Stem Cells Seem to Underlie Colon Cancer

TORONTO, Nov. 21 -- While stem cells have been widely heralded as holding the keys to the cures of chronic diseases, evidence is mounting that mutated stem cells are at the root of cancer.

These cancer stem cells are the bad seed responsible for tumor growth and they form less than one in 60,000 tumor cells, according to researchers here and in Italy.

In parallel articles published online in Nature, the two research groups demonstrated that only a tiny fraction of the cells in colon cancer can give rise to new tumors -- refuting decades of perceived wisdom that held that any cancer cell was a potential tumor.

While current therapies treat colon cancer as a single entity, "not every colon cancer cell has the ability to keep that tumor going," said John Dick, Ph.D., of Toronto's Princess Margaret Hospital, who led the Canadian team.

In 1994, Dr. Dick was the first to show that cancer stem cells underlie some forms of leukemia, and since then such predecessor cells have been identified in breast and brain cancers.

Dr. Dick's team, and an Italian group led by Ruggero De Maria, M.D., of Rome's Istituto Superiore di Sanit, used genetically engineered mice to show that only mutated colon cancer cells expressing a surface protein called CD133 could give rise to a new tumor.

In immunodeficient mice, the Canadian team found, a transplant of 1,000 CD133-positive cells could reliably give rise to a new cancer. Even 100 such cells caused cancer in one in four mice, they reported.

The Italian group got the same results with 3,000 CD133-positive cells, they said.

On the other hand, cancer cells that did not express the marker -- between 81% and 98% of the original tumor mass -- did not produce new tumors, both groups found.

However, tumors generated by the CD133-positive cells had roughly the same proportion of CD133-positive and -negative cells as the original cancer, indicating that the CD133-positive cells were able to give rise to all the cells in the tumor mass, the groups reported.

The findings imply that "colon cancer, like acute myelogenous leukemia, breast, and brain cancer, is organized as a hierarchy in which a small population of (cancer stem cells) sustain the tumor," Dr. Dick and colleagues reported.

The identification of the cancer stem cells is not complete, however. Dr. Dick's group estimated that only about one in every 262 CD133-positive cells was actually able to produce a new tumor, so that additional markers will be needed to isolate the true cancer stem cells, they said.

The findings imply that most cancer therapies have been misdirected, said Alan Bernstein, M.D., of the Canadian Institutes of Health Research.

"All of our therapies have been targeting and killing the pawns," Dr. Bernstein told reporters. "But like chess, you have to kill the king to win the game."

If the cancer stem cells can be better characterized, Dr. Dick and colleagues said, "developing adjuvant therapies directed at specifically eliminating the (stem cell) fraction may prove to be a more effective strategy for reducing both local and distant recurrence."

The Italian researchers likewise concluded that colon cancer is caused by CD133-positive cells, "which should therefore be the target of future therapies."