Cancer stem cells and CD133 controversies

by Alexey Bersenev on November 27, 2008 · 1 comment

in cancer stem cell, under discussion

Blogging on Peer-Reviewed ResearchThe cancer stem cell boom is continuing and it highlights new controversies and brings a new discussions into the field.

I think that today most researchers are convinced by the concept that cancer stem cells (CSC) are a tiny population of cells from the whole tumor mass, which have the ability to generate a new tumor, and therefore are responsible for initiation of cancer growth and relapses.

why do we need to study them?
1. to understand the nature of cancer initiation and it’s progression
2. to selectively target them in order to eradicate cancer and prevent relapses/metastasis
3. to make a prognosis about disease of particular patient and correct the treatment.

It is no problem for researchers to isolate CSC populations from most solid malignant tumors, based on expression of normal stem cell markers. Let’s say to find a CSC you can take any tumor, make suspension from it and sort cells which have “stem cell markers”, then do serial transplant in immunocompromised mice, proving their self-renewal ability by recapitulating tumor growth.

CD133 – is the one of the common adult stem cell markers, was also considered as a bona fide CSC marker. It was described for the first time 5 years ago by Dirks group in human brain tumors and later for multiple solid tumors – hepatocellular carcinoma, pancreatic cancer, colon carcinoma, osteosarcoma, prostate cancer, etc.

Ok, now is when the controversies begin.

1. First I’d like to capture your attention: CD133 is not a marker for most of CSC from solid tumors, as we thought before, but only for some of them.

At least two papers indicated that. First study –
CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors came from Shanin Rafii lab. in Cornell U:

citation from the commentary:

CD133 was thought previously to have a very restricted distribution within tissues; the authors have used genetic knock-in models to demonstrate that CD133 in fact is expressed on a wide range of differentiated epithelial cells in adult mouse tissues and on spontaneous primary colon tumors in mice. In primary human colon tumors, all of the epithelial cells also expressed CD133, whereas metastatic colon cancers isolated from liver had distinct CD133+ and CD133– epithelial populations. Intriguingly, the authors demonstrate that the CD133+ and CD133– populations were equally capable of tumor initiation in xenografts. In light of these new findings, the popular notion that CD133 is a marker of colon CSCs may need to be revised.

scheme of classical xenograft assay (used by researchers to prove self-renewal of CSC) and controversial results that got Rafii group (credit Sergey Shmelkov, 2008):

More about possible difference in methods and between cancers you can read here.

After challenging the concept about uniformity of CD133+ expression on CSC in colon cancer by Shmelkov, glioblastoma (GBM) was the next on the line:

The CD133-low GBMs showed more invasive growth and gene expression profiles characteristic of mesenchymal or proliferative subtypes, whereas the CD133-high GBMs showed features of cortical and well-demarcated tumors and gene expressions typical of proneuronal subtype. Both CD133-positive and CD133-negative cells purified from four out of six GBM patients produced typical GBM tumor masses in NOD-SCID brains, whereas brain mass from CD133-negative cells showed more proliferative and angiogenic features compared to that from CD133-positive cells. Our results suggest, in contrast to previous reports that only CD133-positive cells of GBMs can initiate tumor formation in vivo CD133-negative cells also possess tumor-initiating potential, which is indicative of complexity in the identification of cancer cells for therapeutic targeting.

2. Another controversy is the connect to prognosis of cancer disease and patient survival.

If we believe that CD133+ cells from tumor is CSC, detection of these cells in patient samples could be associate with bad prognosis and might correct treatment protocol. And there is some evidence for it:

A: CD133 expression is an independent prognostic marker for low survival in colorectal cancer.

B: Stem Cell Marker CD133 Expression Predicts Outcome in Glioma Patients

But recent report of Salnikov – Cancer stem cell marker expression in hepatocellular carcinoma and liver metastases is not sufficient as single prognostic parameter shows that it’s not the case for all of cancers, at least for hepatocellular carcinoma:

We profiled suggested cancer stem cell markers in tissue specimens of hepatocellular carcinoma and colorectal carcinoma liver metastases. About 1% of cells co-expressed cancer stem cell antigens, but there was no correlation between the amount of CD133+, CD133+/CD44+ or CD133+/CD24- cells and the patients’ clinical–pathological status or with the cancer stem cell marker-positive cells localization. CD133+ and CD133- fractions of Huh7 cells did not differ in migratory properties. Therefore, presence of markers alone should be taken with caution as single prognostic parameters.

At the end I’d like to conclude:
– there is no universal markers applicable for all CSC in different solid tumors;
– population of tumor-initiating cells from one particular cancer can be describe by combination of markers different from other cancers;
– clinical prognosis based on only one “cancer stem cell marker” could be not credible for some cancers.

read more about cancer stem cell
and even more

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