title: Loss of fibroblast HIF-1α accelerates tumorigenesis.
abstract: Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jung-whan
authors.initials: JW
authors.lastname: Kim
authors.forename: Colin
authors.initials: C
authors.lastname: Evans
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Christian
authors.initials: C
authors.lastname: Stockmann
authors.forename: Cristina
authors.initials: C
authors.lastname: Branco-Price
authors.forename: Filip
authors.initials: F
authors.lastname: Brandberg
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ostrowski
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A