Document Detail


Loss of fibroblast HIF-1α accelerates tumorigenesis.
MedLine Citation:
PMID:  22556263     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Jung-whan Kim; Colin Evans; Alexander Weidemann; Norihiko Takeda; Yun Sok Lee; Christian Stockmann; Cristina Branco-Price; Filip Brandberg; Gustavo Leone; Michael C Ostrowski; Randall S Johnson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-03
Journal Detail:
Title:  Cancer research     Volume:  72     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-10     Revised Date:  2014-08-10    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3187-95     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Transformation, Neoplastic
Fibroblasts / metabolism
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
Immunohistochemistry
Mammary Neoplasms, Experimental / genetics,  pathology*
Mice
Polymerase Chain Reaction
Promoter Regions, Genetic
Vascular Endothelial Growth Factor A / genetics
Grant Support
ID/Acronym/Agency:
092738//Wellcome Trust; 1F32CA157088-01/CA/NCI NIH HHS; CA082515/CA/NCI NIH HHS; CA118165/CA/NCI NIH HHS; F32 CA157088/CA/NCI NIH HHS; P01 CA097189/CA/NCI NIH HHS; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Vascular Endothelial Growth Factor A
Comments/Corrections

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