A biological mechanism counteract colon cancer relapse was identified by a team of Swiss researchers. The approach uses vitamin A to activate a protein that was lost in persisting cancer cells. These findings were published in Cancer Cell (doi:10.1016/j.ccell.2015.11.001).
Colon cancer is a leading cause of cancer deaths worldwide and is known to be resistant to treatment. One reason is a group of persisting cancer cells in the colon that cause relapses and are generally not affected by conventional therapies.
Most colon cancer cells die off with treatments such as chemotherapy. However, the genetic mutations that caused the cancer can survive in some stem cells within the colon. After cancer treatment ends, the surviving stem cells can produce new colon cells, along with any cancer-causing mutations, and result in a relapse of disease.
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The laboratory of Joerg Huelsken, PhD, at École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, studied how differentiated colon cells are developed from stem cells in the gut. Using several techniques, the team looked at cells, mouse models, and samples from human patients.
This study focused on the HOXA5 protein, which belongs to a family of proteins that regulate the fetal development. These proteins are made during early development and work together to ensure that every tissue is correctly identified and that the fetus’s body and limbs are patterned properly.
In the adult body, proteins such as HOXA5 regulate the body’s stem cells to maintain both the identity and function of different tissues. Huelsken’s team found that in the gut, HOXA5 plays a major role in restricting the number of stem cells, as well as the cells that make them.
As with all proteins, HOXA5 originates from a specific gene. The researchers found the cancerous stem cells of the colon use a biological mechanism that blocks it. The mechanism, called a signaling pathway, involves a domino of molecules, each activating the next one down the line. The purpose of a signaling pathway is to transmit biological information from one part of the cell to another, eg, from the outer membrane to the nucleus. By blocking the HOXA5 gene, the cancerous stem cells of the colon can grow uncontrollably and spread, resulting in relapses and metastasis.
The researchers looked for ways to reverse the HOXA5 blockage. Their answer was found in vitamin A. This small chemical structure, called a retinoid, is known to induce differentiation of stem cells in the skin. The EPFL scientists found that retinoids can re-activate HOXA5. In mice with colon cancer, the retinoid treatment blocked tumor progression and normalized the tissue by turning the gene for HOXA5 back on. The treatment eliminated cancer stem cells and prevented metastasis in the live animals. Similar results were achieved with samples from actual patients.
The new study suggests that the expression pattern of the HOXA5 gene can identify those patients who may benefit from this well-tolerated treatment. Retinoid differentiation therapy could be significantly effective against colon cancer, not only as treatment of existing disease but also as preventive in patients at high-risk for the disease.
