Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules
TL;DR: Novel pathways contributing significantly to the understanding of HIF-1 regulation which may be major determinants of tumor radiosensitivity, potentially having high clinical relevance are described.
About: This article is published in Cancer Cell.The article was published on 2004-05-01 and is currently open access. It has received 928 citations till now. The article focuses on the topics: Radiosensitivity & Angiogenesis.
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TL;DR: In this article, the authors propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.
4,361 citations
TL;DR: The two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends are reviewed, and the particular challenges and opportunities these overlapping strategies present are addressed.
Abstract: Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.
2,570 citations
TL;DR: It is shown by genetic means that HIF-1-dependent block to oxygen utilization results in increased oxygen availability, decreased cell death when total oxygen is limiting, and reduced cell death in response to the hypoxic cytotoxin tirapazamine.
1,960 citations
Cites background from "Radiation activates HIF-1 to regula..."
...Current tumor models suggest that inhibiting HIF target genes such as VEGF will reduce tumor angiogenesis (Moeller et al., 2004)....
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TL;DR: This review summarizes the current state of knowledge regarding the molecular mechanisms by which Hif-1 contributes to cancer progression, focusing on clinical data associating increased HIF-1 levels with patient mortality and pharmacological data showing anticancer effects of H IF-1 inhibitors in mouse models of human cancer.
Abstract: Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.
1,549 citations
Cites background from "Radiation activates HIF-1 to regula..."
...Radiation was shown to induce HIF-1 activity, leading to the production of VEGF and other angiogenic cytokines that protect the endothelial cells of the tumor vasculature from radiation-induced death (Moeller et al., 2004)....
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...Treatment of tumor-bearing mice with the HIF-1 inhibitor YC-1 (3-(50-hydroxymethyl20furyl)-1-benzylindazole) dramatically increased radiation-induced vessel destruction and tumor control (Moeller et al., 2004)....
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TL;DR: Radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy.
1,357 citations
Cites background from "Radiation activates HIF-1 to regula..."
...(ROS), and then oxidated DNA modified by ROS is resistant to cytosolic exonuclease TREX-1-mediated degradation (Gehrke et al., 2013; Moeller et al., 2004)....
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...…able to induce tumor cells and phagocytes to generate reactive oxygen species 850 Immunity 41, 843–852, November 20, 2014 ª2014 Elsevier Inc. (ROS), and then oxidated DNA modified by ROS is resistant to cytosolic exonuclease TREX-1-mediated degradation (Gehrke et al., 2013; Moeller et al., 2004)....
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References
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TL;DR: Preclinical studies have shown that endostatin effectively inhibits tumor growth and shrinks existing tumor blood vessels and therapy with endogenous inhibitors of angiogenesis, such asendostatin and angiostatin may reverse the angiogenic switch preventing growth of tumor vasculature.
2,641 citations
TL;DR: In this paper, the authors tested whether mitochondria act as O2 sensors during hypoxia and whether cobalt activated transcription by increasing the generation of reactive oxygen species (ROS).
Abstract: Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular O2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O2 sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (ρ0 cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; (iii) ρ0 cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in ρ° cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.
1,802 citations
TL;DR: Findings reveal that mitochondria-derived ROS are both required and sufficient to initiate HIF-1α stabilization during hypoxia and that catalase abolishes hypoxic response element-luciferase expression during Hypoxia.
1,778 citations
TL;DR: Microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range, indicating that endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth.
Abstract: About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.
1,487 citations
TL;DR: A historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis is provided.
Abstract: Vascular endothelial growth factor (VEGF, VEGF-A) is a major regulator of physiological and pathological angiogenesis. Several VEGF inhibitors have been approved by the FDA for the treatment of advanced cancer and neovascular age-related macular degeneration. This brief review provides a historic account of the challenges associated with the discovery of VEGF and the early steps in elucidating the role of this molecule in the regulation of angiogenesis.
1,270 citations