HIF-1–Dependent Stromal Adaptation to Ischemia Mediates In Vivo Tumor Radiation Resistance
01 Mar 2011-Molecular Cancer Research (American Association for Cancer Research Inc.)-Vol. 9, Iss: 3, pp 259-270
TL;DR: 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 .
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Cites background from "HIF-1–Dependent Stromal Adaptation ..."
...Overexpression of HIF-1 is associated with poor prognosis in several cancers that results in increased cancer cell survival and promotion of tumor progression [90]....
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References
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TL;DR: The supporting players in the tumor microenvironment include stromal fibroblasts, infiltrating immune cells, the blood and lymphatic vascular networks, and the extracellular matrix, which can contribute both positive and negative signals to the tumor.
676 citations
"HIF-1–Dependent Stromal Adaptation ..." refers background in this paper
...Tumor cells which successfully adapt to microenvironmental stress are able to co-opt and/or induce stromal blood vessels to enhance their oxygen and nutrient supply by paracrine growth factor signaling (26)....
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21 Jun 1996
TL;DR: Experimental evidence of the power and generality of the mutual information criterion is given by showing results for various applications involving CT, MR and PET images, which illustrate the large applicability of the approach.
Abstract: Mutual information of image intensities has been proposed as a new matching criterion for automated multi-modality image registration. In this paper the authors give experimental evidence of the power and the generality of the mutual information criterion by showing results for various applications involving CT, MR and PET images. The authors' results illustrate the large applicability of the approach and demonstrate its high suitability for routine use in clinical practice.
637 citations
Washington University in St. Louis1, Stanford University2, University of Texas MD Anderson Cancer Center3, University of Toronto4, University of Pennsylvania5, National Institutes of Health6, University of Washington7, University of Texas Southwestern Medical Center8, Mount Vernon Hospital9, Georgetown University10, St George's, University of London11, Johns Hopkins University12, Dartmouth College13, University of Mainz14
TL;DR: Recommendations are yielded on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning and represent a narrow focus, as hypoxIA measurement might also prove useful in drug development and in increasing the understanding of tumor biology.
Abstract: James L. Tatum, Cancer Imaging Program, Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI)Gary J. Kelloff, Cancer Imaging Program, Division of Cancer Treatment and D...
594 citations
TL;DR: It is found that loss of HIF-1alpha inhibits a number of important parameters of EC behavior during angiogenesis: these include proliferation, chemotaxis, extracellular matrix penetration, and wound healing.
501 citations
TL;DR: The data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxic gene expression and diminution of tumor growth.
Abstract: Chronic hypoxia, a hallmark of many tumors, is associated with angiogenesis and tumor progression. Strategies to treat tumors have been developed in which tumor cells are targeted with drugs or gene-therapy vectors specifically activated under hypoxic conditions. Here we report a different approach, in which the normal transcriptional response to hypoxia is selectively disrupted. Our data indicate that specific blockade of the interaction of hypoxia-inducible factor with the CH1 domain of its p300 and CREB binding protein transcriptional coactivators leads to attenuation of hypoxia-inducible gene expression and diminution of tumor growth. Thus, disrupting the normal co-activational response to hypoxia may be a new and useful therapeutic strategy.
496 citations
"HIF-1–Dependent Stromal Adaptation ..." refers background in this paper
...Targeted inhibition of HIF-1 has been shown both to provide direct antitumor activity (38) and to enhance tumor radiosensitivity (6, 7, 39, 40) in preclinical studies....
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