Clonal Evolution or Cancer Stem Cells?

Nothing biological is ever as simple as it could be - and it usually isn't as simple as your scientific predecessors hoped it to be either. So here we are again, revisiting skepticism on the whole cancer stem cell issue:

According to a longstanding cancer model, known as "clonal evolution," tumors arise from normal cells that mutate and generate abnormal offspring that also mutate, forming a mass of genetically varied cancer cells. However, there has been a new wave of interest in an alternative explanation - that tumors are initiated and driven by a single, abnormal type of adult stem cell found in, for example, breast tissue, resulting in a population of genetically identical tumor cells. Moreover, several pathways and genes required for normal stem cell function are activated in cancer cells and play essential roles in the development of tumors.

It would be a wonderous development if it turns out that a significant fraction of cancers are driven by errant stem cell populations - because that would mean (a) we are very close to being able to efficiently detect and destroy them, (b) the vast influx of resources into the field of regenerative medicine and stem cell research will also contribute to meaningful cures for cancer.

In effect, this is one aspect of asking just how hard it will be to transform cancer into a managed chronic condition. Easier than we thought if it's all stem cells going bad in clearly identifiable ways ... but that may not the case. Nothing is ever simple in biology, remember? I looked at the skeptical viewpoint on cancer stem cells a little while back, and here is a little more context in terms of present research:

According to the cancer stem cell hypothesis, the few self-renewing stem cells that fuel the cancer are difficult to kill, and their persistence may explain why tumors so often recur following successful therapy. In 2003, scientists purified what they proposed were breast cancer stem cells from patients’ tumors. The distinctive molecule, or marker, on the cells’ surface, known as CD44+, was identical to the marker on normal breast cells. When injected into mice lacking an immune system, the CD44+ cells demonstrated the ability to initiate breast tumors. The scientists also found closely related cells with a CD24+ marker and suggested that they were offspring of CD44+ cells.

The team led by Polyak and Michail Shipitsin, also of Dana-Farber and HMS, used gene activity analysis to clarify the relationship of the two cell types. They generated gene libraries from CD24+ and CD44+ cells purified from normal mammary epithelium and fluids within the chest, and from primary invasive tumor samples collected from breast cancer patients.

The findings, the scientists reported, fit more closely with the clonal model than the cancer stem cell hypothesis. That is, the CD24+ cells were very similar to the CD44+ cells, but not always genetically identical - which they would have been if the CD44+ cells were true stem cells and the CD24+ their offspring.

"Although CD44+ cells appear to express many stem cell markers, the genetic difference between CD24+ and CD44+ cells within a tumor questions the validity of the cancer stem cell hypothesis in breast cancer, and suggests clonal evolution involving intra-tumoral heterogeneity as an alternative explanation," the authors wrote.

However it happens, we must see cancer wrestled into control as a part of living much longer lives through advanced medicine. Easy or hard, that goal must be accomplished - otherwise the only benefit resulting from the defeat of other age-related conditions will be a much greater chance to experience death by cancer.

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I agree with Polyak et al. in that the clonal evolution model fit well with the published data. Cancer stem cell hypothesis was arrived with the data from xenotransplantation studies using irradiated NODscid mice. However other studies indicate that C6 glioma cells for example, have more cancer stem cells than the low frequency of cancer stem cells detected by the NODscid mice test system, when tested with another xenotransplantation system consisting of nude mouse. This makes sense because it is well known that there is tumor cell heterogeneity within the same tumor and more than one type of cancer stem cells may exist in the same tumor. Besides, both the clonal evolution hypothesis and the cancer stem cell hypothesis fail to explain the mode of origin of heterogeneity. We have published an alternative model termed the neosis paradigm, based on our studies. Further info on our model can be found in the internet by googling for R. Rajaraman + Neosis. In short, according to our neosis paradigm, cancers produce their own stem-like Raju cells continuously since cancer cells appear not to be immortal as we thought; they undergo senescence several times from which they escape via neosis to yield Tumor Rejuvenating Raju cells (TRRCs), which display stemness with extended, but limited, mitotic life span.

Posted by: R. Rajaraman at December 5th, 2007 9:26 AM

New evidence indicates that neosis may be involved in the execution of Epithelial-Mesenchymal Transition (EMT) [Gosselin et al., Caner Res.2009. Also Mani et al 2008 have shown that the breast cancer stem cells are relatively short-lied and spontaneously undergo Mesenchymal-Epithelial Transition (MET). This suggests that just like the embryo undergoes several EMTs and METs during development, tumor cells also undergo several EMTs and METs spontaneously or after genotoxin-induced senescent phase give rise to newer populations of Raju cells every time a cell undergoes neosis, with varying degrees of resistance, among other properties, thus contributing to the tumor cell heterogeneity, which is constantly subjected to natural selection. It would appear that tumor cells avoid mitotic catastrophe by keeping the nuclear envelope intact during karyokinesis, so that the neotic offsping can inherit genomic plasticity. Thus neosis has important implications for homeostasis, regenerative medicine and also for gene therapy.

Posted by: Dr. R. Rajaraman at July 12th, 2010 2:16 PM

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