Diagnostics and Imaging Week Contributing Writer

The idea that tumors contain a limited subset of cancer stem cells which keep cancer going is currently generating a lot of excitement — as well as searches for the stem cells in question — among cancer researchers.

Find the stem cells, the theory goes, and all one needs to do is kill that population to prevent recurrences and metastases.

However, research published in the March 2007 issue of Cancer Cell may put a damper on some of this enthusiasm.

In their paper, researchers compared two populations of tumor cells that express different markers on their cell surface. One of the populations, so-called CD44 cells, have been suggested to be breast cancer stem cells in earlier studies, while CD24 cells were thought to descend from CD44 cells.

Kornelia Polyak, assistant professor of medicine at Harvard Medical School (Boston), and her colleagues analyzed CD44 and CD24 cells from tumor samples as well as metastases, and found several pieces of evidence arguing against the idea that CD44 cells are true cancer stem cells.

In some tumors, though, the two populations had some of the same genetic alterations and so appeared to be descended from the same cell founder cell. CD24 cells had additional genetic alterations that were not seen in the CD44 cells, suggesting that CD24 cells continue to divide.

“We agree that cancer starts from one cell,” Polyak clarified. But that single cell is not a stem cell in the sense of having unique capabilities to self-renew. As they continue to divide, “the clones can have further genetic alterations.”

The other finding that argues against CD44 cells as stem cells was that in all of their samples from metastases, the scientists found there were “dramatically higher” numbers of CD24 cells — but not CD44 cells — in metastases than in primary tumors, which is hard to reconcile with the notion that CD44 cells are stem cells and CD24 cells their offspring.

The idea that CD44 expressing-cells are cancer stem cells comes from data showing that when they are implanted into mice, these cells are more aggressive and better able to seed new tumors than CD24 cells. Polyak and her team also found a high proportion of CD44 cells correlated with have an alternative explanation for why this is the case.

Pathway analysis showed that several different pathways are up-regulated in the two cell types. CD44 cells may simply have a gene expression pattern that is more favorable to recurrence and metastasis.

Polyak and her colleagues found that the pathways more active in CD44 than CD24 cells “are involved in cell motility, invasion, apoptosis, and ECM remodeling,” while the genes that are highly active in CD24 cells are typically involved in inflammation and immune function.

In the simplest sense, the findings are bad news as far as the treatment of cancer is concerned, since it is presumably easier to go after a single stem cell type than multiple types of cells which continue to accumulate genetic alterations as they divide.

“Heterogeneity will help tumor progression, because any cancer cell that is dividing can acquire a change and be selected for under the right circumstances,” Polyak said.

In practice, this means that if a subset of cancer cells is eradicated by one type of treatment, other cells with mutations that render them resistant can keep replenishing the tumor.

However, the fact that TGF-beta is one pathway that is specifically activated in the CD44 cells is a potential silver lining; it suggests that inhibiting this pathway — a strategy that is currently in clinical trials — might specifically benefit patients who currently have a poor prognosis.

Polyak noted that while treatment implications are in the future, the research shows up the obvious need for more detailed analysis of tumor samples to figure out what’s going on in them.

“What’s important to do, and what we are planning to do, is look at more tumors at the single-cell level,” she said. “Maybe there is much more heterogeneity than we realize.”

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