A leading cause of cancer deaths worldwide, colon cancer is famously resistant to treatment. One reason for this is a group of persisting cancer cells in the colon that cause relapses, with conventional therapies against them mostly ineffective. Now, a study from researchers at EPFL and Kyoto University has identified a biological mechanism that can be exploited to counteract colon cancer relapses. The team state they were able to reactivate a protein lost in the persisting cancer cells using vitamin A, thus eliminating the cancer cells and preventing metastasis. The opensource study is published in the journal Cancer Cell.
Previous studies show that when a colon-cancer patient receives treatment, such as chemotherapy, most of the cancer cells die off. However, the genetic mutations that cause the cancer in the first place can survive in a specific group of cells of the colon. These are actually stem cells, meaning that they are premature cells waiting to grow into full-blown, normal cells of the colon. After cancer treatment ends, the surviving stem cells, still containing the cancerous mutations, can reappear and cause a relapse. It is also known that establishment of about 90% of intestinal cancers is caused by activation of the Wnt signaling pathway. Consequently, many aspects of how this pathway controls growth and proliferation of normal and cancer stem cells has been elucidated. The current study identifies a protein called HOXA5 as an important repressor of intestinal stem cell fate in vivo and identify a reciprocal feedback between HOXA5 and Wnt signaling.
The current study uses cells, mouse models and samples from human patients to shows how differentiated colon cells come from stem cells in the gut. Results show that in the gut, HOXA5 plays a major role in restricting the number of stem cells, as well as the cells that make them. The group explain that HOXA5 belongs to a family of proteins that regulate the development of the fetus and are made during early development to make sure that every tissue is correctly identified in the fetus’s body. They go on to add that in the adult body, proteins like HOXA5 regulate the body’s stem cells to maintain both the identity and function of different tissues.
Data findings show that the cancerous stem cells of the colon use a biological mechanism that blocks the gene which produces HOXA5. Results show that by blocking the HOXA5 gene, the cancerous stem cells of the colon can grow uncontrollably and spread, causing relapses and metastasis. Therefore, the team looked for ways to reverse the blocking of HOXA5; the answer came from vitamin A.
The team state that this small chemical structure is called a retinoid, and it has been known to induce differentiation of stem cells in the skin. The lab observed that retinoids can re-activate HOXA5 and in mice that had colon cancer, retinoids blocked tumour progression and normalized the tissue. The group conclude that by turning the gene for HOXA5 back on, this treatment eliminated cancer stem cells and prevented metastasis in the live animals, with similar results in samples from actual patients.
The team surmise that their study suggests that patients that may profit from this well-tolerated treatment can be identified based on their expression pattern for the HOXA5 gene. They go on to add that they have introduced a new way to treat colon cancer. For the future, the researchers state that retinoid differentiation therapy could be significantly effective against colon cancer, not only for treatment of existing disease but also as a preventive measure in high-risk patients.