Colorectal cancer is the third most common and fourth most deadly type of cancer. Unfortunately, anti-cancer therapies, including immunotherapy, have a relatively low effectiveness in colorectal cancer. In addition to genetic factors, environmental factors linked to a Western lifestyle (such as diet, obesity, and a sedentary lifestyle) also increase the risk for developing colorectal cancer.
The disease originates from the epithelial cells that line the intestines. These ‘barrier’ cells accumulate mutations and acquire malignant properties over time.
In this study, researchers from VIB-UGent Center for Inflammation Research and Ghent University, in Belgium, found that abnormal expression of the protein Zeb2 affects the integrity of the intestinal wall or ‘epithelium’, impeding its function as a barrier to infiltrating bacteria which cause inflammation that drives cancer progression.
Importantly, the scientists demonstrated that manipulating the immune system or removing the microbiota can prevent the development of cancer.
Professor Lars Vereecke, principle investigator in the Host-Microbiota Interaction lab, coordinator of the Ghent Germfree and Gnotobiotic mouse facility, and project leader at the Center for Inflammation Research, said: “There is increasing evidence that the microbes in our gut play a central role in human health and disease.
"Many diseases are associated with distinct shifts in the microbiota-composition, including colorectal cancer."Proving that the microbiota contribute to disease requires functional studies in mice. Recently, we established the first Belgian germ-free mouse facility at Ghent University where we raise mice in completely sterile conditions.
"Using this new technology, we could prove that removing the intestinal microbes prevents colorectal cancer development in our model. Moreover, by modulating the activity of specific immune cells we could also suppress cancer development. Together, these findings demonstrate that complex immune-microbiota interactions contribute strongly to colorectal cancer development.”
Since cancer development in these mice is microbiota-dependent, germ-free Zeb2 mice represent a unique preclinical platform for microbiota research to identify cancer-promoting microbes, but also to test new microbiota-based therapies to prevent or treat colorectal cancer.
Professor Geert van Loo, principal investigator at the VIB Inflammation Research Center and senior lecturer in the faculty of sciences at UGent, added: “We identified a disease-causing mechanism using a new mouse model but also confirmed abnormal Zeb2 expression in human colorectal tumor cells, which proves the clinical significance of our model for human patients.
"Our results are important from a scientific point of view since they help us understand why and how colorectal cancer develops. But this knowledge also has therapeutic implications and suggests that altering the microbiota or targeting specific immune components may be effective strategies for developing new treatment options for colon cancer.”
Source: Nature Cancer
Slowicka, K., Petta, I., Blancke, G. et al.
Zeb2 drives invasive and microbiota-dependent colon carcinoma.