May 04, 2016
Cancer typically doesn’t occur in adults until later in life because it can take years for someone to acquire the right combination of genetic mutations that will cause cancer cells to grow and multiply.
Viruses, bacteria, parasites and other microorganisms can trigger carcinogenesis and are found in about 20 percent of all human cancers. Understanding how these organisms trigger the transformation of normal cells to cancerous ones is the focus of a new National Cancer Institute’s grant awarded to Shahid Umar, Ph.D., member of the Cancer Prevention Research Program at The University of Kansas Cancer Center and Associate Professor of Molecular and Integrative Physiology at the University of Kansas Medical Center.
Dr. Umar will be trying to determine how bacteria can trigger colon tumor formation and the eventual spread of cancer to other parts of the body, along with a possible therapy to stop metastasis.
Bacteria are no strangers to our colon; in fact, some of it are necessary for digestion and other bodily functions.
“While skepticism still exists regarding the role of bacterial infection in the onset of the disease, bacterial infections can promote colon tumorigenesis by combining with host’s genetic susceptibility to create an environment wherein, mutated cells divide rapidly and cause cancer,” said Dr. Umar.
To learn more about how bacteria creates an environment ripe for the creation of colon cancer, Dr. Umar and his team are using a bacterium called Citrobacter rodentium that is similar on a functional level to E. coli, which sickens about 100,000 Americans each year.
They introduce the bacteria to mice and watch as infectious colitis occurs in a genetically susceptible strain. A process called hyperplasia precedes and accompanies inflammation in an otherwise healthy organ. This can be a sign of precancerous activity in humans as well.
- Learn more about cancer research at The University of Kansas Cancer Center in our Research Highlights.
Cell growth, both normal and abnormal, is regulated by two pathways well known in the cancer research world: Wnt and Notch. In his previous studies, Dr. Umar found that functional cross-talks between Wnt/ï¢-catenin and Notch pathways, regulate both crypt hyperplasia and/or tumorigenesis in response to Citrobacter infection.
Wnt and Notch signaling is also vital in regulating the behavior of stem cells. Stem cells divide to create the cells that make up our whole body, whether it’s our skin, bones, muscle or colon. So if the Wnt and Notch pathways are disrupted, cells multiply out of control. A mutation in a stem cell will multiply indefinitely and is thought to be the origin of cancer and cancer relapse in the body.
We all have tumor suppressor genes that are supposed to stop cells from dividing uncontrollably and keep oncogenes, mutated genes that cause cancer development, from thriving. Dr. Umar’s research with bacteria is looking at how the bacteria can upset this balance.
“The combination of oncogenes [like Ezh2, Ctnnb1] and tumor suppressor genes (e.g., Apc) is what balances us out,” said Dr. Umar. “When you lose the tumor suppressor function, but the oncogene function increases, that’s when you have trouble.”
Dr. Umar’s lab found that some colon cells infected with Citrobacter rodentium didn’t contain a protein called E-cadherin. E-cadherin is a tumor suppressor protein, and studies have shown that the loss of this protein can accelerate the progression of cancer and lead to metastasis.
These same colon cells, however, have high levels of EZH2, an enzyme that helps cancerous cells divide and multiply. It’s also a gene suppressor, so when it is overexpressed, tumor suppressor genes like E-cadherin lose their important function.
Based on all these different findings, Dr. Umar is hypothesizing that the change in EZH2 inside stem cells is a precursor to metastasis by inducing a process called epithelial-mesenchymal transition (EMT).
For cancer to metastasize, the cells have to leave the original tumor and migrate to a different spot in the body - but tumor cells can’t just float through your bloodstream.
“They have to be converted into a different kind of cell, a mesenchymal cell,” said Dr. Umar. “Mesenchymal cells can move easily whereas epithelial [tumor] cells cannot move on their own. This transformation makes the cells resistant to chemotherapy treatment.”
Along with studying these epigenetic changes that can happen in our colon when the environment is ripe following bacterial infection, Dr. Umar is trying to use all these findings to look towards a possible treatment.
Tributyrin is a triglyceride found naturally in butter. It also happens to block EZH2 and stops colon cells from dividing abnormally. Dr. Umar will investigate whether or not Tributyrin could stop the EMT process and tumors from spreading.
“Once cancer gets the stage where it’s going through EMT and becoming metastatic, it becomes almost impossible to treat,” said Dr. Umar. “If we can block this protein then perhaps we can stop tumors from spreading.”
Funding sourcesThe project described was supported by grant number ROI CA185322 02 from the National Cancer Institute of the National Institutes of Health.
- Greiner, A. K., Papineni, R. V., & Umar, S. (2014). Chemoprevention in gastrointestinal physiology and disease. Natural products and microbiome. American Journal of Physiology-Gastrointestinal and Liver Physiology,307(1), G1-G15.