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Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors
Gabriele Bergers, … , Emily Bergsland, Douglas Hanahan
Gabriele Bergers, … , Emily Bergsland, Douglas Hanahan
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1287-1295. https://doi.org/10.1172/JCI17929.
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Article Oncology

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

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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 2

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Comparison of vascular morphology (left panels) and association of endot...
Comparison of vascular morphology (left panels) and association of endothelial cells and perivascular cells (right panels) in treated versus control tumors. Tumor-bearing pancreata were taken from end-stage 13.5-week-old control Rip1Tag2 mice and from 16-week-old Rip1Tag2 mice treated with SU5416 or SU6668 (Regression Trial). To visualize the functional blood vessels in tumors, mice were first anesthetized and injected intravenously with 0.05 mg FITC-labeled tomato lectin (Lycopersicon esculentum) and then heart perfused with 4% PFA. Pancreata were frozen in OCT medium and sectioned at 50 μm. To visualize endothelial cells (green in right panels) and pericytes (red in right panels) by immunohistochemical analysis, mice were anesthetized, heart perfused with PFA, and pancreata collected, frozen in OCT medium, and 15-μm sections prepared. Endothelial cells were detected with FITC-labeled lectin; pericytes were identified with CY3-labeled anti-desmin (1:3,000), a marker of mature pericytes.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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