprolonged use in murine retinoblastoma models. Archives of ophthalmology. 2004 Sep 1;122(9):1357-62.

Kaelin WG. Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer. The Journal of Clinical Investigation. 2022 Sep 15;132(18).

Reynolds SA, Shechtman D, Falco L. Complex juxtapapillary capillary hemangioma: a case report. Optometry-Journal of the American Optometric Association. 2008 Sep 1;79(9):512-7.

Bamps S, Van Calenbergh F, De Vleeschouwer S, Van Loon J, Sciot R, Legius E, Goffin J. What the neurosurgeon should know about hemangioblastoma, both sporadic and in Von Hippel-Lindau disease: A literature review. Surgical neurology international. 2013;4.

Offodile R, Walton T, Lee M, Stiles A, Nguyen M. Regression of metastatic breast cancer in a patient treated with the anti-angiogenic drug TNP-470. Tumori Journal. 1999 Jan;85(1):51-3.

Published

06-01-2025

How to Cite

A. Razzak Mahmood, P. D. A., D. A. Mohan Jha, D. J. Abraham, and D. L. Elizabeth Devi. “Targeting Angiogenesis: New Horizons in Ocular Tumor Therapy”. International Journal of Trends in OncoScience, vol. 3, no. 1, Jan. 2025, pp. 13-20, doi:10.22376/ijtos.2025.3.1.13-20.

Issue

Section

Review Articles