Angiogenesis, 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. Within the hypoxic environment of the inner tumor mass, the dimeric protein complex of hypoxia inducible factor-1 (HIF-1) is stabilized and activates the expression of multiple genes contributing to the angiogenic process. HIF-1-induced proteins include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which promote vascular permeability and EC growth, respectively. Other secreted factors, such as platelet-derived growth factor (PDGF), angiopoietin-1 (ANG-1), and angiopoietin-2 (ANG-2), facilitate chemotaxis, while ephrin signaling guides newly formed blood vessels by controlling motility and cell-cell adhesion. Other HIF-1-induced gene products include matrix metalloproteinases (MMPs) that break down the ECM to facilitate EC migration and release associated growth factors. Certain integrins, such as αvβ3 found on the surface of angiogenic ECs, help the sprouting ECs adhere to the provisional ECM, migrate, and survive. Factors secreted into the microenvironment surrounding the tumor activate tumor-associated macrophages (TAMs), which subsequently produce angiogenic factors, such as VEGF and MMPs, further promoting angiogenesis. Pericytes function as support cells, enveloping the basolateral surface of ECs and regulating vasoconstriction and dilation under normal physiologic conditions. Newly formed vessels typically lack pericytes, but these are recruited by ECs to provide additional structural support that further augments angiogenesis of the tumor. For example, PDGF secreted by ECs acts as a ligand for PDGF receptors located on the pericyte membrane, causing pericytes to produce and secrete VEGF that signals through the endothelial VEGF receptor.
In addition to ECs and TAMs, numerous other cell types within the tumor microenvironment contribute to angiogenesis. Neutrophils, which comprise a substantial portion of the immune cell infiltrate, promote tumor angiogenesis through multiple mechanisms. This includes the release of MMPs in the tumor microenvironment, triggering the release of VEGF and other angiogenic factors. Similarly, other immune cell types (eg, B cells and T cells) indirectly influence angiogenesis via secretion of VEGF-A, bFGF, MMP9, interferon γ (IFNγ), and interleukin-17 (IL-17). Adipocytes release an abundance of cytokines, chemokines, and hormones (collectively called adipokines), many of which are pro-angiogenic. Targeting these cell populations may facilitate the deployment of novel therapies to restrict tumor expansion and cancer pathogenesis.
We would like to thank Diane Bielenberg, PhD, Harvard Medical School, Boston Children’s Hospital, Boston, MA for reviewing this diagram.
created April 2015
revised September 2018