Marker Found That May Be Cellular Basis of Colorectal Cancer

The findings indicate that eliminating ABCB5-expressing cells is crucial for effective colorectal cancer treatment, while adding to the growing body of evidence for a theory of cancer growth called the cancer stem cell hypothesis.

An international team led by Brian J. Wilson, PhD, Tobias Schatton, PhD, and Markus Frank, MD, of the Transplantation Research Center at Children's Hospital Boston (MA, USA), and Natasha Frank, MD, of the VA Boston Healthcare System and Brigham and Women's Hospital (Boston, MA, USA), and colleagues at the University of Wurzburg (Germany) reported the findings online in the journal Cancer Research on June 7, 2011.

An estimated 141,000 people in the United States alone will be diagnosed with colorectal cancer this year. While its mortality has been declining over the last 20 years due to screening and improved treatment strategies, colorectal cancer is still the second leading cause of cancer-related death in the United States.

Recognizing ABCB5's role as a marker of tumor recurrence in melanoma and liver cancer, and knowing from earlier studies that the gene for ABCB5 is also active in colorectal cancer, the investigators examine the protein's expression in both normal and cancerous colorectal tissue specimens. They discovered that ABCB5 is found only rarely in healthy colorectal tissue, but is present at levels 23 times greater in cancerous tissue.

Underlying its preferential expression on stem cells, ABCB5 was frequently accompanied on both healthy and cancerous cells by a second protein, CD133, which is believed to be a marker of both healthy intestinal stem cells and colorectal cancer stem cells. CD133 is also associated with aggressiveness in colorectal cancer.

To determine ABCB5's role in treatment resistance, the team examined biopsies gathered from colorectal cancer patients both before and after treatment with 5-fluorouracil (5-FU), a standard chemotherapeutic agent for this tumor. They found that the percentage of cells expressing ABCB5 increased more than five-fold after treatment.

Employing a mouse model of colorectal cancer, the researchers also found that cells expressing ABCB5 were distinctly resistant to 5-FU. Knocking down ABCB5 expression both blocked the growth of these cells and restored their sensitivity to the drug, showing that ABCB5 is not only a marker of treatment resistance but actually drives it.

"iWith ABCB5, we have a molecule that is present at higher levels in colorectal cancers than in healthy cells, that marks the subset of cancer stem cells in human patients that will resist therapy, and that mediates that resistance at a functional level," said Dr. Markus Frank, a staff scientist Children's department of medicine and an assistant professor of pediatrics at Harvard Medical School (Boston, MA, USA). "It's a new mechanism of 5-FU resistance with very significant translational and therapeutic relevance," added Dr. Natasha Frank, a research associate at Children's Hospital Boston, an associate physician in the division of genetics at Brigham and Women's Hospital, and director of the Genetics Clinic at the VA Boston Healthcare System. "We think that these are the cells that need to be eliminated for successful treatment of colorectal cancer."

The cancer stem cell hypothesis holds that a fraction of the malignant cells in a tumor have characteristics tied to normal stem cells, namely, the ability to self-renew and to give rise to other cell types. The hypothesis also holds that to eliminate a tumor effectively, the cancer stem cells must be eliminated as well; if they are not, they could serve as seeds for the tumor to regrow or spread.

"When the cancer stem cell concept was first posited, it was thought that the stem cell subset might coincide with the subset that remains after therapy and that metastasizes," Dr. Frank said. "This subset has historically been a hidden target, because we have not been able to define and isolate it. But therapies capable of killing off those cells at the root of the cancer would be much more effective than those that miss this subset."

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869.

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