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.