Trends in cancer stem cells – What can we learn from gene expression signatures?

by Alexey Bersenev on February 10, 2010 · 1 comment

in cancer, cancer stem cell

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I’ll try to keep you updated with the current opinions and trends in cancer stem cell research and clinical applications in the series of posts.

Clinical oncologists and cancer biologists spend a significant amount of time to investigate “genome-wide” signatures of tumors. This knowledge should help to diagnose, predict cancer development, make a prognosis for outcome and personalize a patient’s treatment. However, if the cancer stem cell (CSC) hypothesis is correct, we should not extrapolate those signatures to all tumor, but rather separate cancer-initiating cells population from non-tumorigenic cells. If you start to compare them, you can came up with quite interesting findings.

Correlation between embryonic stem cell (ESC)-like gene signature and poor clinical prognosis

The positive correlation between ESC-like genetic signature and tumor aggressiveness and poor clinical prognosis has been demonstrated for a number of cancers. For example, in leukemia and epithelial cancers activation of “ESC-like program” was identified. But some of these studies compared only bulk tumor cells versus normal tissue cells, but not cancer-initiating cells versus non-tumorigenic cells. Also, ESC-like signature was not consistently associated with tumor-initiating cells. It’s not surprising for me that poor patient prognosis, which is directly correlated with histologically poorly differentiated cancers (was shown many years ago), is associated with activation of ESC-like “gene module” expression. Most of so called “stemness genes” is also cancer-associate genes”.

Excerpt from the commentary:

Thus, the eSC-like signature in cancers is more likely the results of re-activation of an eSC-like phenotype during the course of tumor progression rather than an inherited phenotype from a cell-of-origin.

Correlation between adult tissue stem cell (TSC)-like gene signature and poor clinical prognosis

A recent study by Thomas Hussenet compared ESC-like and adult TSC-like gene signatures in tumorigenic (aka cancer stem cell (CSC)-enrich) versus non-tumorigenic cancer cells. They showed that TSC-like gene program is specifically activated in breast cancer-initiating cells (dissected by CD24-/CD44+ phenotype) in contrast to ESC-like program, which is activated in both – tumorogenic and non-tumorigenic cancer cells and bulk tumors. This trait was similar among a few murine and human epithelial cancers. Confirming the previous study by Michael Clarke group, they showed that activation of TSC-like gene signature was associated with poor clinical outcome in breast and lung cancer patients.
These findings could be interesting, if surface phenotype of breast CSC is a valid marker.

High level of stem cell markers correlate with poor clinical prognosis

Sometimes you don’t need to look at global or a partial gene expression profile of a tumor to predict an outcome. You can just look at commonly used ” normal stem cell markers” and find a correlation. It was very well shown for CD44+/CD24low and breast cancer, ALDH and breast cancer and leukemia, Bmi-1 and colon cancer, CD133 and colorectal cancer, and others. Interestingly, many of these studies were challenged later and the significance of these markers is still controversial. I guess it happened because different groups used different cohorts of patients and performed different sets of assays.

I also wonder if for each type or malignancy this possible correlation could be so different. For example, for leukemia, prognostic irrelevence of common human hematopoitic progenitor/stem cell marker CD34 was shown in 1992. But also it could depends on how further you can dissect the stem cell phenotype.

Will CSC gene expression signatures be useful in the clinic?

Well, cancer genome studies by microarrays is not a new thing, so what did we learn from it? Serge Koscielnyin his essay wrote:

Gene microarrays have brought little progress to the clinical management of cancer since Shena et al.’s 1995 publication. Van’t Veer et al. gave us a proof-of-concept when they showed that the gene microarray information could be used to predict the prognosis. Unfortunately, these predictions of prognosis are not very accurate and have not improved since 2002. This state of affairs is extremely disappointing given the potential of the technology.

