Can we uncouple stemness and carcinogenesis?

by Alexey Bersenev on December 4, 2010 · 0 comments

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I keep asking this question and trying to find an answer again and again. It is important if we’re going to use cells as a medicine in safe settings. The last two decades of research have unveiled remarkable similarities between malignant cells and stem cells. It becomes more evident with development of the cancer stem cell concept. Last year I’ve asked a question about possible separation of normal stem cells from cancer cells based on cell surface markers. Despite the identification of new targets, this approach is still elusive. Now, I’d like to talk about molecular regulation and signaling in normal stem cells and cancer cells.

I’m really thrilled by the fact that every newly discovered regulator of hematopoietic stem cells self-renewal is a pro-oncogene or tumor-suppressor and vice versa. For example, p53 tumor-suppressor was recently discovered as a potent regulator of HSC self-renewal and quiescence. Once you inhibit tumor-suppressor gene in tissue stem cells, they’ve “gone wild”, with a hyper-activate self-renewal and proliferation program and result in malignant transformation:

The need for cells to proliferate over the life span of an organism may place individuals at risk in the numbers game that underlies cancer. Adult stem cell lineages may have evolved to lower this risk by minimizing the chance of cells escaping the mechanisms that restrict their expansion.

Genes that program self-renewal rather than differentiation are likely to be candidate oncogenes.

Some remarkable similarities between stem cells and cancer I’d like to note:
1. Core pluripotency genes, such as Oct4, Sox2 and Nanog are also overexpressed in some malignant tumors;
2. There are significant similarities in genome-wide signatures between embryonic stem cells (ESC) and bulk tumor cells;
3. Gene expression signature between tissue adult stem cells and tumor-initiation cells can significantly overlap;
4. High level of normal stem cell markers can correlate with poor clinical prognosis in oncology;
5. Both normal and CSC share the same activated signaling pathways (Hedgehog, Notch, Wnt);
6. Normal stem cells and cancer cells sharing the same chemotactic receptor-ligand axises for migration and trafficking (CXCR4-SDF1).
7. The process of induced reprogramming can promote and launch cancer stem cell program:

Nonetheless, our results suggest that the ESC-like transcriptional program may be specifically reactivated in cancer stem cells. This idea poses a challenge for regen- erative medicine to avoid promotion of cancer stem cells during cell-based therapy, such as in the use of iPSC. It is likely that incom- plete or aberrant reprogramming to iPSC may lead to cells with some properties of iCSCs.

So, the mounting evidence suggests that we probably can’t uncouple molecular regulation of normal self-renewal from carcinogenesis and tumorigeneity. In other words if we artificially activate self-renewal program we launch cancer activation program right away. This is a bad news for those aiming at stem cell expansion ex vivo for therapeutic use.

Recently, new interesting data came up from Stuart Orkin lab, which showed significant differences in transcriptional regulation and gene expression between ESC and cancer cells.

Reanalysis of prior data sets in this manner raises concern regarding the hypothesis that cancer cells, or cancer stem cells, recapitulate regulatory programs characteristic of embryonic stem cells. As a unifying view, the hypothesis is attractive and has gained considerable attention in recent literature.

The authors were able to define 3 separate transcriptional genetic modules in ESC – Core module (Oct4, Sox2 and Nanog), Polycomb module and Myc module. Remarkably, only the Myc module appeared to overlap with different human malignant tumors’ genetic signatures. Core module was repressed in all tested tumors, but Myc module was very active and correlated with adverse prognosis.

The relationship between ES cell and cancer signatures has been a focus of attention given that self-renewal is a hallmark of both cell types. It has been proposed that the activation of an ESC-like gene expression program in adult cells may confer self-renewal to cancer cells or cancer stem cells. It is noteworthy that we observed very similar patterns of module activity between our Myc module and the previously defined ESC-likes (Core ESC-like gene module and mouse ESC-like gene module) (Wong et al., 2008), but not with our Core module, in situations we tested.

They argue that the ESC genetic program can not be simply linked to cancer or cancer stem cells, because it is composed from the functionally distinct modules. So, we can’t say that cancer cells reactivate ESC gene signature in order to progress.

Importantly, Myc appeared to have different function in adult (hematopoietic) stem cells and ESC compared with cancer cells. In normal stem cells Myc is marker of proliferation and differentiation rather than self-renewal. There is some evidence that Myc is associated with self-renewal of cancer cells, but it’s not really clear and should be investigated further.

… in the hematopoietic lineage, the proliferating progenitor is actually the cell that upregulates Myc targets rather than the self-renewing stem cell. This suggests that the presence of the Myc module in gene expression signatures from ES cell populations and poor prognosis cancers may be more of a reflection of the active proliferation occurring in both rather than self-renewal.

Authors also tested ESC genetic modules in leukemic stem cell-enriched (LSC) population in mouse models and concluded:

If the gene expression findings are functionally relevant to self-renewal of LSCs, our findings undermine the notion that reactivation of an ESC-like pattern is critical for LSCs in this setting. In contrast, Myc module activity alone appears to correlate with LSC frequency in mouse AML models. Core module activity does not appear to be a major determinant of LSC frequency in AML.

Unfortunately, authors tested only bulk human tumors, without separation for “tumor-initiating (stem)” and the rest (“non-stem”). So, it’s hard to say for sure what is the function of Myc in context of heterogeneity of cancer cell populations.

Based on these data it is still unclear to me how we can play with Myc in order to uncouple such qualities as self-renewal and proliferation in normal stem cells and cancer cells. Even if we can efficiently inhibit Myc in cancer cells, it could affect normal stem cells function. For example, c-Myc is a survival factor, important regulator of proliferation, self-renewal and differentiation balance in hematopoietic stem cells.

I wonder what is the place of the self-renewal program in cancer progression? If Core module (composed from more that 100 “pluripotency genes”) is down, what is active in tumorigenic serially transplantable population of cancer cells?

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