Limits...
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 nutrients to HIF and from HIF to metabolism. a Two different pathways involved in the response to nutrients impact on HIF. First a decrease in the amount of glucose can inhibit the activity of FIH and PHD through decreased production of the co-substrate 2-oxoglutarate by the Krebs cycle. However, it is not sure that it is limiting in vivo. The question as to whether FIH and PHD might be nutritional sensors is still open to discussion. The second pathway responds to nutrient depletion reflecting a decrease in the ATP/AMP ratio. This nutritional stress activates the LKB1/AMPK/TSC1/TSC2 pathway resulting in an inhibition of mammalian target of rapamycin (mTOR). The action of mTOR on HIF is still a subject of debate. Essentially two options have been proposed: inhibition of HIF translation and/or inhibition of proteasomal degradation. Both converge in the activation of HIF under nutrient depletion conditions. b HIF can in turn impact on metabolism and cellular energy due to induction of a variety of target genes (here in green). It promotes glucose import via glucose transporters (GLUT1, 3) and it increases the rate of glucose consumption by inducing expression of glycolytic enzymes. HIF also promotes a shift to anaerobic metabolism by: favoring conversion of pyruvate to lactate through enhanced expression of the enzyme LDH-A and by increased expression of PDK-1 that counteracts the entrance of pyruvate into the Krebs cycle. Finally, through REDD-1, HIF stimulates the TSC1/2 complex, creating a negative feedback loop on mTOR. In summary, HIF allows cancer cells to shift to highly glycolytic anaerobic metabolism and to save energy by downregulating translation in a mTOR-dependent fashion
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Fig5: From nutrients to HIF and from HIF to metabolism. a Two different pathways involved in the response to nutrients impact on HIF. First a decrease in the amount of glucose can inhibit the activity of FIH and PHD through decreased production of the co-substrate 2-oxoglutarate by the Krebs cycle. However, it is not sure that it is limiting in vivo. The question as to whether FIH and PHD might be nutritional sensors is still open to discussion. The second pathway responds to nutrient depletion reflecting a decrease in the ATP/AMP ratio. This nutritional stress activates the LKB1/AMPK/TSC1/TSC2 pathway resulting in an inhibition of mammalian target of rapamycin (mTOR). The action of mTOR on HIF is still a subject of debate. Essentially two options have been proposed: inhibition of HIF translation and/or inhibition of proteasomal degradation. Both converge in the activation of HIF under nutrient depletion conditions. b HIF can in turn impact on metabolism and cellular energy due to induction of a variety of target genes (here in green). It promotes glucose import via glucose transporters (GLUT1, 3) and it increases the rate of glucose consumption by inducing expression of glycolytic enzymes. HIF also promotes a shift to anaerobic metabolism by: favoring conversion of pyruvate to lactate through enhanced expression of the enzyme LDH-A and by increased expression of PDK-1 that counteracts the entrance of pyruvate into the Krebs cycle. Finally, through REDD-1, HIF stimulates the TSC1/2 complex, creating a negative feedback loop on mTOR. In summary, HIF allows cancer cells to shift to highly glycolytic anaerobic metabolism and to save energy by downregulating translation in a mTOR-dependent fashion

Mentions: Another type of nutritional stress, amino-acid depletion, is able to decrease HIF protein expression by activating the adenosine monophosphate kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway (Fig. 5a). In a situation of an energy imbalance and decrease in intracellular ATP, the tumor suppressor serine/threonine kinase LKB1 phosphorylates its downstream effector AMPK that has the potential to target the tuberous sclerosis complex (TSC1/TSC2) [33]. Once activated, the TSC1/TSC2 complex inhibits mTOR resulting in a decrease in protein synthesis. Even if it is generally accepted that a decrease in mTOR activity has a negative effect on HIFα expression, the mechanisms are controversial. Indeed, HIF protein synthesis has been shown to be upregulated by mTOR in various cell types [34, 35]. Genetic evidence reinforces this link at the level of translation between mTOR and HIF, by the presence of a 5′-terminal oligopyrimidine tract (5′-TOP) sequence in the 5′-untranslated region (5′-UTR) of HIF-1α. 5′-TOP sequences can be driven by the S6 ribosomal protein that is itself a downstream target of mTOR via p70S6Kinase. Yet it has been demonstrated that mTOR does not change HIF protein synthesis but modifies stabilization of HIFα in prostate PC3 cells [36]. This result is consistent with the fact that the HIF 5′UTR has been demonstrated to bear an internal ribosome entry site theoretically allowing HIFα to be translated even in the absence of mTOR driven CAP dependent translation [37]. Moreover, evidence indicates that HIF protein synthesis can be controlled by stimulation of an Akt-dependent but mTOR-independent pathway in PC3 cells [38]. To complete the picture, a feedback loop allows HIF to downregulate mTOR via the hypoxia inducible REDD-1 protein by activating the TSC1/TSC2 signaling integrator complex [39]. In conclusion, a close link exists between mTOR and HIF, bringing together two fundamental microenvironmental constraints: nutrient and oxygen, which are central to generation of cellular energy.Fig. 5


