A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Abstract

IntroductionAngiogenesis is a complex process that leads to the formation of new blood vessels from existing ones. During embryogenesis, angiogenesis complements vasculogenesis, the production of new blood vessels from hematopoietic precursors. In the adult organism, angiogenesis takes place under normal conditions during the female reproductive cycle or under pathologic conditions, such as in tumor growth and wound healing. Secretion of angiogenic factors from the tumor mass induces the formation of blood vessels, which feed cancer cells with oxygen and nutrients. These vessels will eventually be used as a route for the spreading of metastases. 1 Several angiogenic factors have been described, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-␣ (TGF-␣), TGF-␤, hepatocyte growth factor (HGF), tumor necrosis factor, angiogenin, interleukin-8, and the angiopoietins. 2 The most prominent angiogenic factor is VEGF-A, a member of the VEGF family of growth factors also including placental growth factor and VEGF-B, -C, -D, and -E. 3 VEGFs bind to 3 related members of the VEGFR family, VEGFR-1, -2, and -3. The importance of VEGFs and their receptors is demonstrated by the phenotypes of the respective knockout mice. Indeed, Vegf-A and Vegfr-2 knockout mice show a failure in vasculature formation and die during embryogenesis, whereas Vegfr-1-deficient mice die of an overgrowth of blood vessels. 3 Fighting angiogenesis has become an attractive aim of cancer therapy. Indeed, targeting angiogenesis rather than directly addressing the tumor cells has the advantage that the same reagents can be applied to many different types of tumors. In addition, because of the low turnover rate of endothelial cells (ECs), they are less susceptible to become resistant to chemotherapy. 4 Several anti-VEGF treatment regimens already exist that can be combined with chemotherapy or radiotherapy. These treatments make use of VEGF inhibitors, such as antibodies against VEGF (bevacizumab), several small molecules inhibiting VEGFR-2 signaling, as well as soluble VEGF receptors that compete with the endogenous receptor for binding to VEGF. 5 However, because all these treatments have a relatively modest benefit for most cancer patients, there is still plenty of room for improvement.HGF is another potent angiogenic factor: the expression of HGF and its receptor c-Met correlates with tumor vascularization, 6 the production of VEGF in a variety of cells and tissues is induced by HGF, 7 and HGF can potentiate the activity of VEGF. [8][9][10] Furthermore, HGF leads to mobilization of endothelial progenitor cells, 11 and the expression of a soluble c-Met receptor (decoy Met) impairs tumor angiogenesis. 12 We have previously shown that HGF depends on a CD44 exon v6 containing isoform for the activation of c-Met on epithelial cells. 13 CD44 isoforms containing the variant exon v6 have been shown to be metastatic determinants. 14 The role of CD44v6 in metastasis results most probably from its coop...

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

“…10 -13 The CD44 -HA complex initiates a series of intracellular signaling events that lead to migration, adhesion, invasion, proliferation, and differentiation of a variety of cells. The transduction of HA/CD44 signaling can occur through various mechanisms including the following: i) HA binding to CD44 can initiate the extracellular clustering of CD44, resulting in the activation of downstream kinases, 14 ii) CD44 can serve as a co-receptor physically associated with other cell signaling receptors, [15][16][17][18] iii) CD44 can serve as a docking protein for pericellular or cytoplasmic proteins, 19,20 and iv) the transmembrane domain of CD44 can be cleaved, allowing the translocation of the cytoplasmic domain to the nucleus, where it functions as a transcription factor regulating the expression of target genes such as CD44 itself. 21,22 CD44 and its variants can induce chemoresistance and invasion of human BC cell lines via different mechanisms.…”

Cluster of Differentiation 44 (CD44) Gene Variants: A Putative Cancer Stem Cell Marker in Risk Prediction of Bladder Cancer in North Indian Population

“…proliferation, motility, invasion and survival [17]. Variety of function of CD44 depends upon binding of ligand-hyaluronic acid [18].…”

Neutrophil-Epithelial Interactions

“…Antibody-mediated ligation of sLe a on CD44v6 appears to prevent this cleavage event and triggers retention of neutrophils on the apical epithelial surface. 46,47 Because cleavage of CD44 is associated with downstream signaling events, 85 it is tempting to speculate that neutrophil-mediated cleavage of CD44v6 plays a role in signaling between the epithelium and post migrated neutrophils. In an analogous manner, other apical ligands for neutrophils have been described in epithelial cells under conditions of inflammation.…”