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Angiogenesis is defined as the process by which new blood vessels form from pre-existing ones in response to a variety of mechanical, chemical, and inflammatory stimuli, thereby enhancing tumor survival and progression. Angiogenesis and lymph angiogenesis are required for tumor growth and metastasis. Angiogenesis plays a critical role in cancer progression, as tumor cells rely on neovascularization for oxygen and nutrients to survive. The formation of new blood vessels from pre-existing blood vessels, plays a key role in tumorigenesis. Benign tumors can exist in a state of dormancy, which can be driven by inadequate access to sufficient blood supply.
However, the "angiogenic switch" occurs when angiogenesis is activated in a dormant tumor and factors are secreted to induce sprouting and chemotaxis of ECs toward the tumor mass.
The dimeric protein complex of hypoxia inducible factor-1 (HIF-1) is stabilized and activates the expression of multiple genes involved in the angiogenic process within the hypoxic environment of the inner tumor mass. VEGF and basic fibroblast growth factor (bFGF) are two HIF-1-induced proteins that promote vascular permeability and endothelial cell growth, respectively. Other secreted factors, such as platelet-derived growth factor (PDGF), angiopoietin-1 (ANG-1), and angiopoietin-2 (ANG-2), promote chemotaxis, whereas ephrin signaling directs newly formed blood vessels by regulating motility and cell-cell adhesion. Other HIF-1-induced gene products include matrix metalloproteinases (MMPs), which degrade the ECM and release associated growth factors to facilitate EC migration. Certain integrins, including v3 on the surface of angiogenic ECs, aid sprouting ECs in adhering to the provisional ECM, migrating, and surviving. Factors secreted into the tumor's microenvironment activate tumor-associated macrophages (TAMs), which then produce angiogenic factors such as VEGF and MMPs, thereby promoting angiogenesis further. Pericytes serve as support cells, enveloping the basolateral surface of ECs and controlling vasoconstriction and dilation under normal physiological conditions. While newly formed vessels are typically devoid of pericytes, these are recruited by ECs to provide additional structural support, thereby enhancing tumor angiogenesis. For instance, PDGF secreted by ECs acts as a ligand for PDGF receptors on the pericyte membrane, causing pericytes to produce and secrete VEGF via the endothelial VEGF receptor.
Along with ECs and TAMs, angiogenesis is facilitated by a variety of other cell types found in the tumor microenvironment. Neutrophils, which account for a sizable proportion of the immune cell infiltrate, contribute to tumor angiogenesis via a variety of mechanisms.
This includes the release of MMPs into the tumor microenvironment, which stimulates the production of VEGF and other angiogenic factors. Similarly, other immune cell types (e.g., B cells and T cells) influence angiogenesis indirectly through their secretion of VEGF-A, bFGF, MMP9, interferon (IFN), and interleukin-17 (IL-17). Adipocytes secrete a profusion of cytokines, chemokines, and hormones (collectively referred to as adipokines), the majority of which are angiogenesis-promoting. By focusing on these cell populations, we may be able to develop novel therapies that inhibit tumor growth and pathogenesis.