HIF-1–Dependent Stromal Adaptation to Ischemia Mediates In Vivo Tumor Radiation Resistance
David L. Schwartz,James A. Bankson,Luc Bidaut,Yi He,Ryan R. Williams,Robert Lemos,Arun Kumar Thitai,Junghwan Oh,Andrei Volgin,Suren Soghomonyan,Hsin Hsien Yeh,Ryuichi Nishii,Uday Mukhopadhay,Mian M. Alauddin,Ioseb Mushkudiani,Norihito Kuno,Sunil Krishnan,William G. Bornman,Stephen Y. Lai,Garth Powis,John D. Hazle,Juri G. Gelovani +21 more
TLDR
The 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.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. ©2011 AACR .read more
Citations
More filters
Journal ArticleDOI
Radiobiology for the Radiologist
TL;DR: This text is a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA.
Journal ArticleDOI
HIF Inhibitors: Status of Current Clinical Development
Jaleh Fallah,Brian I. Rini +1 more
TL;DR: Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies ofThe Hif inhibitors either as a single agent or in combination with other therapeutic agents.
Journal ArticleDOI
The Role of Hypoxia Inducible Factor-1 in Hepatocellular Carcinoma
TL;DR: The mechanism by which Hif-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues are described, which could shed light on new therapeutic approaches for the treatment of HCC.
Journal ArticleDOI
Hypoxia-inducible factors as molecular targets for liver diseases
TL;DR: The evidence for HIF stabilization in liver disease is summarized, the mechanistic involvement of HIFs in disease development is discussed, and the potential of pharmacological HIF modifiers in the treatment of liver disease are explored.
Journal ArticleDOI
Understanding the role of cytokines in Glioblastoma Multiforme pathogenesis.
TL;DR: This review summarizes the current understanding of the functions of key cytokines on Glioblastoma Multiforme, and highlights potential therapeutic applications targeting these cytokines.
References
More filters
Journal ArticleDOI
Reduced oxygen enhancement ratio at low doses of ionizing radiation.
B. Palcic,L. D. Skarsgard +1 more
TL;DR: It is believed that the dose-dependent OER is a true radiobiological phenomenon and not an artifact of the experimental method used in the low dose survival assay.
Journal ArticleDOI
Molecular Imaging of Temporal Dynamics and Spatial Heterogeneity of Hypoxia-Inducible Factor-1 Signal Transduction Activity in Tumors in Living Mice
Inna Serganova,Michael Doubrovin,Jelena Vider,Vladimir Ponomarev,Suren Soghomonyan,Tatiana Beresten,Ludmila Ageyeva,Alexander Serganov,Shangde Cai,Julius Balatoni,Ronald G. Blasberg,Juri G. Gelovani +11 more
TL;DR: In this paper, the authors used repetitive noninvasive positron emission tomography (PET) imaging of hypoxia-induced HIF-1 transcriptional activity in tumors in living mice.
Journal ArticleDOI
Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1
Kaye J. Williams,Brian A. Telfer,Dia Xenaki,Dia Xenaki,Mary R. Sheridan,Isabelle Desbaillets,Hans J.W. Peters,Davina J. Honess,Adrian L. Harris,Gabi U. Dachs,Albert J. van der Kogel,Ian J. Stratford +11 more
TL;DR: The differences in radioresponse do not correlate with tumour oxygenation, suggesting that the hypoxic cells within the HIF-1 deficient tumours do not contribute to the outcome of radiotherapy.
Journal ArticleDOI
Targeting Heat Shock Protein 90 Overrides the Resistance of Lung Cancer Cells by Blocking Radiation-Induced Stabilization of Hypoxia-Inducible Factor-1α
TL;DR: In vivo, it is determined in vivo that systemic administration of deguelin resulted in profound inhibition of tumor growth and angiogenesis when combined with radiation, providing a strong rationale to target Hsp90 as a means to block radiation-induced HIF-1alpha and thus to circumvent radioresistance in lung cancer cells.
Journal ArticleDOI
Hypoxia inducible factor-1: a novel target for cancer therapy.
TL;DR: This work highlights some of the recently developed small-molecule inhibitors of HIF-1 function, which disrupt the H IF-1 signaling pathway through a variety of mechanisms, including the inhibition of Hif-1&agr; protein synthesis, stabilization, nuclear translocation and HIF1 transactivation of target genes.