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Journal ArticleDOI

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 .
Topics: Tumor progression (58%), Stromal cell (56%), Radioresistance (54%), Squamous carcinoma (54%), Angiogenesis (52%)
Citations
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Journal ArticleDOI
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.
Abstract: The text consists of two sections, one for those studying or practicing diagnostic radiology, nuclear medicine and radiation oncology; the other for those engaged in the study or clinical practice of radiation oncology--a new chapter, on radiologic terrorism, is specifically for those in the radiation sciences who would manage exposed individuals in the event of a terrorist event. The 17 chapters in Section I represent 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. The 11 chapters in Section II address more in-depth topics in radiation oncology, such as cancer biology, retreatment after radiotherapy, chemotherapeutic agents and hyperthermia.

1,209 citations


Journal ArticleDOI
Dongjun Luo1, Zhongxia Wang2, Junyi Wu2, Chunping Jiang2  +1 moreInstitutions (2)
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.
Abstract: Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC) Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC

107 citations


Journal ArticleDOI
Jaleh Fallah1, Brian I. Rini1Institutions (1)
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.
Abstract: In this review, the importance of the hypoxia inducible factor (HIF) pathway in tumorigenesis and cancer treatment outcomes will be discussed. The outcomes of phase II and III clinical trials of direct HIF inhibitors in the treatment of cancer will be reviewed. The HIF signaling pathway is activated by tumor-induced hypoxia or by inactivating mutations of the VHL gene. HIF is a transcription factor which regulates the expression of genes involved in adjusting mechanisms to hypoxia such as angiogenesis or apoptosis as well as tumor growth, invasion, and metastasis. The HIF pathway has a key role in development of resistance to different treatment modalities and higher expression of the HIF molecule is associated with poor prognosis. Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies of the HIF inhibitors either as a single agent or in combination with other therapeutic agents.

105 citations


Journal ArticleDOI
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.
Abstract: Cytokines play a significant role in cancer diagnosis, prognosis and therapy. The immune system’s failure to recognize the malignant tumor cells and mount an effective response may be the result of tumor-associated cytokine deregulation. Glioblastoma Multiforme (GBM) has a characteristic cytokine expression pattern, and abnormalities in cytokine expression have been implicated in gliomagenesis. Within the heterogeneous GBM microenvironment, the tumor cells, normal brain cells, immune cells, and stem cells interact with each other through the complex cytokine network. This review summarizes the current understanding of the functions of key cytokines on GBM, and highlights potential therapeutic applications targeting these cytokines.

88 citations


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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Journal ArticleDOI
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.
Abstract: Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease.

77 citations


References
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Journal ArticleDOI
Gregg L. Semenza1Institutions (1)
TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

5,551 citations


"HIF-1–Dependent Stromal Adaptation ..." refers background in this paper

  • ...Given prosurvival and angiogenic effects of HIF-1, targeted inhibition of HIF-1 signaling has generated interest as a target for therapeutic modulation of radioresistance (5)....

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Journal ArticleDOI
Frederik Maes1, A Collignon1, Dirk Vandermeulen1, Guy Marchal1  +1 moreInstitutions (1)
TL;DR: The results demonstrate that subvoxel accuracy with respect to the stereotactic reference solution can be achieved completely automatically and without any prior segmentation, feature extraction, or other preprocessing steps which makes this method very well suited for clinical applications.
Abstract: A new approach to the problem of multimodality medical image registration is proposed, using a basic concept from information theory, mutual information (MI), or relative entropy, as a new matching criterion. The method presented in this paper applies MI to measure the statistical dependence or information redundancy between the image intensities of corresponding voxels in both images, which is assumed to be maximal if the images are geometrically aligned. Maximization of MI is a very general and powerful criterion, because no assumptions are made regarding the nature of this dependence and no limiting constraints are imposed on the image content of the modalities involved. The accuracy of the MI criterion is validated for rigid body registration of computed tomography (CT), magnetic resonance (MR), and photon emission tomography (PET) images by comparison with the stereotactic registration solution, while robustness is evaluated with respect to implementation issues, such as interpolation and optimization, and image content, including partial overlap and image degradation. Our results demonstrate that subvoxel accuracy with respect to the stereotactic reference solution can be achieved completely automatically and without any prior segmentation, feature extraction, or other preprocessing steps which makes this method very well suited for clinical applications.

4,580 citations


"HIF-1–Dependent Stromal Adaptation ..." refers methods in this paper

  • ...This initial registration was then further refined through the multiresolution iterative maximization of a normalized mutual information cost function (18)....

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Book
01 Jan 1973
Abstract: Radiobiology for the radiologist , Radiobiology for the radiologist , کتابخانه دیجیتال جندی شاپور اهواز

4,038 citations


Journal ArticleDOI
Peter Carmeliet1Institutions (1)
15 Dec 2005-Nature
TL;DR: Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
Abstract: The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.

3,124 citations


"HIF-1–Dependent Stromal Adaptation ..." refers background in this paper

  • ...Tumor vessels are distinct from their normal counterparts by virtue of their dependence on prosurvival stimulatory cytokines such as VEGF (8)....

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Journal ArticleDOI
TL;DR: The role of HIF in developmental, adaptive and neoplastic angiogenesis, and the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype are discussed.
Abstract: The regulation of angiogenesis by hypoxia is an important component of homeostatic mechanisms that link vascular oxygen supply to metabolic demand. Molecular characterization of angiogenic pathways, identification of hypoxia-inducible factor (HIF) as a key transcriptional regulator of these molecules, and the definition of the HIF hydoxylases as a family of dioxygenases that regulate HIF in accordance with oxygen availability have provided new insights into this process. Here we review these findings, and the role of HIF in developmental, adaptive and neoplastic angiogenesis. We also discuss the implications of oncogenic activation of extensive, physiologically interconnected hypoxia pathways for the tumor phenotype.

2,162 citations


"HIF-1–Dependent Stromal Adaptation ..." refers background in this paper

  • ...HIF-1– stimulated tumor expression of VEGF and other proangiogenic factors is key to this process (27)....

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