Targeting Cancer Stem Cells in Colorectal Cancer

A diagram illustrating the distinction between conventional (left) cancer therapies and cancer stem cell targeted (right) agents

A population of self-renewing cancer stem cells are thought to be more resistant to chemotherapy and other treatments compared with other cancer cells that make up a tumor. These stem cells are thought to drive both resistance and subsequent relapse after seemingly effective treatment.

In a new study, researchers at the Princess Margaret Cancer Centre in Toronto show that targeting the protein BMI-1 in colorectal cancer can eliminate the self-renewing cell population and lead to long-term inhibition of tumor growth. The results so far have been conducted in primary colorectal cancer xenograft models, but this proof of principle study may lead to testing the small-molecule inhibitor in clinical trials. The results of the study are published in Nature Medicine.

"This is the first step toward clinically applying the principles of cancer stem cell biology to control cancer growth and advance the development of durable cures," said lead author John Dick, PhD, Canada Research Chair in Stem Cell Biology and senior scientist at the University Health Network, in a statement.

Cancer stem cells, also called cancer-initiating cells (CICs), have distinct transcriptional and epigenetic profiles which are thought to allow these cells to self-renew. Serial transplantation studies have suggested that these cells are what initiates tumors and maintains tumor cell populations in several tumor types that have been studied, including breast and colorectal tumors. Targeting the specific biological properties of these cell population is thought to be a potential new way to treat cancer. Still, whether targeting these properties arrests tumor growth and prevents relapse has not been well demonstrated.

The researchers targeted BMI-1, which has previously been linked to the property of self-renewal and the maintenance of stem cells in different tissue types. In colorectal cancer, BMI-1 is found overexpressed in a proportion of tumors and has been associated with an increased risk of metastasis.

The researchers demonstrated that knock-down of BMI-1 in human colorectal cancer cell lines using small hairpin RNAs reduced the number of cells that are actively undergoing cell division. Knock-down of BMI-1 also impaired the ability of these colorectal cancer cells to initiate tumors in vitro, demonstrating that the cells had a lower ability to self-renew. The knock-down also resulted in a lower frequency of self-renewing tumor cells in tumors formed in mice from a single cancer stem cell.

The study authors identified a small-molecule inhibitor of BMI-1, PTC-209, using a high-throughput screening approach and gene expression assay. The molecule selectively reduced protein levels of BMI-1, which also led to decreased growth of human colorectal cancer cells in vitro. In culture, the inhibition irreversibly inhibited the colorectal cancer stem cells tested. PTC-209 also inhibited growth of primary colorectal cancer xenografts in a mouse model. Analysis of the tumors in the mice showed a 16-fold lower frequency of functionally defined colorectal cancer stem cells in the tumors from mice treated with the drug compared with placebo.

“The finding that BMI-1 plays a central part in colorectal CIC self-renewal opened an avenue to target the stemness function of CICs with small-molecule inhibition,” state the authors in their discussion of the results.

The data suggest that even a short-term inhibition of BMI-1 results in impaired growth of colorectal tumors. However, many more studies are needed to better define cancer stem cells in both colorectal cancers and other cancer types. Additionally, BMI-1 may play a major role in promoting the growth and renewal of normal, noncancerous human intestinal cells and potentially other normal tissue. Understanding this affect will be important before a BMI-1 inhibitor is tested in humans. The authors noted that at the dosage used to treat mice in their studies, there were no notable changes in digestive function.