So, do we have any hope about CSC gene expression signatures? I think, at this point in time, it is important to study gene expression signatures of CSC, because first of all we need to answer the question: Are CSCs clinically relevant? And if the answer is YES, overlapping of gene modules will allow us to identify new molecular therapeutic targets. Many researchers (not sure about clinicians) hope that defined CSC molecular signatures will allow us make a clinical prognosis and design personalized treatment.

also read cancer stem cell category
twitter hashtag: #cancerSC
Connotea tags: cancer SC; gene expression profile

{ 1 comment… read it below or add one }

James E. Trosko February 12, 2010 at 1:21 pm

These comments continue to add to the debate on the two hypotheses of the origin of cancers(adult stem cell versus the de-differentiation or “re-programming” of a somatic differentiated cell). Isn’t it interesting that those who claim cancers are the result of the re-programming during the multi-stage, multi-mechanism process of carcinogenesis fail to mention that no one has successfully neoplastically transformed a primary culture of human fibroblasts or epithelial cell, which ,under normal culture conditions, contain few, if any, adult stem cells. However, when “immortalizing viruses” ( SV40 or HPV-e6-e7)are added to early primary cultures, a few “immortalized” , but non-tumorigenic clones, are obtained, which, then, can be subsequently neoplastically transformed.

Might it explained more easily that these viruses entered all cells ( the few adult stem cells; the transit-amplifying and terminally differentiated cells) but only blocked the “mortalization” of the adult stem cells [one does not immortalize an already normal immortal adult stem cell? The fact that only a few such “immortalized” cells are recovered from a primary culture is equivalent to the few rare adult stem cells in the primary culture. Also, the frequency of “iPS” cells is about what one would expect from the number of adult stem cells in a primary culture.

In effect, those who still believe that “iPS” cells are really reprogrammed somatic differentiated fibroblast must believe that carcinogenesis starts with the induction of an “iPS” cell during the single “hit” of the initiation process, such as what happens when the skin is exposed to UV light. Yet those “initiated” skin cells do not form teratomas but, only after chronic exposure to non-mutagenic tumor promoters, such as TPA, does one see papillomas and later , carcinomas.

The real problem is that no one has produced “iPS” cells from differentiated skin keratinocytes or mature hepatocytes, yet our lab has easily produced human breast carcinomas from a normal human breast adult stem cell. Moreover, no one has compared the frequency of “iPS” cells from a primary culture of human cells versus that from a pure culture of human adult stem cells. I find it interesting that almost every day, new ways of producing “reprogramming” cells are reported( i.e., mouse skin cells directly, without the need for vector transmission of embryonic stem cell genes).

Ultimately, while this forum allows for academic freedom of thought in science, the current atmosphere of science, as is evidenced in trying to get grants or papers published, has not allowed easy access to challenge prevailing paradigms. When one views the power of the “iPS” story, via its publications in very influencing scientific journals ( and even the public media), and the absence of any challenge ( not to the reality of the production of the “iPS” but of the interpretation of the origin of these cells), one can see how science and the public are not well served.

In my own case, all my grants have been “trashed” or “triaged” and all of my publication, those that ultimately did get published, were rejected by the same journals that can’t publish the “iPS” stories fast enough.

It seems that science ( peer reviewers of grant proposals and manuscripts), while trying to assure quality, rigorous methodology, and ethical standards, should let the individual with “crazy” ideas or their own unique interpretations of their own data, make a fool” of themselves by allowing them to interpret their own data. In my case, I know I might not be correct…but then again, I’m sitting on my experience (of over 20 years of working with human adult stem cells and 44 years of studying all phases of carcinogenesis). With this experience as my guide to understand the “iPS” interpretation and the “re-programming” of differentiated somatic cells makes no sense to me. It does not help me rationalize all my research experience. If someone can demonstrate to me with new experiments ( not all those published as of yesterday), I will immediately be “converted”. I’m not so stupid as to hold onto a scientific idea that no longer has validity.

If one has not read my ideas , see: Tai, M.H. et. al, “Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis”. Carcinogenesis 20: 495-502, 2005; Trosko, J.E., “Cancer stem cells and cancer nonstem cells: From adult stem cells or reprogramming of differentiated somatic cells”. Vet. Pathol. 46: 176-193, 2009; Trosko, J.E. “Reprogramming or selecting adult stem cells?” Stem Cell Rev.4:81-88, 2008).


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