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

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

From nutrients to HIF and from HIF to metabolism. a Two different pathways involved in the response to nutrients impact on HIF. First a decrease in the amount of glucose can inhibit the activity of FIH and PHD through decreased production of the co-substrate 2-oxoglutarate by the Krebs cycle. However, it is not sure that it is limiting in vivo. The question as to whether FIH and PHD might be nutritional sensors is still open to discussion. The second pathway responds to nutrient depletion reflecting a decrease in the ATP/AMP ratio. This nutritional stress activates the LKB1/AMPK/TSC1/TSC2 pathway resulting in an inhibition of mammalian target of rapamycin (mTOR). The action of mTOR on HIF is still a subject of debate. Essentially two options have been proposed: inhibition of HIF translation and/or inhibition of proteasomal degradation. Both converge in the activation of HIF under nutrient depletion conditions. b HIF can in turn impact on metabolism and cellular energy due to induction of a variety of target genes (here in green). It promotes glucose import via glucose transporters (GLUT1, 3) and it increases the rate of glucose consumption by inducing expression of glycolytic enzymes. HIF also promotes a shift to anaerobic metabolism by: favoring conversion of pyruvate to lactate through enhanced expression of the enzyme LDH-A and by increased expression of PDK-1 that counteracts the entrance of pyruvate into the Krebs cycle. Finally, through REDD-1, HIF stimulates the TSC1/2 complex, creating a negative feedback loop on mTOR. In summary, HIF allows cancer cells to shift to highly glycolytic anaerobic metabolism and to save energy by downregulating translation in a mTOR-dependent fashion
© Copyright Policy
Related In: Results  -  Collection

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Fig5: From nutrients to HIF and from HIF to metabolism. a Two different pathways involved in the response to nutrients impact on HIF. First a decrease in the amount of glucose can inhibit the activity of FIH and PHD through decreased production of the co-substrate 2-oxoglutarate by the Krebs cycle. However, it is not sure that it is limiting in vivo. The question as to whether FIH and PHD might be nutritional sensors is still open to discussion. The second pathway responds to nutrient depletion reflecting a decrease in the ATP/AMP ratio. This nutritional stress activates the LKB1/AMPK/TSC1/TSC2 pathway resulting in an inhibition of mammalian target of rapamycin (mTOR). The action of mTOR on HIF is still a subject of debate. Essentially two options have been proposed: inhibition of HIF translation and/or inhibition of proteasomal degradation. Both converge in the activation of HIF under nutrient depletion conditions. b HIF can in turn impact on metabolism and cellular energy due to induction of a variety of target genes (here in green). It promotes glucose import via glucose transporters (GLUT1, 3) and it increases the rate of glucose consumption by inducing expression of glycolytic enzymes. HIF also promotes a shift to anaerobic metabolism by: favoring conversion of pyruvate to lactate through enhanced expression of the enzyme LDH-A and by increased expression of PDK-1 that counteracts the entrance of pyruvate into the Krebs cycle. Finally, through REDD-1, HIF stimulates the TSC1/2 complex, creating a negative feedback loop on mTOR. In summary, HIF allows cancer cells to shift to highly glycolytic anaerobic metabolism and to save energy by downregulating translation in a mTOR-dependent fashion
Mentions: Another type of nutritional stress, amino-acid depletion, is able to decrease HIF protein expression by activating the adenosine monophosphate kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway (Fig. 5a). In a situation of an energy imbalance and decrease in intracellular ATP, the tumor suppressor serine/threonine kinase LKB1 phosphorylates its downstream effector AMPK that has the potential to target the tuberous sclerosis complex (TSC1/TSC2) [33]. Once activated, the TSC1/TSC2 complex inhibits mTOR resulting in a decrease in protein synthesis. Even if it is generally accepted that a decrease in mTOR activity has a negative effect on HIFα expression, the mechanisms are controversial. Indeed, HIF protein synthesis has been shown to be upregulated by mTOR in various cell types [34, 35]. Genetic evidence reinforces this link at the level of translation between mTOR and HIF, by the presence of a 5′-terminal oligopyrimidine tract (5′-TOP) sequence in the 5′-untranslated region (5′-UTR) of HIF-1α. 5′-TOP sequences can be driven by the S6 ribosomal protein that is itself a downstream target of mTOR via p70S6Kinase. Yet it has been demonstrated that mTOR does not change HIF protein synthesis but modifies stabilization of HIFα in prostate PC3 cells [36]. This result is consistent with the fact that the HIF 5′UTR has been demonstrated to bear an internal ribosome entry site theoretically allowing HIFα to be translated even in the absence of mTOR driven CAP dependent translation [37]. Moreover, evidence indicates that HIF protein synthesis can be controlled by stimulation of an Akt-dependent but mTOR-independent pathway in PC3 cells [38]. To complete the picture, a feedback loop allows HIF to downregulate mTOR via the hypoxia inducible REDD-1 protein by activating the TSC1/TSC2 signaling integrator complex [39]. In conclusion, a close link exists between mTOR and HIF, bringing together two fundamental microenvironmental constraints: nutrient and oxygen, which are central to generation of cellular energy.Fig. 5

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