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 Powis; John Hazle; Juri Gelovani

doi:10.1158/1541-7786.MCR-10-0469

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 journal › Article › peer-review

24 Citations (Scopus)

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

Original language	English
Pages (from-to)	259-270
Number of pages	12
Journal	Molecular Cancer Research
Volume	9
Issue number	3
DOIs	https://doi.org/10.1158/1541-7786.MCR-10-0469
Publication status	Published - Mar 2011

Keywords

Inducible factor 1
Contrast enhanced sonography
Magnetic resonance
Cancer therapy
Dilated cardiomyopathy
Inhibitor PX-478
Gene expression
Hypoxia
HIF-1
Angiogenesis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1541-7786.MCR-10-0469

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Schwartz, D. L., Bankson, J., Bidaut, L., He, Y., Williams, R., Lemos, R., Thitai, A. K., Oh, J., Volgin, A., Soghomonyan, S., Yeh, H.-H., Nishii, R., Mukhopadhay, U., Alauddin, M., Mushkudiani, I., Kuno, N., Krishnan, S., Bornman, W., Lai, S. Y., ... Gelovani, J. (2011). HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance. Molecular Cancer Research, 9(3), 259-270. https://doi.org/10.1158/1541-7786.MCR-10-0469

@article{a06733710a4a46428a5e98a11ffea716,

title = "HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance",

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

keywords = "Inducible factor 1, Contrast enhanced sonography, Magnetic resonance, Cancer therapy, Dilated cardiomyopathy, Inhibitor PX-478, Gene expression, Hypoxia, HIF-1, Angiogenesis",

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

year = "2011",

month = mar,

doi = "10.1158/1541-7786.MCR-10-0469",

language = "English",

volume = "9",

pages = "259--270",

journal = "Molecular Cancer Research",

issn = "1541-7786",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

Schwartz, DL, Bankson, J, Bidaut, L, He, Y, Williams, R, Lemos, R, Thitai, AK, Oh, J, Volgin, A, Soghomonyan, S, Yeh, H-H, Nishii, R, Mukhopadhay, U, Alauddin, M, Mushkudiani, I, Kuno, N, Krishnan, S, Bornman, W, Lai, SY, Powis, G, Hazle, J & Gelovani, J 2011, 'HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance', Molecular Cancer Research, vol. 9, no. 3, pp. 259-270. https://doi.org/10.1158/1541-7786.MCR-10-0469

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 -

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

Abstract

Keywords

UN SDGs

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