Intestinal microbes as crucial drivers of cancer development in a new mouse model for colorectal cancer

In a collaboration between the research groups of Prof. Geert van Loo, Prof. Lars Vereecke and Prof. Geert Berx, Dr. Karolina Slowicka, Dr. Ioanna Petta and colleagues found that abnormal expression of the protein ZEB2 in epithelial gut cells can induce colorectal cancer.

In their model, ZEB2 destabilizes the integrity of the intestinal barrier, allowing bacteria to infiltrate the tissue, provoking inflammatory reactions eventually leading to abnormal proliferation of epithelial cells and the development of malignant intestinal tumours. The involvement of bacteria is key, as antibiotics treatment or raising mice in sterile conditions could prevent cancer development completely.

Prof. Geert Berx: “We study the molecular mechanisms that regulate tissue invasion and metastasis in various types of cancer. We knew Zeb2 regulates a molecular process which allows cancer cells to acquire tissue-invasive properties, resulting in malignant disease progression. By using transgenic mice expressing Zeb2, we can study this process in multiple tissues, including the intestine. This study demonstrates that Zeb2 reprograms the epithelial cells of the intestinal wall, which allows bacteria to pass and cause inflammation that can lead to tumor development.”

Prof. Lars Vereecke: “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.”

The study, recently published in Nature Cancer, as such not only identifies a new disease-causing mechanism, but also suggests that altering the microbiota or targeting specific immune components may be effective strategies to treat colon cancer, still the third most common and fourth most deadly type of cancer.

Prof. Geert van Loo: "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."

This research, financed by  the VIB, the Research Foundation Flanders, the Foundation against Cancer, ‘Kom op tegen Kanker’, Cancer Research Institute Ghent (CRIG) and the innovation fund of the Ghent University Hospital, is an excellent example of collaboration between CRIG’s core partners Ghent University, Ghent University Hospital and VIB-UGent.

Read more in the VIB press release via this link.

Discover the original article Slowicka, Petta. et al. Zeb2 drives invasive and microbiota-dependent colon carcinoma. Nature Cancer, 2020.