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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

Model that questions the molecular significance of the two HIF-1α TAD and the impact of the oxygen sensor FIH on the intra-tumor location of gene expression as a function of the oxygen gradient. aUpper panel: If the two HIF-1α TAD are functionally different they would target different genes. In green are represented the potential N-TAD-only target genes while in blue are represented the potential C-TAD sensitive genes. Lower panel: By targeting specifically the C-TAD, FIH would inhibit only a subset of HIF-dependent genes. Consequently, FIH would not be a pure inhibitor but rather a switch between two categories of HIF spectrum genes. b In accordance with our working model, overexpression of FIH should delocalize C-TAD sensitive genes (blue dotted line) to highly hypoxic areas. In contrast FIH inhibition by siRNA should delocalize C-TAD sensitive genes to moderately hypoxic areas in the vicinity of blood vessels (lower panel). In parallel, N-TAD only genes (green dotted line) should not be sensitive to modulation of FIH activity
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Fig3: Model that questions the molecular significance of the two HIF-1α TAD and the impact of the oxygen sensor FIH on the intra-tumor location of gene expression as a function of the oxygen gradient. aUpper panel: If the two HIF-1α TAD are functionally different they would target different genes. In green are represented the potential N-TAD-only target genes while in blue are represented the potential C-TAD sensitive genes. Lower panel: By targeting specifically the C-TAD, FIH would inhibit only a subset of HIF-dependent genes. Consequently, FIH would not be a pure inhibitor but rather a switch between two categories of HIF spectrum genes. b In accordance with our working model, overexpression of FIH should delocalize C-TAD sensitive genes (blue dotted line) to highly hypoxic areas. In contrast FIH inhibition by siRNA should delocalize C-TAD sensitive genes to moderately hypoxic areas in the vicinity of blood vessels (lower panel). In parallel, N-TAD only genes (green dotted line) should not be sensitive to modulation of FIH activity

Mentions: Selective modulation of the spectrum of genes induced by HIF can occur in two ways. First, HIF-1α and HIF-2α can differentially transactivate a series of genes. For example adrenomedullin is a HIF-2 only gene in mouse stem cells, carbonic anhydrase IX (ca9) is a HIF-1 targeted gene in human HeLa cells, whereas phd3 is regulated by both HIF-1 and HIF-2 in human cells [19, 20]. Relative HIF-1 and HIF-2 activities differ depending on the cell type. Second, through the bifunctional TAD activity of HIF-1α [20] (Fig. 3a). FIH specifically hydroxylates the C-TAD, and does not touch the N-TAD. So experimentally, FIH inhibits only a subset of HIF-1-target genes. Knowing this we put forward a model that divides the HIF-1 spectrum of genes into two categories: one that is C-TAD sensitive and the other N-TAD only sensitive. FIH would inhibit the C-TAD spectrum and as a result pilot the shift between these two categories of HIF-1 target genes. This double TAD regulation model can be easily transposed to HIF-2α, since this isoform is regulated in a highly homologous mode.Fig. 3


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

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

Model that questions the molecular significance of the two HIF-1α TAD and the impact of the oxygen sensor FIH on the intra-tumor location of gene expression as a function of the oxygen gradient. aUpper panel: If the two HIF-1α TAD are functionally different they would target different genes. In green are represented the potential N-TAD-only target genes while in blue are represented the potential C-TAD sensitive genes. Lower panel: By targeting specifically the C-TAD, FIH would inhibit only a subset of HIF-dependent genes. Consequently, FIH would not be a pure inhibitor but rather a switch between two categories of HIF spectrum genes. b In accordance with our working model, overexpression of FIH should delocalize C-TAD sensitive genes (blue dotted line) to highly hypoxic areas. In contrast FIH inhibition by siRNA should delocalize C-TAD sensitive genes to moderately hypoxic areas in the vicinity of blood vessels (lower panel). In parallel, N-TAD only genes (green dotted line) should not be sensitive to modulation of FIH activity
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654353&req=5

Fig3: Model that questions the molecular significance of the two HIF-1α TAD and the impact of the oxygen sensor FIH on the intra-tumor location of gene expression as a function of the oxygen gradient. aUpper panel: If the two HIF-1α TAD are functionally different they would target different genes. In green are represented the potential N-TAD-only target genes while in blue are represented the potential C-TAD sensitive genes. Lower panel: By targeting specifically the C-TAD, FIH would inhibit only a subset of HIF-dependent genes. Consequently, FIH would not be a pure inhibitor but rather a switch between two categories of HIF spectrum genes. b In accordance with our working model, overexpression of FIH should delocalize C-TAD sensitive genes (blue dotted line) to highly hypoxic areas. In contrast FIH inhibition by siRNA should delocalize C-TAD sensitive genes to moderately hypoxic areas in the vicinity of blood vessels (lower panel). In parallel, N-TAD only genes (green dotted line) should not be sensitive to modulation of FIH activity
Mentions: Selective modulation of the spectrum of genes induced by HIF can occur in two ways. First, HIF-1α and HIF-2α can differentially transactivate a series of genes. For example adrenomedullin is a HIF-2 only gene in mouse stem cells, carbonic anhydrase IX (ca9) is a HIF-1 targeted gene in human HeLa cells, whereas phd3 is regulated by both HIF-1 and HIF-2 in human cells [19, 20]. Relative HIF-1 and HIF-2 activities differ depending on the cell type. Second, through the bifunctional TAD activity of HIF-1α [20] (Fig. 3a). FIH specifically hydroxylates the C-TAD, and does not touch the N-TAD. So experimentally, FIH inhibits only a subset of HIF-1-target genes. Knowing this we put forward a model that divides the HIF-1 spectrum of genes into two categories: one that is C-TAD sensitive and the other N-TAD only sensitive. FIH would inhibit the C-TAD spectrum and as a result pilot the shift between these two categories of HIF-1 target genes. This double TAD regulation model can be easily transposed to HIF-2α, since this isoform is regulated in a highly homologous mode.Fig. 3

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