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

TY - JOUR

T1 - HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance

AU - Schwartz, David L.

AU - Bankson, James

AU - Bidaut, Luc

AU - He, Yi

AU - Williams, Ryan

AU - Lemos, Robert

AU - Thitai, Arun Kumar

AU - Oh, Junghwan

AU - Volgin, Andrei

AU - Soghomonyan, Suren

AU - Yeh, Hsin-Hsien

AU - Nishii, Ryuichi

AU - Mukhopadhay, Uday

AU - Alauddin, Mian

AU - Mushkudiani, Ioseb

AU - Kuno, Norihito

AU - Krishnan, Sunil

AU - Bornman, William

AU - Lai, Stephen Y.

AU - Powis, Garth

AU - Hazle, John

AU - Gelovani, Juri

PY - 2011/3

Y1 - 2011/3

N2 - 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. Mol Cancer Res; 9(3); 259-70. (C) 2011 AACR.

AB - 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. Mol Cancer Res; 9(3); 259-70. (C) 2011 AACR.

KW - Inducible factor 1

KW - Contrast enhanced sonography

KW - Magnetic resonance

KW - Cancer therapy

KW - Dilated cardiomyopathy

KW - Inhibitor PX-478

KW - Gene expression

KW - Hypoxia

KW - HIF-1

KW - Angiogenesis

U2 - 10.1158/1541-7786.MCR-10-0469

DO - 10.1158/1541-7786.MCR-10-0469

M3 - Article

SN - 1541-7786

VL - 9

SP - 259

EP - 270

JO - Molecular Cancer Research

JF - Molecular Cancer Research

IS - 3

ER -