HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance

David L. Schwartz, James Bankson, Luc Bidaut, Yi He, Ryan Williams, Robert Lemos, Arun Kumar Thitai, Junghwan Oh, Andrei Volgin, Suren Soghomonyan, Hsin Hsien Yeh, Ryuichi Nishii, Uday Mukhopadhay, Mian Alauddin, Ioseb Mushkudiani, Norihito Kuno, Sunil Krishnan, William Bornman, Stephen Y. Lai, Garth PowisJohn Hazle, Juri Gelovani

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Purpose: Hypoxia-inducible factor 1 (HIF-1) promotes cancer cell survival and tumor progression. The specific role played by HIF-1 and tumor - stromal interactions toward determining tumor resistance to radiation treatment remains undefined. We applied a multimodality preclinical imaging platform to mechanistically characterize tumor response to radiation, with a focus on HIF-1 - dependent resistance pathways. Methods: C6 glioma and HN5 human squamous carcinoma cells were stably transfected with a dual HIF-1 signaling reporter construct (dxHRE-tk/eGFP-cmvRed2XPRT). Reporter cells were serially interrogated in vitro before and after irradiation as monolayer and multicellular spheroid cultures and as subcutaneous xenografts in nu/nu mice. Results:In vitro, single-dose irradiation of C6 and HN5 reporter cells modestly impacted HIF-1 signaling in normoxic monolayers and inhibited HIF-1 signaling in maturing spheroids. In contrast, irradiation of C6 or HN5 reporter xenografts with 8 Gy in vivo elicited marked upregulation of HIF-1 signaling and downstream proangiogenic signaling at 48 hours which preceded recovery of tumor growth. In situ ultrasound imaging and dynamic contrast-enhanced (DCE) MRI indicated that HIF-1 signaling followed acute disruption of stromal vascular function. High-resolution positron emission tomography and dual-contrast DCE-MRI of immobilized dorsal skin window tumors confirmed postradiotherapy HIF-1 signaling to spatiotemporally coincide with impaired stromal vascular function. Targeted disruption of HIF-1 signaling established this pathway to be a determinant of tumor radioresistance. Conclusions: Our results illustrate that tumor radioresistance is mediated by a capacity to compensate for stromal vascular disruption through HIF-1 - dependent proangiogenic signaling and that clinically relevant vascular imaging techniques can spatially define mechanisms associated with tumor irradiation.

Original languageEnglish (US)
Pages (from-to)259-270
Number of pages12
JournalMolecular Cancer Research
Volume9
Issue number3
DOIs
Publication statusPublished - Mar 2011

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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