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Targeting Tie2 to Increase Breast Cancer Responsiveness to Antiangiogenic Therapy

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Annual rept. 19 May 2004-18 May 2005

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Antiangiogenic therapy of cancers involves inhibiting tumor blood vessel development to deprive tumors of vital oxygen and nutrients. The potential benefits of antiangiogenic strategies have been dramatically shown in mouse tumor models. Results in human clinical trials, however, have been less striking. Recent trials have shown survival benefits, but tumor regression, which is often reported in murine tumors, is rarely seen in treated human cancers. A potential explanation for this disparity in treatment outcomes is that the vasculature of human tumors may be more resistant to antiangiogenic therapies. This may be due, at least in part, to extensive pericyte coverage of vessels in many common human cancers, such as breast cancers, compared to a relative paucity of pericytes surrounding vessels in commonly studied mouse tumors. Pericytes are periendothelialmesenchymal cells that surround capillaries, are thought to be a marker of vessel maturity and stability, and may confer resistance to certain antiangiogenic agents. Mouse mammary tumor virus MMTV-induced mammary carcinomas arising in C3HHeN mice may more faithfully model human breast cancer vasculature inasmuch as vessels in these tumors have extensive pericyte coverage like in human breast cancers. Interestingly, we found these tumors were resistant to rIL-12 antiangiogenic therapy, which was effective against every other mouse tumor model tested.

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  • Medicine and Medical Research

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