The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy

Abstract

During tumor growth and angiogenesis there is a dynamic remodelling of tissue architecture often accompanied by the release of extracellular matrix constituents full of biological activity. One of the key constituents of the tumor microenvironment is the large heparan sulfate proteoglycan perlecan. This proteoglycan, strategically located at cell surfaces and within basement membranes, is a well-defined pro-angiogenic molecule when intact. However, when partially processed by proteases released during cancer remodelling and invasion, the C-terminal fragment of perlecan, known as endorepellin, has opposite effects than its parent molecule. Endorepellin is a potent inhibitor of angiogenesis by exerting a dual receptor antagonism by simultaneously engaging VEGFR2 and α2β1 integrin. Signaling through the α2β1 integrin leads to actin disassembly and block of endothelial cell migration, necessary for capillary morphogenesis. Signaling through the VEGFR2 induces dephosphorylation of the receptor via activation of SHP-1 and suppression of downstream proangiogenic effectors, especially attenuating VEGFA expression. A novel and emerging role of endorepellin is its ability to evoke autophagy by activating Peg3 and various canonical autophagic markers. This effect is specific for endothelial cells as these are the primary cells expressing both VEGFR2 and α2β1 integrin. Thus, an endogenous fragment of a ubiquitous proteoglycan can regulate both angiogenesis and autophagy through a dual receptor antagonism. The biological properties of this natural endogenous protein place endorepellin as a potential therapeutic agent against cancer or diseases where angiogenesis is prominent.

Decorin as a multivalent therapeutic agent against cancer

“…This new function integrates well with the traditional oncosuppressive properties of decorin exerted on RTKs. Thus, decorin and related SLRPs, including soluble ECM fragments derived from larger parental molecules [95,189], hold great therapeutic potential and clinical benefit for combating cancer.…”

A current view of perlecan in physiology and pathology: A mosaic of functions

“…Moreover, perlecan is involved in regulating solute transport and mechanosensing in the osteocyte lacunar-canalicular system [62], and its protein core can withstand over 100 pN of tension, suggesting that perlecan could act as an elastic tether in the lacunar-canalicular system [63]. Collectively, these properties culminate in a multifaceted biological agent that has been implicated in diseases such as osteoarthritis [64], atherosclerosis [65,66], muscle hypertrophy [67] cancer progression [22,24,27,68,69], aging [70], and pulmonary hypertension [71]…”

Extracellular Matrix, a Hard Player in Angiogenesis

“…Endorepellin is also able to directly interact with VEGFR2 at the EC surface inducing the transcriptional repression of HIF-1α and VEGF-A [153]. The binding of endorepellin with VEGFR2 is concurrent with its binding to α 2 β 1 integrin and the dual receptor antagonism concur in the inhibition of EC migration and blood vessel maturation [154,155]. More recently, it was also demonstrated that endorepellin evokes autophagy via VEGFR2 signaling contributing to the angiostatic function of the fragment [156,157].…”