Posted by: Dan | May 2, 2007

Hypoxia: Selecting for Maligant Phenotypes in Cancers

One paper that peripherally caught my interest last week was a review by Richard Sullivan and Charles Graham, on Hypoxia-driven selection of the metastatic phenotype. Hypoxia – the deprivation of oxygen to cells, in this case, cells at the center of a tumor mass – both kills a lot of tumor cells, as well as being an indicator of poor patient prognosis in a wide variety of tumors. How can this be, you ask? Well, that’s the topic of the review, which aimed to illustrate:

… how adaptation to hypoxia facilitates cancer cell dissemnation through the upregulation of critical metastasis-associated genes that allow cells to escape the hostile microenvironment of the primary tumor. Studies suggest that the acquisition of the metastatic phenotype is not simply the result of dysregulated signal transduction pathways, but instead is achieved through a stepwise selection proess driven by multiple hypoxia-inducible mechanisms.

In particular, the review’s authors reference studies on the role of hypoxia in the epithelial-mesenchymal transition, heavily citing one paper published last year by Krishnamachary et al., who found that HIF(Hypoxia-induced factor)-1 contributes to the epithelial-mesenchymal transition in VHL(von Hippel-Lindau)-null RCC(Renal Cell Carcinoma) by indirect repression of E-cadherin.

More topically, Sullivan and Graham discuss how hypoxia likely impacts cell motility. That is, Scatter Factors (such as hepatocyte growth factor, HGF, aka Scatter Factor-1), which are stromal cell-derived cytokines, signals through its receptor MET to impact MAPK, PI3K and Jak/STAT signaling cascades. HGF/MET signaling also alters the expression, localization and activity of cadherins, integrins and MMPs – all critically involved in metastatis. These changes lead to the loss of normal tissue architecture, breakdown of the underlying basement membrane, and altered cell-ECM interactions.

And I haven’t even gotten to the role of hypoxia in inducing angiogenesis, through vascular-endothelial growth factor (VEGF) activity.

The clear conclusion from the available data is that hypoxia is one selective pressure for tumor cells, selecting for cells that can escape the constrictive tissue architecture and/or alleviate the hypoxia through angiogenesis. Other selective pressures include programmed cell death (apoptosis), immune surveillance (e.g. by cytotoxic Natural Killer granulocytes), and therapeutic approaches (i.e. chemotherapy).

  • Sullivan R, Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007 Apr 26; [Epub ahead of print]
  • Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, Semenza GL. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 2006 Mar 1;66(5):2725-31.
  • Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: Cell signaling for invasive growth. Nat Rev Cancer. 2002 Apr;2(4):289-300.

Appropriate timing! Just a few days after posting this blog entry, Cell has a relevant article on Hypoxia-inducible factors, stem cells, and cancer:

The links between the HIFs, Notch, and Oct4 reveal specific molecular mechanisms whereby oxygen responses can inhibit differentiation and, possibly, promote stem cell identity. They also raise the possibility of crosstalk between hypoxia and other stem cell signaling pathways. Direct connections between BMPs or Shh pathways and the HIFs have not yet been demonstrated, although TGF-β has been reported to induce HIF-α stabilization by inhibiting PHD2, one of the proline hydroxylases that target HIF-α subunits for degradation under normal oxygen conditions (McMahon et al., 2006). In addition, a recent paper describing physical interaction between β-catenin and HIF-1α suggests at least one mechanism by which Wnt signaling might affect HIF activity in stem cells (Kaidi et al., 2007). Determining the degree of crosstalk, if any, between the HIFs and these important signaling networks in stem cells is an exciting prospect for future research.


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