Protein protects intestine against cancer

An international team of researchers has identified a novel function for the cell death-regulating protein MCL1: it is essential in protecting the intestine against cancer development, independent of bacterial-driven inflammation. Their findings have been published in the journal Gastroentrology and have implications for the use of MCL1 inhibitors, currently being tested for cancer treatment.

Colorectal carcinoma (CRC), the most common form of intestinal cancer, is the second-leading cause of cancer-related death worldwide. While some patients have a genetic predisposition to the disease, the majority of cases are sporadic and largely influenced by the ever-increasing ‘Western lifestyle’, which includes obesity, poor diet and physical inactivity.

Through the use of genetically modified mice, an international team of researchers has now been able to shed new light on how this disease develops, revealing that the protein MCL1 is essential for maintaining intestinal homeostasis and thus protecting against intestinal cancer formation. The research project was led by Professor Achim Weber from the University of Zurich and the University Hospital Zurich, in collaboration with researchers from the German Cancer Research Center in Heidelberg and the Beatson Institute for Cancer Research in Glasgow.

For their study, the researchers modified the genetic make-up of mice so that the animals’ intestinal cells would no longer produce the MCL1 protein. This protein normally prevents the death of cells and thus maintains the right balance of dying and new cells in the intestinal mucosa. The loss of MCL1 resulted in irreparable damage to the intestine and the subsequent formation of intestinal tumours. Similar changes can also be observed in the intestine of humans suffering from chronic intestinal inflammation, who also carry an elevated risk of developing intestinal cancer.

Microbiota-driven chronic intestinal inflammation has long been considered essential in the development of intestinal cancer. “What’s remarkable, however, is that the loss of MCL1 can drive intestinal cancer even without bacteria-driven inflammation,” Prof Weber said. This was demonstrated by experiments in which mice without the MCL1 protein were held in a germ-free environment.

“This means that the loss of certain genes is apparently enough to cause intestinal cancer — even in the absence of inflammation. This groundbreaking finding significantly furthers our understanding of the critical early steps associated with intestinal cancer development.”

The study also reveals a second surprising result: in some types of tumour — including colorectal carcinoma — there is too much MCL1, rather than too little. Researchers assume that these tumours ramp up the production of MCL1 to gain an advantage for survival and enable them to better resist conventional treatment methods. As a result, a number of new therapies are currently being trialled to interfere with and reduce MCL1 function.

However, the study’s findings show that not only the overexpression of MCL1 can be detrimental, but also its loss. Indeed, it is possible that the loss of MCL1 function — even only temporarily — may trigger a disturbance of the intestinal mucosa and the initial steps of tumour development.

“The regulation of this protein is like walking a tightrope,” said Zurich’s Marc Healy, first author of the study. “Our study therefore urges an element of caution when it comes to using MCL1 inhibition in cancer therapy.”

Image caption: The protein MCL1 (red dots) within the small intestine of a healthy mouse. The nuclei of individual cells (blue) are also visible. Image credit: Marc Healy, UZH.

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