Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells
- 10 September 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (40), E2707-E2716
- https://doi.org/10.1073/pnas.1214019109
Abstract
Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.Keywords
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