In a new study, researchers uncovered a new mechanism causing colorectal cancer.
They found that abnormal expression of the protein Zeb2 affects the integrity of the intestinal wall or ‘epithelium.’
This epithelium normally functions as a barrier to prevent infiltration by intestinal microbes.
Zeb2 undermines this barrier and allows infiltrating bacteria to 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.
These findings may lead to new treatments.
The research was conducted by a team from the VIB-UGent Center for Inflammation Research and Ghent University.
Colorectal cancer is the third most common and fourth most deadly type of cancer. Unfortunately, anti-cancer therapies, including immunotherapy, have 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 of 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.
A better understanding of the molecular mechanisms responsible for colorectal cancer development is essential to develop new therapies to effectively combat this deadly disease.
In the study, the team identified the protein Zeb2 as a possible cause of colorectal cancer.
They showed that the abnormal expression of this protein in the epithelial cells of the gut in mice can induce colorectal cancer.
Zeb2 destabilizes the integrity of the intestinal barrier which allows bacteria to infiltrate the tissue and provoke inflammatory reactions.
This causes an abnormal proliferation of epithelial cells which ultimately leads to the development of malignant intestinal tumors.
Importantly, by treating mice with broad-spectrum antibiotics to kill intestinal bacteria, or by raising mice in completely sterile conditions, cancer development could be completely prevented.
The team says 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 contributes to disease requires functional studies in mice.
This study proves that removing the intestinal microbes prevents colorectal cancer development in our model. Moreover, by modulating the activity of specific immune cells they could also suppress cancer development.
The new Zeb2 mouse colorectal cancer model represents a unique tool to study tumor-immune-microbe interactions, which is very useful in the search for new therapies targeting colorectal cancer.
One author of the study is Prof. Geert van Loo.
The study is published in the leading journal Nature Cancer.
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