Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors
Gabriele Bergers, Steven Song, Nicole Meyer-Morse, Emily Bergsland, Douglas Hanahan
Gabriele Bergers, Steven Song, Nicole Meyer-Morse, Emily Bergsland, Douglas Hanahan
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Article Oncology

Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors

Abstract

Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR+ pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor.

Authors

Gabriele Bergers, Steven Song, Nicole Meyer-Morse, Emily Bergsland, Douglas Hanahan

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Figure 3

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Identification of the cell types expressing PDGF ligands and receptors i...
Identification of the cell types expressing PDGF ligands and receptors in pancreatic islet carcinomas. (a) Primary tumors were fractioned into constituent cell types by flow cytometry. RNA was isolated from unsorted and sorted populations and analyzed by RT-PCR. Pancreatic tumors of end-stage Rip1Tag2 mice were excised and enzymatically dispersed with collagenase into single cells. The cell suspension was incubated with Ab’s for CD31 and Gr1 and Mac1. Endothelial cells were collected by FACS as a CD31+, Gr1–, Mac1– population, whereas tumor cells were gated by size and collected as unlabeled with these three Ab’s. Inflammatory cells were collected as Gr1+, Mac1+; these cells did not express PDGF ligands or receptors (not shown). (b) Tumor sections (prepared as in Figure 2) were costained with anti–PDGFR-β-FITC (1:200) and anti–CD31-rhodamine to reveal PDGFR-β-expressing cells in green and endothelial cells in red. (c) PDGFR-β+ cells from tumors were isolated by FACS (PDGFR-β Ab, 1:50), RNA isolated, and analyzed by RT-PCR for pericyte markers. ECs, endothelial cells; TCs, tumor cells; PCs, perivascular cells.