A research team led by Dr. Jorge Moscat, PhD., program director of the Cell Death and Survival Networks Program at Sanford-Burnham Medical Research Institute (Sanford-Burnham), has made an important discovery that may lead to new approaches for treating intestinal cancers. Their research findings, entitled “The atypical PKCs in inflammation: NF-κB and beyond” and published online in Cell Reports, identified signaling molecules in intestinal stem cells that may give rise to cancerous tumors if left unregulated.
The tissue surrounding the lumen of the intestines has a superficial single-celled layer of epithelial cells that are fast renewing (replaced every 3 to 5 days). This replacement process utilizes intestinal stem cells and has to be properly regulated to maintain homeostasis (balance) and normal cellular growth. This homeostasis can be impaired by cancer treatments such as radiation and chemotherapy, which selectively target rapidly proliferating cells such as cancer cells, as well as inevitably causing damage to normal tissues, particularly those undergoing rapid self-renewal, such as intestinal stem cells.
When interpreting these results, Dr. Maria Diaz-Meco, PhD, professor Cell Death and Survival Networks Program at Sanford-Burnham, and senior co-author, stated that “Disturbing the homeostasis of the stem cell pool can go two ways: it can either reduce intestinal epithelial cell regeneration or increase the proliferation of stem cells. Cancer is produced by the accumulation of mutations in critical genes that control central mechanisms of cell growth. Stem cells are a ‘permanent’ population in the intestine and a reservoir for those mutations.”
To understand how these mechanisms lead to mutations, the researchers used a genetically modified mouse model for intestinal cancer to explore the role that protein kinase C, zeta (PKC-zeta), a possible tumor suppressor, has in the oncogenic process. The experimental results showed that this process is kept under control by direct phosphorylation (addition of a phosphate molecule) by PKC-zeta on two essential tumor promoters: beta-catenin and Yap.
When explaining the findings, Dr. Moscat stated that, “if stem cell activity is increased, as in the case of intestines deficient in PKC-zeta, then the likelihood of developing tumors is much higher, and when the tumor is initiated it becomes more aggressive. Our results offer new possibilities for the prevention and treatment of intestinal cancers by blocking the pathways that lead to tumors. They also highlight a new strategy to promote intestinal regeneration after acute or chronic damage, such as that triggered by chemotherapy and radiation.”
These results offer researchers a better understanding of the mechanisms that regulate stem cell signaling, which may lead to the development of future drugs that will be more successful in treating intestinal cancers.
