title: Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells.
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.
authors.affiliation: Vascular Program, Institute for Cell Engineering, McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Luana
authors.initials: L
authors.lastname: Schito
authors.forename: Sergio
authors.initials: S
authors.lastname: Rey
authors.forename: Marco
authors.initials: M
authors.lastname: Tafani
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.forename: Andrea
authors.initials: A
authors.lastname: Russo
authors.forename: Matteo A
authors.initials: MA
authors.lastname: Russo
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D001549:Benzamides; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004077:Digoxin / Q000494:pharmacology; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D007150:Immunohistochemistry; D008156:Luciferases; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000503:physiopathology*; D010879:Piperazines / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
chemical_list: D001549:Benzamides; D051793:Hypoxia-Inducible Factor 1; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D034741:RNA, Small Interfering; D004077:Digoxin; D000068877:Imatinib Mesylate; D008156:Luciferases