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Hypoxia-inducible factors in stem cells and cancer.

Mazumdar J, Dondeti V, Simon MC - J. Cell. Mol. Med. (2009)

Bottom Line: Recently, HIFs have been shown to modulate specific stem cell effectors, such as Notch, Wnt and Oct4 that control stem cell proliferation, differentiation and pluripotency.Direct molecular links have also been established between HIFs and critical cell signalling pathways such as cMyc and p53.These novel links suggest a new role for HIFs in stem cell and tumour regulation.

View Article: PubMed Central - PubMed

Affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

ABSTRACT
Cellular properties are influenced by complex factors inherent to their microenvironments. While oxygen deprivation (hypoxia) occurs in tumours because of rapid cell proliferation and aberrant blood vessel formation, embryonic cells develop in a naturally occurring hypoxic environment. Cells respond to hypoxia by stabilizing hypoxia-inducible factors (HIFs), which are traditionally viewed to function by altering cellular metabolism and blood vessel architecture. Recently, HIFs have been shown to modulate specific stem cell effectors, such as Notch, Wnt and Oct4 that control stem cell proliferation, differentiation and pluripotency. Direct molecular links have also been established between HIFs and critical cell signalling pathways such as cMyc and p53. These novel links suggest a new role for HIFs in stem cell and tumour regulation.

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HIF-dependent regulation of hypoxic tumours. A schematic diagram of the molecular links between the HIFs and the cancer associated genes cMyc and p53 is shown. (A) Whereas, HIF-1α interacts with cMyc leading to the inhibition of cMyc activity, HIF-1α effects on p53 result in the activation of p53 activity. (B) HIF-2α interacts with cMyc leading to the activation of cMyc activity. In contrast, HIF-2α opposes p53 activity by promoting intracellular redox homeostasis. The net effect of the interactions of the HIFs with cMyc and p53 is dependent upon the cellular context. *These activities are inferred from the literature.
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fig02: HIF-dependent regulation of hypoxic tumours. A schematic diagram of the molecular links between the HIFs and the cancer associated genes cMyc and p53 is shown. (A) Whereas, HIF-1α interacts with cMyc leading to the inhibition of cMyc activity, HIF-1α effects on p53 result in the activation of p53 activity. (B) HIF-2α interacts with cMyc leading to the activation of cMyc activity. In contrast, HIF-2α opposes p53 activity by promoting intracellular redox homeostasis. The net effect of the interactions of the HIFs with cMyc and p53 is dependent upon the cellular context. *These activities are inferred from the literature.

Mentions: Hypoxia is a key component of the tumour microenvironment, and plays an important role in the progression of cancer, particularly in solid tumours [85]. HIF-1α and HIF-2α are the key mediators of the hypoxic response in cells. The HIFs regulate cellular responses to hypoxia by modulating numerous pathways, such as angiogenesis, metabolism, translation, and cell growth. In the context of tumour physiology, hypoxia can enhance glycolysis and promote dedifferentiation, invasion, and metastasis. The broad spectrum of activities influenced by the HIFs overlaps with many of the pathways affected by cMyc [86]. This interaction between HIF and cMyc can influence tumorigenesis (Fig. 2). HIF and cMyc interactions have been documented to play a role in colon cancer [87], clear cell renal cancer [57], breast cancer [88], multiple myeloma [89] and skin cancer [90].


Hypoxia-inducible factors in stem cells and cancer.

Mazumdar J, Dondeti V, Simon MC - J. Cell. Mol. Med. (2009)

HIF-dependent regulation of hypoxic tumours. A schematic diagram of the molecular links between the HIFs and the cancer associated genes cMyc and p53 is shown. (A) Whereas, HIF-1α interacts with cMyc leading to the inhibition of cMyc activity, HIF-1α effects on p53 result in the activation of p53 activity. (B) HIF-2α interacts with cMyc leading to the activation of cMyc activity. In contrast, HIF-2α opposes p53 activity by promoting intracellular redox homeostasis. The net effect of the interactions of the HIFs with cMyc and p53 is dependent upon the cellular context. *These activities are inferred from the literature.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2874971&req=5

fig02: HIF-dependent regulation of hypoxic tumours. A schematic diagram of the molecular links between the HIFs and the cancer associated genes cMyc and p53 is shown. (A) Whereas, HIF-1α interacts with cMyc leading to the inhibition of cMyc activity, HIF-1α effects on p53 result in the activation of p53 activity. (B) HIF-2α interacts with cMyc leading to the activation of cMyc activity. In contrast, HIF-2α opposes p53 activity by promoting intracellular redox homeostasis. The net effect of the interactions of the HIFs with cMyc and p53 is dependent upon the cellular context. *These activities are inferred from the literature.
Mentions: Hypoxia is a key component of the tumour microenvironment, and plays an important role in the progression of cancer, particularly in solid tumours [85]. HIF-1α and HIF-2α are the key mediators of the hypoxic response in cells. The HIFs regulate cellular responses to hypoxia by modulating numerous pathways, such as angiogenesis, metabolism, translation, and cell growth. In the context of tumour physiology, hypoxia can enhance glycolysis and promote dedifferentiation, invasion, and metastasis. The broad spectrum of activities influenced by the HIFs overlaps with many of the pathways affected by cMyc [86]. This interaction between HIF and cMyc can influence tumorigenesis (Fig. 2). HIF and cMyc interactions have been documented to play a role in colon cancer [87], clear cell renal cancer [57], breast cancer [88], multiple myeloma [89] and skin cancer [90].

Bottom Line: Recently, HIFs have been shown to modulate specific stem cell effectors, such as Notch, Wnt and Oct4 that control stem cell proliferation, differentiation and pluripotency.Direct molecular links have also been established between HIFs and critical cell signalling pathways such as cMyc and p53.These novel links suggest a new role for HIFs in stem cell and tumour regulation.

View Article: PubMed Central - PubMed

Affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

ABSTRACT
Cellular properties are influenced by complex factors inherent to their microenvironments. While oxygen deprivation (hypoxia) occurs in tumours because of rapid cell proliferation and aberrant blood vessel formation, embryonic cells develop in a naturally occurring hypoxic environment. Cells respond to hypoxia by stabilizing hypoxia-inducible factors (HIFs), which are traditionally viewed to function by altering cellular metabolism and blood vessel architecture. Recently, HIFs have been shown to modulate specific stem cell effectors, such as Notch, Wnt and Oct4 that control stem cell proliferation, differentiation and pluripotency. Direct molecular links have also been established between HIFs and critical cell signalling pathways such as cMyc and p53. These novel links suggest a new role for HIFs in stem cell and tumour regulation.

Show MeSH
Related in: MedlinePlus