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A dialogue between the hypoxia-inducible factor and the tumor microenvironment.

Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J - Cancer Microenviron (2008)

Bottom Line: The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension.Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix.From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Signaling, Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, Nice, France.

ABSTRACT
The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

No MeSH data available.


Related in: MedlinePlus

From oxygen to HIF and from HIF to oxygen. a A drop in the partial pressure of oxygen results in the inactivation of PHDs and FIH. Consequently the HIF pathway is activated, due respectively to inhibition of proteasomal degradation and a release of the C-TAD activity. b HIF in turn impacts on oxygen homeostasis by a double mechanism touching metabolism (green) and oxygen distribution/angiogenesis (red). HIF increases the glycolytic flux and represses the entrance of pyruvate into the Krebs cycle. The consequence is a decrease in oxygen consumption by mitochondrial respiration. In parallel HIF promotes angiogenesis via stimulation of vascular endothelial growth factor (VEGF), interleukin-A (IL-8) and angiopoitin-2 (Ang-2) leading to endothelial cell stimulation and blood vessel destabilization. In combination, HIF simultaneously increases tissue perfusion and decreases local oxygen consumption, thus promoting oxygen diffusion through hypoxic areas
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Fig4: From oxygen to HIF and from HIF to oxygen. a A drop in the partial pressure of oxygen results in the inactivation of PHDs and FIH. Consequently the HIF pathway is activated, due respectively to inhibition of proteasomal degradation and a release of the C-TAD activity. b HIF in turn impacts on oxygen homeostasis by a double mechanism touching metabolism (green) and oxygen distribution/angiogenesis (red). HIF increases the glycolytic flux and represses the entrance of pyruvate into the Krebs cycle. The consequence is a decrease in oxygen consumption by mitochondrial respiration. In parallel HIF promotes angiogenesis via stimulation of vascular endothelial growth factor (VEGF), interleukin-A (IL-8) and angiopoitin-2 (Ang-2) leading to endothelial cell stimulation and blood vessel destabilization. In combination, HIF simultaneously increases tissue perfusion and decreases local oxygen consumption, thus promoting oxygen diffusion through hypoxic areas

Mentions: A number of HIF-induced genes directly influence environmental oxygenation (Fig. 4a). One of the best known is vascular endothelial growth factor (vegf-a) which favors the growth of new blood vessels into hypoxic zones [23]. Endothelial tip cells are capable of guiding the growth of blood capillaries towards hypoxic areas rich in VEGF-A. These endothelial tip cells emit long filopodia that are very rich in VEGF-R2 [24]. Hence the chemotactic gradient of VEGF-A is a guide for neo-vascularization to favor the sprouting of newly generated vessels toward poorly oxygenated areas. This phenomenon of angiogenesis, which is highly HIF-dependent [25], then substantially remodels the oxygen profile of the ischemic tissue or hypoxic tumor (Fig. 4b).Fig. 4


A dialogue between the hypoxia-inducible factor and the tumor microenvironment.

Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J - Cancer Microenviron (2008)

From oxygen to HIF and from HIF to oxygen. a A drop in the partial pressure of oxygen results in the inactivation of PHDs and FIH. Consequently the HIF pathway is activated, due respectively to inhibition of proteasomal degradation and a release of the C-TAD activity. b HIF in turn impacts on oxygen homeostasis by a double mechanism touching metabolism (green) and oxygen distribution/angiogenesis (red). HIF increases the glycolytic flux and represses the entrance of pyruvate into the Krebs cycle. The consequence is a decrease in oxygen consumption by mitochondrial respiration. In parallel HIF promotes angiogenesis via stimulation of vascular endothelial growth factor (VEGF), interleukin-A (IL-8) and angiopoitin-2 (Ang-2) leading to endothelial cell stimulation and blood vessel destabilization. In combination, HIF simultaneously increases tissue perfusion and decreases local oxygen consumption, thus promoting oxygen diffusion through hypoxic areas
© Copyright Policy
Related In: Results  -  Collection

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Fig4: From oxygen to HIF and from HIF to oxygen. a A drop in the partial pressure of oxygen results in the inactivation of PHDs and FIH. Consequently the HIF pathway is activated, due respectively to inhibition of proteasomal degradation and a release of the C-TAD activity. b HIF in turn impacts on oxygen homeostasis by a double mechanism touching metabolism (green) and oxygen distribution/angiogenesis (red). HIF increases the glycolytic flux and represses the entrance of pyruvate into the Krebs cycle. The consequence is a decrease in oxygen consumption by mitochondrial respiration. In parallel HIF promotes angiogenesis via stimulation of vascular endothelial growth factor (VEGF), interleukin-A (IL-8) and angiopoitin-2 (Ang-2) leading to endothelial cell stimulation and blood vessel destabilization. In combination, HIF simultaneously increases tissue perfusion and decreases local oxygen consumption, thus promoting oxygen diffusion through hypoxic areas
Mentions: A number of HIF-induced genes directly influence environmental oxygenation (Fig. 4a). One of the best known is vascular endothelial growth factor (vegf-a) which favors the growth of new blood vessels into hypoxic zones [23]. Endothelial tip cells are capable of guiding the growth of blood capillaries towards hypoxic areas rich in VEGF-A. These endothelial tip cells emit long filopodia that are very rich in VEGF-R2 [24]. Hence the chemotactic gradient of VEGF-A is a guide for neo-vascularization to favor the sprouting of newly generated vessels toward poorly oxygenated areas. This phenomenon of angiogenesis, which is highly HIF-dependent [25], then substantially remodels the oxygen profile of the ischemic tissue or hypoxic tumor (Fig. 4b).Fig. 4

Bottom Line: The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension.Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix.From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

View Article: PubMed Central - PubMed

Affiliation: Institute of Signaling, Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, Nice, France.

ABSTRACT
The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

No MeSH data available.


Related in: MedlinePlus