Such discrepancies between mouse and human provide the impetus for understanding the molecular and cellular resistance mechanisms of anti-angiogenic therapy. For example, Avastin only adds a 4–5 month survival benefit in patients with advanced colorectal cancer. However, despite the growing list of FDA approvals, anti-angiogenesis drugs have had a modest impact on patient survival.
Hundreds of clinical trials for multiple solid cancers targeting VEGF-A alone or in combination with other therapies have been initiated. There are over 20 drugs with anti-angiogenic activity approved by the FDA for cancer indications, with Avastin-humanized anti-VEGF-A monoclonal antibody-being the first granted approval in 2004. Many preclinical models using anti-angiogenesis therapies blocking VEGF-A signaling have broadly prohibited or slowed tumor growth and reduced metastatic spread. New blood vessels not only deliver nutrients and oxygen to growing tumors but also provide a route of cancer cell exit to distant organs. Through binding to VEGFR-2 vascular endothelial growth factor receptor-2 (VEGFR-2)/human kinase insert domain receptor, VEGF-A triggers activation of VEGFR-2 and intracellular signaling mediators that promote endothelial cell proliferation, migration, and survival, as well as vascular permeability and ultimately neovascularization. Vascular endothelial growth factor-A (VEGF-A) is the most comprehensively studied and perhaps potent mediator of sprouting angiogenesis. Recruitment of blood vessels is critical to support tumor growth past 1–2 mm in diameter.
Therapies designed to improve lymphatic vessel function while limiting metastasis may represent a viable approach to enhance immunotherapy and limit cancer progression.Īngiogenesis, the development of new blood vessels, is a feature of many solid cancers. Vessels that are abnormal or compromised by tumor cells can lead to immunosuppression. Recent studies have elucidated how these vasculatures often regulate immune responses. Blood and lymphatic vessels are more than just conduits for nutrient, fluid, and cancer cell transport. This review highlights several of the key resistance mechanisms to anti-angiogenic therapy and potential challenges facing anti-lymphangiogenic therapy. However, there are no FDA-approved drugs that target tumor lymphangiogenesis, despite the consequences of metastasis through the lymphatic system. Resistance to FDA-approved anti-angiogenic therapies designed to limit blood vessel growth has emerged as a significant clinical challenge. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point of cancer research for several decades. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Metastasis is the primary cause of cancer-related mortality.
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