Progression of primary tumours and metastases

Parallel progression of tumour and metastases by Serge Koscielny and Maurice Tubiana, Nat Rev Cancer 2010(Feb); 10(2): 156 [PubMed citation]. Commentary on an opinion article: Parallel progression of primary tumours and metastases by Christoph Klein, Nat Rev Cancer 2009(Apr); 9(4): 302-12 [PubMed citation]. An excerpt from the full text of the commentary:

[Data are presented that] are consistent with the linear progression model when it is assumed that there are two types of cells in tumours: those that can initiate metastases (metastasis-forming cells (MFCs)), which probably derive from tumour stem cells[ref 7] and those that probably cannot initiate metastasis because their proliferative ability is limited[refs 7,8,9].

Response to the commentary: Tumour cell dissemination and growth of metastasis by Christoph A Klein, Nat Rev Cancer 2010(Feb); 10(2): 156. Excerpt from the full text of the response:

Finally, the authors declare that the parallel progression model is incompatible with the cancer stem cell hypothesis. As defined above, parallel progression does not address this issue.

The 'linear progression model' described by Christoph Klein "places major evolutionary events in the primary tumour and late dissemination of fully malignant cells that subsequently grow to manifest metastases". In the 'parallel progression model', there is "early dissemination of tumour cells from the primary tumour and ectopic selective adaptation (which is associated with the emergence of genomes fully able to form metastases)" (see Christoph Klein's response).

CD133 and poorer prognosis in locally advanced colon cancer

Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB by Chun-Yan Li and 11 co-authors, including Xiao-Shi Zhang, J Transl Med 2009(Jul 7); 7: 56. [Full text via Libre OA][PMC version of the full text][PubMed Abstract] Final paragraph of the Abstract:

CONCLUSION: The fact that a higher percentage CD133+ cells were strongly associated with a poorer prognosis in patients with locally advanced colon cancer implicated that CD133+ cancer cells contribute to the tumor progression, and the overpopulation hypothesis of cancer stem cell seems reasonable.

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.