Impact of vessel maturation on antiangiogenic therapy in ovarian cancer

Abstract

Condensation-Pericytes contribute to endothelial survival in tumor vasculature and represent a potential therapeutic target.Objective-To examine the functional and therapeutic significance of pericytes in ovarian cancer vasculature.Study Design-Tumor vessel morphology and efficacy of endothelial and pericyte targeting were examined using in vivo ovarian cancer models. The expression of platelet derived growth factor (PDGF) ligands and receptors was examined in endothelial, pericyte-like, and ovarian cancer cells.Results-Relative to normal vessels, tumor vasculature was characterized by loosely attached pericytes in reduced density. PDGF-BB was expressed predominantly by the endothelial and cancer cells whereas PDGFRβ was present in pericyte-like cells. PDGF-BB significantly increased migration of and VEGF production by pericyte-like cells while PDGFRβ blockade abrogated these effects. Dual VEGF (VEGF-Trap) and PDGF-B (PDGF-Trap) targeted therapy was more effective in inhibiting in vivo tumor growth than either agent alone.Conclusions-Aberrations in the tumor microenvironment contribute to endothelial cell survival. Strategies targeting both endothelial cells and pericytes should be considered for clinical trials.

Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma

“…Similar normalized revascularization was observed in the H441 orthotopic model (Figures 7 and 8). Prior studies have indicated that pericyte coverage may exert a protective effect on tumor endothelium (66,67), potentially through the production of factors promoting endothelial survival and VEGF independence. Our findings were consistent with this hypothesis and revealed pericyte EGFR signaling to be a potential mediator of this effect.…”

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

“…The FGF family activates angiogenesis via interaction with FGF receptors 1 and 2 [33]. It is thought that signaling via these alternate pathways (PDGF, FGF) may mediate resistance to VEGF inhibition, supporting a multi-targeted approach [34][35][36][37][38]. In response to receptor-ligand binding, downstream signaling pathways, PI3K-Akt-mTOR and Ras-MEK-Erk, are activated and have been identified as potential targets for drug development [39,40].…”

Paraneoplastic Thrombocytosis in Ovarian Cancer

“…10B in the Supplementary Appendix). 18,23 Platelet depletion with the use of antiplatelet antibody, as compared with control IgG, resulted in an increase in tumorcell and endothelial-cell apoptosis by a factor of four and a factor of eight, respectively (P = 0.008 and P<0.001, respectively) ( Fig. 10C in the Supplementary Appendix).…”

“…16,17 Dual immunofluorescence staining for CD31 and desmin and for CD31 and terminal deoxynucleotidyl transferase dUTP biotin nick end labeling (TUNEL) was used to assess pericyte coverage and apoptotic tumor and endothelial cells, respectively. 18 The in vitro effects of gel-filtered platelets (see the Supplementary Appendix) on cell migration and proliferation in epithelial ovarian cancer were evaluated with the use of two-chamber chemotaxis and bromodeoxyuridine flow-cytometric assays (Click-iT EdU, Invitrogen), respectively. 19…”