Oxygen, hypoxia and the stem cell niche

Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche by Ahmed Mohyeldin, Tomás Garzón-Muvdi and Alfredo Quiñones-Hinojosa, Cell Stem Cell 2010(Aug 6); 7(2): 150-61. Review. [PubMed citation][FriendFeed entry]. Via Twitter @CellStemCell: Access [to the full text] is free in August worldwide so readers can try out new enhanced online format.

Abstract:

The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche.

Hypoxic responses in glioma stem cells

Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells by Zhizhong Li and 11 co-authors, including Jeremy N Rich, Cancer Cell 2009(Jun 2); 15(6): 501-13 [FriendFeed entry] PubMed Abstract:

Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2alpha and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2alpha colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2alpha might represent a promising target for antiglioblastoma therapies.

Cancer stem cells, hypoxia and metastasis

Cancer stem cells, hypoxia and metastasis, Richard P Hill, Delphine T Marie-Egyptienne, David W Hedley, Semin Radiat Oncol 2009(Apr);19(2):106-11. Abstract:

The successful growth of a metastasis, by definition, requires the presence of at least 1 cancer stem cell. Metastasis is a complex process, and an important contributor to this process is the influence of the tissue microenvironment, both cell-cell and cell-matrix interactions and the pathophysiologic conditions in tumors, such as hypoxia. A number of studies have suggested that normal stem cells may reside in “niches,” where cell-cell and cell-matrix interactions can provide critical signals to support and maintain the undifferentiated phenotype of the stem cells. In this article, the evidence that these niches may be hypoxic is described, and the potential role that hypoxia may play in maintaining the stem cell phenotype in cancers is discussed. Recent work has suggested that there may be a linkage between the stem cell phenotype and that induced by the process of epithelial-mesenchymal transition (EMT). EMT plays an important role in cell movement and organ formation during embryogenesis, and it is currently hypothesized to be a major mechanism by which epithelial cancers may generate cells that can form metastases. Recent evidence suggests that the expression of certain genes involved in EMT is influenced by low oxygen levels, again suggesting a linkage between stem cells and hypoxia. Whether this supposition is correct remains an open question that will only be answered by further experimentation, but the potential role of hypoxia is critical because of its widespread existence in tumors and its known role in resistance to both radiation and drug treatment.

CD133 is a marker of bioenergetic stress in human glioma

CD133 is a marker of bioenergetic stress in human glioma by Corinne E Griguer and 6 co-authors, including G Yancey Gillespie, PLoS ONE 2008; 3(11): e3655. Epub 2008 Nov 5. PubMed Abstract:

Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.

Excerpts from the Discussion section of the full text (openly accessible):

Figure 7. Tumor progression model

Last paragraph:

We described here that hypoxia and modification of the bioenergetic status of glioma cells govern the regulation of CD133 at post-transcriptional level. Data presented here strongly indicated that changes in the cellular environment that results in alteration of mitochondrial function are responsible for the enhanced up-regulation of CD133 antigen in glioma cells, suggesting that CD133 expression in human glioma cells is not obligatory relative to the stem cell phenotype but rather, reveals the occurrence of a stress response.