Sequential Loss of Tumor Vessel Pericytes and Endothelial Cells after Inhibition of Platelet-Derived Growth Factor B by Selective Aptamer AX102

Abstract

Inhibition of platelet derived growth factor (PDGF) can increase the efficacy of other cancer therapeutics, but the cellular mechanism is incompletely understood. We examined the cellular effects on tumor vasculature of a novel DNA oligonucleotide aptamer (AX102) that selectively binds PDGF-B. Treatment with AX102 led to progressive reduction of pericytes, identified by PDGF receptor B, NG2, desmin, or A-smooth muscle actin immunoreactivity, in Lewis lung carcinomas. The decrease ranged from 35% at 2 days, 63% at 7 days, to 85% at 28 days. Most tumor vessels that lacked pericytes at 7 days subsequently regressed. Overall tumor vascularity decreased 79% over 28 days, without a corresponding decrease in tumor size. Regression of pericytes and endothelial cells led to empty basement membrane sleeves, which were visible at 7 days, but only 54% remained at 28 days. PDGF-B inhibition had a less pronounced effect on pancreatic islet tumors in RIP-Tag2 transgenic mice, where pericytes decreased 47%, vascularity decreased 38%, and basement membrane sleeves decreased 21% over 28 days. Taken together, these findings show that inhibition of PDGF-B signaling can lead to regression of tumor vessels, but the magnitude is tumor specific and does not necessarily retard tumor growth. Loss of pericytes in tumors is an expected direct consequence of PDGF-B blockade, but reduced tumor vascularity is likely to be secondary to pericyte regression. [Cancer Res 2007;67(15):7358-67]

Targeting Olfactomedin-like 3 Inhibits Tumor Growth by Impairing Angiogenesis and Pericyte Coverage

“…However, inhibition of platelet-derived growth factor receptor (PDGFR)b signaling, which is critical for pericyte recruitment, reduces pericyte coverage but has limited efficacy on endothelial cell regression (36,37). Inhibition of PDGFb signaling can indirectly reduce tumor vascularization but does not necessarily retard tumor growth (38). Several studies have shown that the dual targeting of endothelial cells and pericytes is more efficient than targeting either cell type alone, even in established or drug-resistant tumors (39)(40)(41).…”

Increased Vascular Delivery and Efficacy of Chemotherapy after Inhibition of Platelet-Derived Growth Factor-B

“…6 RIP-Tag2 mice in a C57BL/6 background were treated beginning at 12 weeks of age. AX102 or vehicle (0.9% NaCl) was injected at a dose of 50 mg/kg i.p.…”

“…6,[17][18][19] Tumor vessels that are stripped of pericytes are preferentially pruned and leave behind tumor vessels that have a more normalized phenotype that can support more rapid tumor growth despite the reduced vascularity. 6 PDGF-B inhibitors can increase the efficacy of low-dose metronomic chemotherapy, 20 but it is unclear whether the increased efficacy is a consequence of normalization of tumor vessels, increased tumor vessel efficacy, and improved drug delivery after PDGF-B inhibition. 6 The aim of the present study was to determine whether inhibition of PDGF-B can increase the efficiency of tumor blood vessels and improve the delivery and efficacy of the cytotoxic agent, cyclophosphamide (CTX), in tumors.…”

“…6 PDGF-B inhibitors can increase the efficacy of low-dose metronomic chemotherapy, 20 but it is unclear whether the increased efficacy is a consequence of normalization of tumor vessels, increased tumor vessel efficacy, and improved drug delivery after PDGF-B inhibition. 6 The aim of the present study was to determine whether inhibition of PDGF-B can increase the efficiency of tumor blood vessels and improve the delivery and efficacy of the cytotoxic agent, cyclophosphamide (CTX), in tumors. To address this, we examined the effects of selective sequestration of PDGF-B by a DNA oligonucleotide aptamer (AX102, Archemix Corporation) 6,17 or inhibition of PDGF receptor signaling by imatinib mesylate (Gleevec, Novartis) 21 on Lewis lung carcinoma (LLC) and on islet cell tumors in RIP-Tag2 transgenic mice.…”

“…6 The aim of the present study was to determine whether inhibition of PDGF-B can increase the efficiency of tumor blood vessels and improve the delivery and efficacy of the cytotoxic agent, cyclophosphamide (CTX), in tumors. To address this, we examined the effects of selective sequestration of PDGF-B by a DNA oligonucleotide aptamer (AX102, Archemix Corporation) 6,17 or inhibition of PDGF receptor signaling by imatinib mesylate (Gleevec, Novartis) 21 on Lewis lung carcinoma (LLC) and on islet cell tumors in RIP-Tag2 transgenic mice. Tumor vessel labeling by FITC-Lycopersicon esculentum lectin (FITC-LEA lectin), which was injected i.v.…”