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

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.

Raising the bar: how HIF-1 helps determine tumor radiosensitivity.

Through a poorly understood mechanism, tumors respond to radiation by secreting cytokines which inhibit endothelial cell apoptosis, thereby limiting treatment response by minimizing vessel damage. We have recently discovered that this pathway is governed by a major angiogenesis regulator, hypoxia-inducible factor-1 (HIF-1). We uncovered dual mechanisms initiated by radiation that both simultaneously lead to HIF-1 activation: (1) reoxygenation-induced stabilization of the HIF-1 dimer through free radical intermediates, and (2) reoxygenation-mediated depolymerization of hypoxia-induced translational suppressors known as stress granules. These findings have implications both for understanding the basic science of hypoxic signaling in tumors, and for discovering novel methods of enhancing conventional anti-tumor therapeutics in the clinic. In this article, we will highlight the apparent importance of free radical species in protecting tumor vasculature, stress granules in regulating hypoxic gene expression, and HIF-1 in regulating tumor sensitivity to ionizing radiation. The potential therapeutic utility of these findings will also be explored, with emphasis placed on putative targets in these pathways which may enhance tumor radiotherapy.