Intratumoral oxygen tension in metastatic melanoma

Lartigau, Éric; Randrianarivelo, H; Mf, Avril; Margulis, A; Spatz, Alan; Eschwège, F.; Guichard, M.

doi:10.1097/00008390-199710000-00006

Cited by 87 publications

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“…Tumor cells maintain a high proliferation rate and consumption of nutrients and oxygen that often overcomes the support capacity of existing local blood vessels. 24 As a result, areas with low oxygen develop in most solid tumors, 25,26 and cells have diverse mechanisms to adjust to hypoxia. Although adaptation to an acute decrease in oxygen levels is mainly mediated by reversible posttranscriptional modifications such as phosphorylation, under chronic deprivation, cells induce the expression of new genes that allow the tumor to adapt to these stressful conditions.…”

Section: Mechanisms Of Gapdh Regulationmentioning

confidence: 99%

Novel roles for GAPDH in cell death and carcinogenesis

2009

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Growing evidence points to the fact that glucose metabolism has a central role in carcinogenesis. Among the enzymes controlling this energy production pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest. Initially identified as a glycolytic enzyme and considered as a housekeeping gene, this enzyme is actually tightly regulated and is involved in numerous cellular functions. Particularly intriguing are recent reports describing GAPDH as a regulator of cell death. However, its role in cell death is unclear; whereas some studies point toward a proapoptotic function, others describe a protective role and suggest its participation in tumor progression. In this study, we highlight recent findings and discuss potential mechanisms through which cells regulate GAPDH to fulfill its diverse functions to influence cell fate.

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Section: Mechanisms Of Gapdh Regulationmentioning

confidence: 99%

Novel roles for GAPDH in cell death and carcinogenesis

2009

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“…Oxygen supply is further worsened by an inadequate tumor vasculature until de novo angiogenesis is induced [2,3]. The presence of hypoxic areas within a tumor mass is invariably a poor prognosis marker for patients with a range of cancer types, including aggressive melanoma [4]. Furthermore, the failure of overall survival benefit due to increased metastatic dissemination after antiangiogenic therapies suggests that hypoxia may cooperate with endothelial inflammation for metastasis spread [5][6][7].…”

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confidence: 99%

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

Comito

Calvani

Giannoni

et al. 2011

Free Radical Biology and Medicine

141

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The "angiogenic switch" during tumor progression is increasingly recognized as a milestone event in tumorigenesis, although the surprising prometastatic effect of antiangiogenic therapies has recently shaken the scientific community. Tumor hypoxia has been singled out as a possible responsible factor in this prometastatic effect, although the molecular pathways are completely unknown. We report herein that human melanoma cells respond to hypoxia through a deregulation of the mitochondrial release of reactive oxygen species (ROS) by the electron transfer chain complex III. These ROS are mandatory to stabilize hypoxia-inducible factor-1α (HIF-1α), the master transcriptional regulator of the hypoxic response. We found that melanoma cells sense hypoxia-enhancing expression/activation of the Met proto-oncogene, which drives a motogenic escape program. Silencing analyses revealed a definite hierarchy of this process, in which mitochondrial ROS drive HIF-1α stabilization, which in turn activates the Met proto-oncogene. This pathway elicits a clear metastatic program of melanoma cells, enhancing spreading on extracellular matrix, motility, and invasion of 3D matrices, as well as growth of metastatic colonies and the ability to form capillary-like structures by vasculogenic mimicry. Both pharmacological and genetic interference with mitochondrial ROS delivery or Met expression block the hypoxiadriven metastatic program. Hence, we propose that hypoxia-driven ROS act as a primary driving force to elicit an invasive program exploited by aggressive melanoma cells to escape from a hypoxic hostile environment.

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“…Moreover, because HIF regulates ␣v␤3 integrin-mediated adhesion, we reasoned that hypoxia also may up-regulate ␣v␤3 integrin expression in tumors, leading to increased metastasis. Melanoma metastases contain hypoxic regions, and metastatic progression is associated with increased ␣v␤3 integrin expression (Gehlsen et al, 1992;Nip et al, 1992;Lartigau et al, 1997;Felding-Habermann et al, 2002). Poorly and highly metastatic melanoma cells (B16F0 and B16F10, respectively) were used to study hypoxic regulation of adhesion pathways that may be relevant to tumor metastasis.…”

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Hypoxia-inducible Factor Regulates αvβ3 Integrin Cell Surface Expression

Dahl

Robertson

Weaver

et al. 2005

MBoC

117

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Hypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of ␣ and ␤ aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt Ϫ/Ϫ and Hif␣ Ϫ/Ϫ TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin ␣v␤3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O 2 ). Culturing B16F0 melanoma cells at 1.5% O 2 resulted in increased ␣v␤3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O 2 tension influence placental invasion and tumor migration by increasing cell surface expression of ␣v␤3 integrin. INTRODUCTIONOxygen (O 2 ) deprivation or "hypoxia" acting through hypoxia-inducible factors (HIFs) influences cell adhesion and migration in a number of biological contexts. For example, HIF regulates progenitor cell adhesion and migration in ischemic tissue by inducing expression of SDF-1 and promotes tumor invasion through the tyrosine kinase receptor MET (Pennacchietti et al., 2003;Ceradini et al., 2004). Hif1␣ Ϫ/Ϫ macrophages exhibit poor migration and Matrigel invasion (Cramer et al., 2003), and directed migration of renal cell carcinoma cells is regulated by HIF activation of the chemokine receptor CXCR4 (Staller et al., 2003). HIF activity also is clearly important during placentation (Kozak et al., 1997;Adelman et al., 2000): placentas from embryos lacking HIF exhibit a variety of defects, including poor invasion of the maternal decidua (Adelman et al., 2000; Cowden Dahl, Mack, Compernolle, Adelman, Carmeliet, and Simon, unpublished data). Furthermore, tumor hypoxia is often clinically correlated with increased metastatic potential (Vaupel et al., 2001). The integrin adhesion receptors promote placental invasion, macrophage adhesion and migration, and metastatic progression of neoplasms (Zhou et al., 1997b;Ding et al., 1999;Jin and Varner, 2004), and hypoxia has been shown to increase mRNA levels of multiple integrins (␤3, ␤2, and ␣5) (Walton et al., 2000;Iwaki et al., 2004;Koike et al., 2004;Kong et al., 2004). Therefore, HIF regulates cell motility in a variety of developmental and pathological situations.The transcriptional response to hypoxia is mediated by the dimeric basic-helix-loop-helix-PAS (bHLH-PAS) transcription factor HIF. HIF is composed of an ␣ subunit (HIF1␣ or HIF2␣) and ␤ subunit (aryl hydrocarbon receptor nuclear translocator; ARNT) and activates tran...

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Intratumoral oxygen tension in metastatic melanoma

Cited by 87 publications

References 0 publications

Novel roles for GAPDH in cell death and carcinogenesis

Novel roles for GAPDH in cell death and carcinogenesis

HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells

Hypoxia-inducible Factor Regulates αvβ3 Integrin Cell Surface Expression

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