Soluble receptor-mediated selective inhibition of VEGFR and PDGFRβ signaling during physiologic and tumor angiogenesis

Abstract

The simultaneous targeting of both endothelial cells and pericytes via inhibition of VEGF receptor (VEGFR) and PDGF␤ receptor (PDGFR␤) signaling, respectively, has been proposed to enhance the efficacy of antiangiogenic tumor therapy. Clinical and preclinical modeling of combined VEGFR and PDGFR␤ signaling inhibition, however, has used small molecule kinase inhibitors with inherently broad substrate specificities, precluding detailed examination of this hypothesis. Here, adenoviral expression of a soluble VEGFR2/Flk1 ectodomain (Ad Flk1-Fc) in combination with a soluble ectodomain of PDGFR␤ (Ad sPDGFR␤) allowed highly selective inhibition of these pathways. The activity of Ad sPDGFR␤ was validated in vitro against PDGF-BB and in vivo with near-complete blockade of pericyte recruitment in the angiogenic corpus luteum, resulting in prominent hemorrhage, thus demonstrating an essential function for PDGF signaling during ovarian angiogenesis. Combination therapy with Ad PDGFR␤ and submaximal doses of Ad Flk1-Fc produced modest additive antitumor effects; however, no additivity was observed with maximal VEGF inhibition in numerous s.c. models. Notably, VEGF inhibition via Ad Flk1-Fc was sufficient to strongly suppress tumor endothelial and pericyte content as well as intratumoral PDGF-B mRNA, obscuring additive Ad sPDGFR␤ effects on pericytes or tumor volume. These studies using highly specific soluble receptors suggest that additivity between VEGFR and PDGFR␤ inhibition depends on the strength of VEGF blockade and appears minimal under conditions of maximal VEGF antagonism. combination therapy ͉ pericytes

FGF2 is crucial for the development of bovine luteal endothelial networks in vitro

“…Previous experiments to block luteal PDGFRB signalling using an adenoviral approach induced luteal pericyte deficiency, with a reduction in pericyte coverage of O90% (Kuhnert et al 2008). Interestingly, the inhibition of luteal pericyte recruitment was accompanied by a 45% reduction in microvessel endothelial cell density (Kuhnert et al 2008). The results of the current study suggest that pericyte activation through PDGFRB signalling is important in stimulating luteal angiogenesis, thus highlighting the considerable intercellular communication and interdependency that exits between endothelial cells and pericytes (Armulik et al 2005).…”

“…Their roles include providing a physical scaffold, guiding the proliferating tips of newly sprouting vessels, and communicating with and between endothelial cells (Bergers & Song 2005). Previous experiments to block luteal PDGFRB signalling using an adenoviral approach induced luteal pericyte deficiency, with a reduction in pericyte coverage of O90% (Kuhnert et al 2008). Interestingly, the inhibition of luteal pericyte recruitment was accompanied by a 45% reduction in microvessel endothelial cell density (Kuhnert et al 2008).…”

“…PDGFB is involved in attracting pericytes to new vessels during angiogenesis via activation of PDGFRB located on pericytes (Betsholtz 2004), and intraovarian PDGF-receptor blockade resulted in a reduction in the number of corpora lutea in the rat and mouse (Sleer & Taylor 2007b, Kuhnert et al 2008. Nevertheless, still very little is known about the role of PDGF in regulating luteal angiogenesis in general and there have been no studies in the cow.…”

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

“…This is in line with previous results from a Lewis lung carcinoma study, where Tie2-Fc alone did not have any effects on the recruitment of pericytes. 46 We achieved a significant antitumor effect in mice using sVEGFR-1, -3 and sTie2. Thus, inhibition of VEGF and angiopoietin pathways of angiogenesis seems to be more efficient than focusing on the single pathways.…”

Pericyte–fibroblast transition promotes tumor growth and metastasis

“…Paradoxically, inhibition of PDGF-BB-mediated pericyte association to tumor vessels has also been reported to be a valid target for cancer therapy, particularly when targeted in combination with other angiogenic factors (35,(37)(38)(39). For example, combining anti-VEGF and anti-PDGF drugs provides an additive therapeutic effect (40). One explanation of the combination approach is that anti-PDGF drugs increase exposure of vascular endothelial cells to anti-VEGF agents by ablating perivascular cells.…”