Posted by: Dan | August 18, 2006

Those Subversive Cancer Cells again…

Self-renewal
Along the lines of my previous posts on Cancer Stem Cells (CSCs) and genetic programming comes a research report and commentary in the journal Nature echoing what I’ve been saying for a while: Krivtsov et al. (Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9), and the commentary from Emmanuelle Passegué – A game of subversion.

While they continue to use the CSC terminology, the authors define it simply on the basis of self-renewal shared by true stem cells (in this case hematopoietic stem cells) and neoplastic cancer cells, and they ask whether stem cells might not be the only source of cancer stem cells.

First, their definition of stem cells:

Hence, stem-cell identity can be summed up as a gene-expression signature that differs from the signature of non-stem-cell populations.

To which I ask, why do genetic definitions reign supreme? (rhetorical question)

Seriously though – from a cell biology perspective, stem cells and cancer cells display different proliferation schemes. The former is a well-defined and physiological lineage of cells, where cells of each type deviate little from the specified phenotype, while the latter benefits from dysfunction and genetic variation in the acquisition of pathological traits – hence the stem cell paradigm is not as accurate a description as the “evolving ecosystem model of neoplasms.”

But okay, back to the commentary which says:

What Krivtsov et al. show is that transformed myeloid progenitors aberrantly express a small number of stem-cell genes (363 genes), while still displaying the overall gene-expression profile of myeloid progenitor cells. So the transformed progenitors do not become stem cells but rather acquire stem-cell-like behavior

Yes! Exactly!

And more on Krivtsov et al.:

…these findings support the idea that subversion of stem-cell properties in non-stem-cell populations can happen in the course of a human disease.

Is this really so unexpected? A fundamental property of cancer cells is the ability to subvert the normal mechanisms that restrain unfettered growth. The loss of self-renewal potential during normal differentiation might be viewed as such a safeguard, so it follows that uncoupling the property of self-renewal fro other stem-cell characteristics could have potent cancerous effects.

Indeed, as Passegué suggests, the next step is to characterize the genes and/or pathways that are crucial for establishing self-renewal in cancer cells. And I’m sure we’ll discover that in more cases, genes involved in development and heirarchical transcriptional regulation are playing significant roles in cancer progression, and therapies directed against the acquisition and subversion of such key regulators may prove potent tools for oncologists.

References:

  • Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9. Krivtsov AV, et al., Nature. 2006 Mar 17; 442(7104):818-822. Epub 2006 Jul 16. Pubmed.
  • Cancer biology: A game of subversion. Passegue E. Nature. 2006 Aug 17; 442(7104):754-755. Pubmed.

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