HIF-1-Dependent Stromal Adaptation to Ischemia Mediates In Vivo Tumor Radiation Resistance

Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Molecular Cancer Research (Impact Factor: 4.38). 03/2011; 9(3):259-70. DOI: 10.1158/1541-7786.MCR-10-0469
Source: PubMed


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.
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.
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.
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.

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    • "On the one hand, upregulation of HIF-1 stimulates tumor cells to produce VEGF and other proangiogenic factors during radiotherapy, which protect the microvasculature from radiation-induced endothelial apoptosis. On the other hand, recent researches show that HIF-1 inhibition results in metabolic alterations that could enhance the therapeutic efficacy of radiotherapy [78, 79]. Based on the work by Yang et al., HIF-1 downregulation by siRNA enhances radiosensitivity in chemical hypoxic HCC cells in vitro suggesting that radiotherapy in combination with specific inhibition of HIF-1 would be expected to have a stronger anticancer effect on human hepatoma [80]. "
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