Researchers Hone in on Cancer Stem Cells for Melanoma
WEDNESDAY Jan. 16, 2008 -- Melanoma has joined the list of cancers that can arise from a rare population of primordial cancer stem cells, Harvard researchers report.
Even more importantly, the scientists demonstrated for the first time that targeting these cells can slow down the growth of a tumor.
"The findings validate for the first time the potential therapeutic utility of the cancer stem cell concept," explained study author Markus Frank. "To my knowledge, cancer stem cells have not been specifically targeted to date via a prospective molecular marker."
Frank and his colleagues were interested in a particular protein called ABCB5, which is expressed on the surface of some progenitor skin cells and has been shown to confer cancer drug resistance to melanoma.
Hypothesizing that the pool of ABCB5-positive cells could include cancer stem cells, the researchers separated human melanoma cells based on whether or not they expressed ABCB5, transplanted both types of cells into mice, and monitored their ability to form tumors.
Fourteen of 23 mice injected with ABCB5-positive cells developed tumors, compared to one of 23 mice injected with cells that did not express the protein.
When a mixture of both types of cells were injected into mice, the authors found the ABCB5-positive cells were more likely to fuel tumors, and they exhibited stem cell-like properties -- that is, they divided to form both the bulk of the tumor and to regenerate the stem cells themselves.
Those findings -- that a stem cell subpopulation appears to contain the ability to reconstitute a tumor -- have been observed before in colon, brain, breast and pancreatic cancers, among others, albeit using a different cellular protein. However, the Harvard researchers added a novel twist: They showed both that ABCB5 expression correlated with disease severity, and that treatment of mice with an antibody directed against ABCB5 halted growth of existing tumors and inhibited the formation of new cancers.
Dr. Jeremy Rich, a cancer stem cell researcher at Duke University Medical Center, said, "The exciting thing is they have done things others haven't, which is to ask what is the impact of the marker on disease. First, there is an increase in ABCB5 levels as malignancy increases, and second, if you block its function with an antibody, you slow the growth of these tumors."
The results were published in the Jan. 17 issue of Nature.
According to the American Cancer Society, there were an estimated 108,230 new cases of melanoma in 2007 and 8,110 deaths.
The cancer stem cell hypothesis posits that tumors (like other noncancerous tissues) derive from a small population of primitive cells, which can divide and differentiate to form both the bulk of the cancer, and also more stem cells. Because most chemotherapeutic agents kill off the tumor cells, but leave the stem cells unscathed, the cancers return and metastasize.
The bottom line, according to the researchers, is that anti-cancer strategies need to be overhauled to kill off these stem cells.
Previous cancer stem cell studies have focused on the protein CD133. But it is not clear whether CD133 plays a role in stem cell behavior. According to Rich, such markers have sometimes been compared to the stripes painted on race cars: They do not make the car go faster, but they do help to identify it.
"This time, they have found a marker that is very interesting, because it looks like it may make the car go faster," he noted.
Also interesting, Frank noted, is the potential involvement of ABCB5 in mediating the cancer's resistance to chemotherapeutic agents.
"The findings establish a direct relationship between cancer stem cells, cancer progression, and chemoresistance in a human solid malignancy," Frank said. "This is a relationship that has been invoked often, but these findings provide first evidence of such a direct link."
But first more work needs to be done characterizing these cells. The cancer stem cells identified in this study are very rare; the authors estimated they represent about one in 1 million melanoma cells overall, and about one in 100,000 ABCB5-positive cells.
In other words, Rich explained, the researchers have not so much identified the cancer stem cells, as they have narrowed the search.
"They know the ZIP code of the cancer stem cell, but the full identity remains yet to be discovered," he said.
For more on melanoma, visit the American Academy of Dermatology.
Posted: January 2008