scispace - formally typeset
Search or ask a question
Journal ArticleDOI

HIF-1–Dependent Stromal Adaptation to Ischemia Mediates In Vivo Tumor Radiation Resistance

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 .
Citations
More filters
Journal ArticleDOI
TL;DR: Targeting α(v) integrins with the monoclonal antibody intetumumab represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.
Abstract: Object Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor–1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. Methods Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc. Results Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic cont...

10 citations

Journal ArticleDOI
Huaxin Hou1, Danrong Li, Daohai Cheng1, Li Li, Ying Liu1, Yi Zhou1 
16 Apr 2013
TL;DR: It is reported that regulation of cellular redox status is required for radiosensitization of nasopharyngeal carcinoma (NPC) cells by emodin and the mechanism appears to involve ROS generation and ROS-mediated inhibition of HIF-1α expression.
Abstract: Here, we report that regulation of cellular redox status is required for radiosensitization of nasopharyngeal carcinoma (NPC) cells by emodin. We evaluated emodin's radiosensitivity-enhancing ability by using NPC cells in vitro and xenografts in vivo. A clonogenic assay was performed to evaluate NPC cell survival and to determine dose modification factors. Flow cytometry, western blot analysis, and in vivo radiation-induced tumor regrowth delay assays were performed to characterize emodin's effects. Exposure of CNE-1 NPC cells to emodin enhanced their radiosensitivity. HIF-1α expression significantly increased under hypoxic conditions but did not change after treatment with emodin alone. Emodin downregulated mRNA and protein expression of HIF-1α. Cells exposed to radiation and emodin underwent significant cell cycle arrest at the G2/M phase. The percentage of apoptotic cells and reactive oxygen species (ROS) levels were significantly higher in the group exposed to emodin and radiation hypoxic group than in the other groups. Compared to the CNE-1 xenografts exposed to radiation alone, CNE-1 xenografts exposed to radiation with emodin showed significantly enhanced radiation effects. Our data suggest that emodin effectively enhanced the radiosensitivity of CNE-1 cells in vitro and in vivo. The mechanism appears to involve ROS generation and ROS-mediated inhibition of HIF-1α expression.

8 citations

Journal ArticleDOI
TL;DR: It is found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner, suggesting that promoting the degradation of Hif-1 α could be a strategy to manage progression and that HIF -1α inhibitors are potent drugs for thyroid cancer treatment.
Abstract: Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.

6 citations


Cites background from "HIF-1–Dependent Stromal Adaptation ..."

  • ...In addition, high expression of HIF-1α is related to resistance to chemotherapy [30] and radiation therapy [31]....

    [...]

01 Jan 2013
TL;DR: In this article, Smit onderzocht welke patienten hiervan het meest profiteren, and concludeert that er meer onderzoek gedaan moet worden naar welke tumorcellen resistent zijn tegen chemoradiotherapie.
Abstract: Slokdarmkanker is een van de snelst stijgende kankersoorten in Nederland. De ziekte wordt meestal pas vastgesteld als hij zich al heeft verspreid. Ook al zijn de behandelmethoden de afgelopen jaren verbeterd, de keuze voor de juiste behandelmethode blijft complex. Vast onderdeel in de huidige behandeling van slokdarmpatienten is neoadjuvante (preoperatieve) chemoradiotherapie. Justin Smit onderzocht welke patienten hiervan het meest profiteren. Smit ging na welke biologische kenmerken van de tumor voorspellen hoe effectief chemoradiotherapie zal zijn. Besmette lymfeklieren nabij de tumor hebben een negatieve invloed op ziektevrije overleving. Smit ontdekte dat dit effect mogelijk versterkt wordt door preoperatieve chemoradiotherapie. Ook concludeert hij dat er meer onderzoek gedaan moet worden naar welke tumorcellen resistent zijn tegen chemoradiotherapie. Het grote verschil tussen patienten bij wie de behandeling wel en niet aanslaat, wijst namelijk op een verschil in tumorbiologie bij beide groepen. Een verdere subtypering kan een beter op het individu gerichte behandeling mogelijk maken.

3 citations


Additional excerpts

  • ...n= 63 (%) Tumor outside CTV n=9 (%) Tumor within CTV n=54 (%) Histopathological T-stage ypT0 15 (24) 1 (11) 14 (27) ypT1 12 (19) 0 (0) 12 (22) ypT2 9 (14) 2 (22) 7 (13) ypT3 27 (43) 6 (67) 21 (38) ypT4 0 (0) 0 (0) 0 (0)...

    [...]

Dissertation
01 Jan 2014
TL;DR: An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biomedical Engineering in the Graduate School of Duke University is submitted.
Abstract: Liposomal Drug Delivery Mediated by MR-guided High Intensity Focused Ultrasound: Drug Dose Painting and Influence of Local Tissue Transport Parameters By Pavel Sergeyevich Yarmolenko Department of Biomedical Engineering Duke University Date: _______________________ Approved: ___________________________ Mark W. Dewhirst ___________________________ Bruce Klitzman ___________________________ G Allan Johnson ___________________________ Ashutosh Chilkoti ___________________________ Matthew R Dreher An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biomedical Engineering in the Graduate School of Duke University

3 citations


Cites background from "HIF-1–Dependent Stromal Adaptation ..."

  • ...Likely reasons for this radioresistance include the proposed mechanism of reactions with oxygen radicals causing and stabilizing radiation-caused DNA damage [80] as well a post-radiation HIF-driven response that promotes tumor growth and angiogenesis [81]....

    [...]

References
More filters
Journal ArticleDOI
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)....

    [...]

Journal ArticleDOI
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)....

    [...]

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

Journal ArticleDOI
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.

3,300 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)....

    [...]

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.

2,328 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)....

    [...]

Related Papers (5)