The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine-and proline-rich (His/Pro-rich) domain.

Histidine-rich glycoprotein (HRGP) is an abundant heparinbinding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/ proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate A-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving A v B 3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility. (Cancer Res 2006; 66(4): 2089-97)

Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor b-positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth factors contained in platelet granules. Here, we show that tumor vascular function, as well as pericyte coverage is significantly impaired in mice with conditional knockout of PDGFB in platelets. A lack of PDGFB in platelets led to enhanced hypoxia and epithelial-to-mesenchymal transition in the primary tumors, elevated levels of circulating tumor cells, and increased spontaneous metastasis to the liver or lungs in two mouse models. These findings establish a previously unknown role for plateletderived PDGFB, whereby it promotes and maintains vascular integrity in the tumor microenvironment by contributing to the recruitment of pericytes.Significance: Conditional knockout of PDGFB in platelets demonstrates its previously unknown role in the maintenance of tumor vascular integrity and host protection against metastasis.