UF researcher identifies stem cell marker for possible 'root' of colon cancer

April 7, 2009

GAINESVILLE, Fla. — To truly kill colon cancer and eliminate the risk of recurrence, it is important to kill the “root” of the disease, according to a University of Florida College of Medicine surgeon.

“It’s like a dandelion, if you don’t kill the root it just keeps coming back,” said Dr. Emina Huang, a UF colorectal surgeon, who added that colon and rectal cancers have high recurrence and spread rates, especially if the disease is not found until advanced stages.

Her findings, available online now and to be featured on the cover of the April 15 print version of Cancer Research, identify a biomarker for colon cancer stem cells that she believes will help researchers further evaluate the cancers’ origins and progression. The discovery sheds light on the cancer stem cell theory, an idea that has arisen because cancer cells and stem cells share many qualities, including the ability of cancer stem cells to demonstrate self-renewal.

The research determined a protein called aldehyde dehydrogenase 1, or ALDH1, can be used to identify, isolate and track these ultra-resilient cells throughout the development of malignant colon or rectum disease. Previously used markers cannot as precisely track colon cancer stem cells.

“Without a better handle on what cells might be contributing to cancer metastases and recurrence, we won’t have any targets to go after,” said Huang, an associate professor in the UF department of surgery and a member of the Program in Stem Cell Biology and Regenerative Medicine at the UF College of Medicine. “This gives us a potential target.”

According to the American Cancer Society, about 150,000 Americans are diagnosed each year with colorectal cancer, and more than 50,000 die from the disease. In addition to the potential advances in therapeutic strategies, Huang said having a more direct target to explore will benefit progress in the areas of diagnostics and prevention.

In collaboration with Dr. Bruce Boman, a professor of medical oncology at Thomas Jefferson University in Philadelphia, Huang chose to evaluate ALDH1 because of its known association with breast, brain and other cancers. In addition to being a strong marker for malignant colon stem cells, the researchers believe ALDH1 may be a marker for benign colonic stem cells. Whether these two types of colonic stem cells are one of a kind still needs to be determined.

Researchers implanted human colon tissue cells into mice and analyzed the resulting growth. Although normal cell tissue was evaluated, it never replicated in the mice — only the tissue that was malignant grew. Comparing ALDH1 patterns with that of the previously used markers, the researchers found ALDH1’s presence was much more targeted, suggesting a way to more definitively identify colon cancer stem cells in the original tissues.

They also noted that ALDH1 indicated an increasing number of colonic stem cells throughout the progression of colon tissue’s transformation from normal cells to premalignant cells to cancerous cells. These findings support the theory that an increase in ALDH1 expression marks the tumor growth in colon cancer stem cells.

Dr. Sanford Markowitz, the Markowitz-Ingalls professor of cancer genetics in the department of medicine at Case Western Reserve University in Cleveland, said this research marks an important new advance in demonstrating that ALDH1 is the most specific marker yet described for identifying stem cells in both the normal colon and in colon cancers.

“The work advances our understanding of how the health of the normal colon is maintained, and also offers a chance for helping to identify new targets that may lead to new approaches for treating colon cancers, by focusing on the stem cells that maintain these tumors,” said Markowitz, who also is an investigator with the Howard Hughes Medical Institute.

Although the theory that cancers are seeded by cancer stem cells is still becoming scientifically accepted, Huang said she thinks that in every cancer there is a small fraction of cells capable of reproducing the cancer. If these unique cells are not killed or removed during treatment, the cancer will not be entirely destroyed.

While changes in patient care are most likely years away, she says the findings give researchers an immediate target to focus on as they try to develop new medical interventions and optimize treatment regimens to completely kill the disease.

Potentially, tumors could be examined to determine if there is an overwhelming expression of the biomarker, or tests taken to determine if the biomarker may be circulating in the bloodstream — scenarios that could possibly indicate a worse outcome, thus signaling the need for more aggressive treatment.

“The next step is to look at some of the predisposing conditions and see if the pattern is suggestive of anything we can do in the prevention mode,” said Huang, who noted that people with inflammatory bowel disease, for example, have a higher risk of cancer.

Primarily conducted at the University of Michigan in Ann Arbor, the team’s research was funded in part by the National Cancer Institute, the Will and Jeanne Caldwell Fund for Cancer Research and private grants.