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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TL;DR: Novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site‐specific delivery of quercetin via CD44 receptor in glioblastoma cells, leading to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.
Abstract: Glioblastoma multiforme is the most common and aggressive primary brain cancer with only ∼3% of patients surviving more than 3 years from diagnosis. Several mechanisms are involved in drug and radiation resistance to anticancer treatments and among them one of the most important factors is the tumor microenvironment status, characterized by cancer cell hypersecretion of interleukins and cytokines. The aim of our research was the synthesis of a nanocarrier of quercetin combined with temozolomide, to enhance the specificity and efficacy of this anticancer drug commonly used in glioblastoma treatment. The nanohydrogel increased the internalization and cytotoxicity of quercetin in human glioblastoma cells and, when co-delivered with temozolomide, contribute to an improved anticancer effect. The nanohydrogel loaded with quercetin had the ability to recognize CD44 receptor, a brain cancer cell marker, through an energy and caveolae dependent mechanism of internalization. Moreover, nanohydrogel of quercetin was able to reduce significantly IL-8, IL-6, and VEGF production in pro-inflammatory conditions with interesting implications on the mechanism of glioblastoma cells drug resistance. In summary, novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site-specific delivery of quercetin via CD44 receptor in glioblastoma cells. This targeted therapy lead to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.
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Cites background from "HIF-1–Dependent Stromal Adaptation ..."
...Furthermore, observed differences in tumor cell radiosensitivity in vitro and in vivo have been linked to the presence of host derived supporting cells in vivo, which include endothelial cells (Fenton et al., 2001; Fiebig et al., 2004; Garcia-Barros et al., 2003; García-Barros et al., 2010; Gerweck et al., 2006; Moeller et al., 2004; Ogawa et al., 2007; Ruka et al., 1996; Schwartz et al., 2011)....
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...…to the presence of host derived supporting cells in vivo, which include endothelial cells (Fenton et al., 2001; Fiebig et al., 2004; Garcia-Barros et al., 2003; García-Barros et al., 2010; Gerweck et al., 2006; Moeller et al., 2004; Ogawa et al., 2007; Ruka et al., 1996; Schwartz et al., 2011)....
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TL;DR: Mibefradil response is schedule dependent and enhances survival and reduces glioblastoma when combined with ionizing radiation.
Abstract: Object The survival of patients with high-grade gliomas remains unfavorable. Mibefradil, a T-type calcium channel inhibitor capable of synchronizing dividing cells at the G1 phase, has demonstrated potential benefit in conjunction with chemotherapeutic agents for gliomas in in vitro studies. In vivo study of mibefradil and radiosurgery is lacking. The authors used an intracranial C6 glioma model in rats to study tumor response to mibefradil and radiosurgery. Methods Two weeks after implantation of C6 cells into the animals, each rat underwent MRI every 2 weeks thereafter for 8 weeks. After tumor was confirmed on MRI, the rats were randomly assigned to one of the experimental groups. Tumor volumes were measured on MR images. Experimental Group 1 received 30 mg/kg of mibefradil intraperitoneally 3 times a day for 1 week starting on postoperative day (POD) 15; Group 2 received 8 Gy of cranial radiation via radiosurgery delivered on POD 15; Group 3 underwent radiosurgery on POD 15, followed by 1 week of mibef...
20 citations
TL;DR: Metabolic reprogramming allows gliomas to thrive in harsh microenvironments such as hypoxia, acidity, and nutrient depletion, which contribute to tumor initiation, maintenance, and treatment resistance.
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20 citations
01 Mar 2020
TL;DR: The aim of this review is to summarize the current knowledge about the role and the related signal pathways of HIF-1 in association with the resistance of cancers to radiotherapy, and to suggest a promising strategy for sensitization of cancersto radiotherapy.
Abstract: Hypoxia is a big roadblock for cancer radiotherapy, in which the hypoxia-inducible factor (HIF-1) creates a microenvironment and cancer cells’ intrinsic signaling networks conferring radioresistance to cancers. HIF-1 is a heterodimeric transcription factor HIF-1α/HIF-1β, that regulates the transcription of a broad range of down-stream genes possessing an E-box-like hypoxia response element (HRE). The expression of HIF-1α is oxygen-sensitive while HIF-1β is constitutively expressed. In addition to hypoxia, ionizing radiation can also induce the expression of HIF-1α. The HIF-1 modulates a set of signaling pathways to cause profound effects on the response of cancer to radiotherapy, including radiation-induced DNA damage response (DDR), vasculogenesis and glucose metabolism reprograming, epithelial mesenchymal transition (EMT), etc. In this review, our aim is to summarize the current knowledge about the role and the related signal pathways of HIF-1 in association with the resistance of cancers to radiotherapy. Targeting HIF-1 and its signal pathways is a promising strategy for sensitization of cancers to radiotherapy.
18 citations
References
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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.
6,024 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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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.
4,773 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
TL;DR: Radiobiology for the radiologist, Radiobiology in general, Radiology for radiologists as mentioned in this paper, Radiology in the field of radiology, radiology for radiology.
Abstract: Radiobiology for the radiologist , Radiobiology for the radiologist , کتابخانه دیجیتال جندی شاپور اهواز
4,040 citations
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.
3,300 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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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.
2,328 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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