Study Questions "Cancer Stem Cell" Hypothesis in Breast Cancer

A Dana-Farber Cancer Institute study challenges the hypothesis that "cancer stem cells" - a small number of self-renewing cells within a tumor - are responsible for breast cancer progression and recurrence, and that wiping out these cells alone could cure the disease.

Instead, the scientists report in the March issue of Cancer Cell that they have identified two genetically distinct populations of cancer cells in samples of human breast tumors - one of the types being a cell recently proposed by other scientists to be a true breast cancer stem cell.

“If the breast cancer cells were all coming from a single cancer stem cell, you might be able to cure the disease with just one drug,” said Kornelia Polyak, MD, PhD, of Dana-Farber, senior author of the paper. “But our findings suggest that the tumor cells come from a ‘stem-like’ progenitor cell, and then diverge genetically, so I think you have to treat both cell types.”

The results suggest that both cell types, and probably others, are involved in the development of breast cancer. While analyzing the genetics of each cell type, the researchers discovered that the proposed “cancer stem cells” were driven by an activated molecular pathway that makes them resemble normal stem cells.

Women whose breast tumors are largely made up of these “stem-like” cells are at higher risk of recurrences.

On the positive side, the abnormal activated pathway in these cells, known as the TGF-Beta1 signaling pathway, can be blocked by experimental drugs now entering clinical trials, said Polyak, who is also an associate professor at Harvard Medical School. Such inhibitors, in combination with other therapies, may improve the prognosis in breast cancers fueled by these cells.

Clonal evolution or cancer stem cells?
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.

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.