Angiogenesis Signaling Interactive Pathway
Angiogenesis, the formation of new blood vessels from pre-existing blood vessels, plays a key role in tumorigenesis. When a small dormant tumor initiates angiogenesis, referred to as the ‘angiogenic switch’, it secretes factors that induce sprouting and chemotaxis of endothelial cells (ECs) towards the tumor mass. Within the hypoxic environment of the inner tumor mass the transcription factor 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 PDGF, angiopoietin 1 and angiopoietin 2 facilitate chemotaxis, while ephrins guide newly formed blood vessels through maintenance of cell-cell separation. Other HIF-1 induced gene products include matrix metalloproteinases (MMPs) that breakdown the extracellular matrix to facilitate EC migration and release associated growth factors. Certain integrins such as V3 found on the surface of angiogenic ECs help the sprouting ECs adhere to the provisional Extracellular Matrix (ECM), migrate and survive. Factors secreted into the microenvironment surrounding the tumor activate tumor-associated macrophages (TAMs), that subsequently produce angiogenic factors, such as VEGF and MMPs, further promoting angiogenesis. Pericytes function as support cells enveloping the basolateral surface of ECs and regulate vasoconstriction and dilation under normal physiologic conditions. During the process of tumor angiogenesis sprouting vessels lack pericytes, which are later recruited by ECs to provide structural support that indirectly promotes tumor survival. For example, PDGF secreted by ECs acts as a ligand for PDGF receptor located on the pericyte membrane, causing pericytes to produce and secrete VEGF that signals through the endothelial VEGF receptor.
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We would like to thank Diane Bielenberg, Ph.D., Harvard Medical School, Boston Children’s Hospital, Boston, MA for reviewing this diagram.
created September 2008
revised August 2014