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Autocrine Human Growth Hormone Promotes Tumor Angiogenesis in Mammary Carcinoma

Liggins Institute and National Research Centre for Growth and Development (S.E.B.-D., V.P., L.J.-P.V., P.E.L., J.K.P.) and Department of Molecular Medicine and Pathology (C.P., P.E.L.), Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand; and Centre National de la Recherche Scientifique (H.C.M., C.V., S.A.), Unite Mixte de Recherche 5123, Physiologie Moléculaire, Université Claude Bernard Lyon I, Université de Lyon, 69622 Villeurbanne, France

Address all correspondence and requests for reprints to: Jo K. Perry, Ph.D., The Liggins Institute, University of Auckland, 2-6 Park Avenue, Private Bag 92019 Auckland, New Zealand. Email: j.perry{at}auckland.ac.nz.

Accumulating literature implicates pathological angiogenesis and lymphangiogenesis as playing key roles in tumor progression. Autocrine human growth hormone (hGH) is a wild-type orthotopically expressed oncogene for the human mammary epithelial cell. Herein we demonstrate that autocrine hGH expression in the human mammary carcinoma cell line MCF-7 stimulated the survival, proliferation, migration, and invasion of a human microvascular endothelial cell line (HMEC-1). Autocrine/paracrine hGH secreted from mammary carcinoma cells also promoted HMEC-1 in vitro tube formation as a consequence of increased vascular endothelial growth factor-A (VEGF-A) expression. Semiquantitative RT-PCR analysis demonstrated that HMEC-1 cells express both hGH and the hGH receptor (hGHR). Functional antagonism of HMEC-1-derived hGH reduced HMEC-1 survival, proliferation, migration/invasion, and tube formation in vitro. Autocrine/paracrine hGH secreted by mammary carcinoma cells increased tumor blood and lymphatic microvessel density in a xenograft model of human mammary carcinoma. Autocrine hGH is therefore a potential master regulator of tumor neovascularization, coordinating two critical processes in mammary neoplastic progression, angiogenesis and lymphangiogenesis. Consideration of hGH antagonism to inhibit angiogenic processes in mammary carcinoma is therefore warranted.

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