Loss of fibroblast HIF-1α accelerates tumorigenesis

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

44 Citations (Scopus)

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-1a 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.

Original languageEnglish
Pages (from-to)3187-3195
Number of pages9
JournalCancer Research
Volume72
Issue number13
DOIs
Publication statusPublished - 01 Jul 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kim, J. W., Evans, C., Weidemann, A., Takeda, N., Lee, Y. S., Stockmann, C., Branco-Price, C., Brandberg, F., Leone, G., Ostrowski, M. C., & Johnson, R. S. (2012). Loss of fibroblast HIF-1α accelerates tumorigenesis. Cancer Research, 72(13), 3187-3195. https://doi.org/10.1158/0008-5472.CAN-12-0534