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

Schwartz, David L., Bankson, James and Bidaut, Luc (2011) HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance. Molecular Cancer Research, 9 (3). pp. 259-270. ISSN 1541-7786

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Item Type:Article
Item Status:Live Archive


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. ©2011 AACR.

Keywords:4 bis(2 chloroethyl)oxidoaminophenylalanine, 5 ethyl 2' fluorouracil arabinoside, 5 ethyl 2' fluorouracil arabinoside f 18, dxHRE tk eGFP cmvRed2XPRT protein, gene product, hypoxia inducible factor 1, radiopharmaceutical agent, short hairpin RNA, unclassified drug, angiogenesis, article, cancer radiotherapy, cancer resistance, cell hypoxia, cell maturation, computer assisted tomography, contrast enhancement, controlled study, gene construct, gene disruption, genetic transfection, glioma, human, human cell, human tissue, immunohistochemistry, irradiation, multimodality cancer therapy, nuclear magnetic resonance imaging, positron emission tomography, priority journal, radiation dose, radiosensitivity, reporter gene, spheroid cell, squamous cell carcinoma, treatment response, tumor growth, tumor microenvironment, tumor xenograft, upregulation, Adaptation, Physiological, Animals, Cell Line, Tumor, Cell Survival, Humans, Hypoxia-Inducible Factor 1, Ischemia, Mice, Mice, Nude, Neoplasms, Positron-Emission Tomography, Radiation Tolerance, Rats, Spheroids, Cellular, Transplantation, Heterologous, Tumor Burden, Vascular Endothelial Growth Factors, Mus
Subjects:F Physical Sciences > F350 Medical Physics
Divisions:College of Science > School of Computer Science
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ID Code:24129
Deposited On:28 Dec 2016 21:23

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