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Review
. 2007 May 4;129(3):465-72.
doi: 10.1016/j.cell.2007.04.019.

V体育官网 - Hypoxia-inducible factors, stem cells, and cancer

Brian Keith  1 , M Celeste Simon
Affiliations
Review

Hypoxia-inducible factors, stem cells, and cancer

Brian Keith et al. Cell. .

Abstract

Regions of severe oxygen deprivation (hypoxia) arise in tumors due to rapid cell division and aberrant blood vessel formation VSports手机版. The hypoxia-inducible factors (HIFs) mediate transcriptional responses to localized hypoxia in normal tissues and in cancers and can promote tumor progression by altering cellular metabolism and stimulating angiogenesis. Recently, HIFs have been shown to activate specific signaling pathways such as Notch and the expression of transcription factors such as Oct4 that control stem cell self renewal and multipotency. As many cancers are thought to develop from a small number of transformed, self-renewing, and multipotent "cancer stem cells," these results suggest new roles for HIFs in tumor progression. .

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Figures

Figure 1
Figure 1
Traditional view of HIFs in tumor progression. Tumor cells residing closer to blood vessels are relatively well oxygenated (red), whereas those at more distant sites become hypoxic (blue). Stabilization of HIF-α proteins in these cells stimulates the expression of numerous target genes encoding factors that mediate adaptation to the hypoxic stress. Some target genes are regulated specifically by HIF-1α, such as those encoding glycolytic enzymes ALDA and PGK, whereas others are specific targets of HIF-2α, such as those encoding TGF-α and cyclin D1. Most HIF target genes are regulated by both HIF-1α and HIF-2α, including those encoding the angiogenic cytokine VEGF and the glucose transporter GLUT1 (Raval et al., 2005, and references therein).
Figure 2
Figure 2
One mode of cancer stem cell generation. Normal stem cells (top) typically divide slowly, but retain the capacity for apparently limitless self-renewal (circular green arrow). Asymmetric division of a multipotent stem cell produces one daughter stem cell and one committed progenitor (or transit amplifying) cell that undergoes a limited, if rapid, series of divisions. The progeny of this transit amplifying cell differentiate to produce a tissue or tissues. A stem cell may undergo oncogenic transformation (vertical dashed line) and lose important homeostatic control mechanisms: the resultant transit amplifying cell and its progeny may consequently fail to differentiate normally or exhibit normal growth controls, thereby generating a tumor. Whereas the transformed cancer stem cell retains the property of self-renewal and can produce new tumors in serial transplantation experiments, its progeny do not (Huntly and Gilliland, 2005). Growing evidence suggests that progenitor cells can, under certain circumstances, regain stem cell properties (horizontal dashed lines) (Krivstov et al., 2006, Morrison and Kimble, 2006).
Figure 3
Figure 3
Proposed model for HIF activity in generating cancer stem cells. Cells in hypoxic tumor regions stabilize HIFs and activate adaptive gene expression (see Figure 1). HIF activity in a rare subset of hypoxic tumor cells could also enhance the activity or expression of Notch, Oct4, c-Myc, ABC transporters (ABC-Ts), and telomerase. Increased expression of KLF4, Sox2, and other factors could promote further dedifferentiation and confer stem cell-like properties, such as self-renewal (circular green arrow), on what was originally a transformed cell with limited replicative potential. Inhibition of HIF activity in the resultant cancer stem cells might block, or reverse, this effect.
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References

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