Dual Targeting of Endothelial Cells and Pericytes in Antivascular Therapy for Ovarian Carcinoma

Abstract

Purpose: Pericytes are known to provide a survival advantage for endothelial cells.We hypothesize that strategies aimed at dual targeting of tumor-associated endothelial cells and pericytes will be highly efficacious. Experimental Design: Paclitaxel-sensitive (HeyA8 and SKOV3ip1) or paclitaxel-resistant (HeyA8-MDR) orthotopic tumors in mice were examined for therapeutic efficacy by targeting the endothelial cells (using a vascular endothelial growth factor receptor inhibitor, AEE788) and pericytes (using STI571) alone or in combination. Additional therapy and survival studies in combination with paclitaxel were also done. Following therapy, tumors were examined for endothelial cell apoptosis, pericyte coverage, microvessel density, and proliferation. Results: AEE788 inhibited tumor growth by 45% and 59% in the HeyA8 and SKOV3ip1models, respectively, whereas STI571 alone was not effective. AEE788 plus STI571 resulted in 69% to 84% inhibition of tumor growth in both models. Moreover, combination of these agents with paclitaxel was even more effective, resulting in up to 98% inhibition of tumor growth. The triple combination was even effective in the HeyA8-MDR model. Remarkably, this triple combination also resulted in improved survival compared with all other groups (P < 0.001) and caused regression of formed tumors. Pericyte coverage was significantly decreased in the STI571 treatment groups, and microvessel density was significantly reduced in the AEE788 treatment groups. AEE788 induced endothelial cell apoptosis, which was further enhanced by the addition of STI571. Conclusions: Strategies targeting both endothelial cells and pericytes are highly effective for in vivo treatment of ovarian carcinoma. This antiangiogenic effect may be partially due to decreased pericyte coverage, thus increasing the sensitivity of tumor vasculature to therapy. These encouraging data support the development of clinical trials based on this strategy.

Impact of vessel maturation on antiangiogenic therapy in ovarian cancer

“…For bioluminescence imaging, luciferase transfected HeyA8 (HeyA8-Luc) cells were used and the animals were imaged longitudinally, as described previously. 21 For the intraperitoneal metastasis model, mice (n = 10 per group) were injected i.p. with HeyA8 cells (2.5 × 10 5 ) and 7 d later, randomized into 4 groups: 1) control (hFc 25 mg/kg, 2 times/ week), 2) VEGF-Trap (12.5 mg/kg i.p., 2 times/week), 3) PDGF-Trap (12.5 mg/kg i.p., 2 times/ week), 4) VEGF-Trap plus PDGF-Trap (same dosing as above).…”

“…21 To examine potential mechanisms underlying this observation, HUVECs were exposed to conditioned media from pericyte-like cells (basal PCM), PDGF-BB or both. No protective effects against endothelial cell apoptosis were noted ( Figure 4A).…”

“…21 In combination with paclitaxel, the triple-drug combination was highly effective in chemotherapy-sensitive and resistant tumors. As was observed in the current study, interruption of the PDGF receptor/ligand axis reduced pericyte coverage and blockade of VEGF receptor phosphorylation induced endothelial cell apoptosis.…”

“…Interestingly, the remaining vasculature appears to have greater pericyte coverage, suggesting that this cell type may limit the efficacy of some antiangiogenic therapies. 20,21 Pericyte homeostasis is regulated to a large extent by the platelet-derived growth factor (PDGF) ligand/receptor system. 22-24 PDGF is composed of four polypeptide chains that form homodimers PDGF-AA, BB, CC, and DD as well as the heterodimer PDGF-AB.…”

The use of the orthotopic model to validate antivascular therapies for cancer

“…A dual vascular targeting efficacy was evaluated in orthotopicallyimplanted tumour animal models by targeting both the endothelial cells (using a vascular endothelial growth factor receptor inhibitor, AEE788) and the pericytes (using STI571) (Lu, 2007). The combination therapy showed a significantly decrease in pericyte coverage with reduction of microvessel density and an enhanced endothelial cell apoptosis.…”