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

Cyclic dynamics of tumor growth and putative anti-cancer approaches. Massive tumor cell proliferation leads to the formation of hypoxic zones at the periphery of blood vessels. The hypoxic signal stimulates a series of adaptation genes controlled by both the N-TAD and C-TAD of HIF-1α. Consequently, a set of adaptative changes (for instance involved in angiogenesis) make the microenvironment permissive for cell proliferation (for instance by reoxygenating hypoxic areas). From a therapeutic point of view, there are different ways to break this cycle. Classical chemotherapy inhibits cell proliferation but results in severe patient side-effects. Anti-angiogenics aim at blocking one feature of this adaptation phenomenon: the growth of new blood vessels. An alternative strategy consists in abolishing the overall adaptation mechanism by disorganizing the HIF-target genes. In addition, FIH inhibitors would represent a new class of anti-cancer drugs. Such candidate molecular targets may lead to innovative anti-microenvironmental adaptation approaches
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Fig8: Cyclic dynamics of tumor growth and putative anti-cancer approaches. Massive tumor cell proliferation leads to the formation of hypoxic zones at the periphery of blood vessels. The hypoxic signal stimulates a series of adaptation genes controlled by both the N-TAD and C-TAD of HIF-1α. Consequently, a set of adaptative changes (for instance involved in angiogenesis) make the microenvironment permissive for cell proliferation (for instance by reoxygenating hypoxic areas). From a therapeutic point of view, there are different ways to break this cycle. Classical chemotherapy inhibits cell proliferation but results in severe patient side-effects. Anti-angiogenics aim at blocking one feature of this adaptation phenomenon: the growth of new blood vessels. An alternative strategy consists in abolishing the overall adaptation mechanism by disorganizing the HIF-target genes. In addition, FIH inhibitors would represent a new class of anti-cancer drugs. Such candidate molecular targets may lead to innovative anti-microenvironmental adaptation approaches

Mentions: The goal of anti-angiogenic approaches is to disturb vessels and consequently the oxygen profile in the tumor. By inhibiting VEGF [23, 95] or the endothelial VEGF-receptor [96–98] the formation of new vessels, a crucial process in the dynamics of tumor growth, is impaired. However, this approach paradoxically has limitations since anti-angiogenic agents will increase the hypoxic score of tumors, which is likely to increase cell virulence (Fig 8).Fig. 8


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

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

Cyclic dynamics of tumor growth and putative anti-cancer approaches. Massive tumor cell proliferation leads to the formation of hypoxic zones at the periphery of blood vessels. The hypoxic signal stimulates a series of adaptation genes controlled by both the N-TAD and C-TAD of HIF-1α. Consequently, a set of adaptative changes (for instance involved in angiogenesis) make the microenvironment permissive for cell proliferation (for instance by reoxygenating hypoxic areas). From a therapeutic point of view, there are different ways to break this cycle. Classical chemotherapy inhibits cell proliferation but results in severe patient side-effects. Anti-angiogenics aim at blocking one feature of this adaptation phenomenon: the growth of new blood vessels. An alternative strategy consists in abolishing the overall adaptation mechanism by disorganizing the HIF-target genes. In addition, FIH inhibitors would represent a new class of anti-cancer drugs. Such candidate molecular targets may lead to innovative anti-microenvironmental adaptation approaches
© Copyright Policy
Related In: Results  -  Collection

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

Fig8: Cyclic dynamics of tumor growth and putative anti-cancer approaches. Massive tumor cell proliferation leads to the formation of hypoxic zones at the periphery of blood vessels. The hypoxic signal stimulates a series of adaptation genes controlled by both the N-TAD and C-TAD of HIF-1α. Consequently, a set of adaptative changes (for instance involved in angiogenesis) make the microenvironment permissive for cell proliferation (for instance by reoxygenating hypoxic areas). From a therapeutic point of view, there are different ways to break this cycle. Classical chemotherapy inhibits cell proliferation but results in severe patient side-effects. Anti-angiogenics aim at blocking one feature of this adaptation phenomenon: the growth of new blood vessels. An alternative strategy consists in abolishing the overall adaptation mechanism by disorganizing the HIF-target genes. In addition, FIH inhibitors would represent a new class of anti-cancer drugs. Such candidate molecular targets may lead to innovative anti-microenvironmental adaptation approaches
Mentions: The goal of anti-angiogenic approaches is to disturb vessels and consequently the oxygen profile in the tumor. By inhibiting VEGF [23, 95] or the endothelial VEGF-receptor [96–98] the formation of new vessels, a crucial process in the dynamics of tumor growth, is impaired. However, this approach paradoxically has limitations since anti-angiogenic agents will increase the hypoxic score of tumors, which is likely to increase cell virulence (Fig 8).Fig. 8

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