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Loss of protein disturbs intestinal homeostasis and can drive cancer

Date:
March 18, 2020
Source:
University of Zurich
Summary:
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. These findings have implications for the use of MCL1 inhibitors, currently being tested for cancer treatment.
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FULL STORY

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.

A recently published study now sheds new light on how this disease develops: Through the use of genetically modified mice, an international team of researchers was able to demonstrate that the protein MCL1 is essential for maintaining intestinal homeostasis and thus protecting against intestinal cancer formation. The research project was led by Achim Weber, professor at the Institute of Molecular Cancer Research at the University of Zurich and at the Institute of Pathology and Molecular Pathology of the University Hospital Zurich, in collaboration with researchers from the German Cancer Research Center in Heidelberg and the Beatson Institute in Glasgow, Scotland.

MCL1 protein protects the intestine against cancer

For their study, the researchers modified the genetic makeup 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 tumors. 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.

Tumors also develop without bacterial-driven inflammation

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," says Weber. This was demonstrated by experiments in which mice without the MCL1 protein were held in a germfree 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," says Weber.

Treating cancer with MCL1 inhibitors is like walking a tightrope

This study also reveals a second surprising result: In some types of tumor -- including colorectal carcinoma -- there is too much MCL1, rather than too little. Researchers assume that these tumors 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, but also the loss of MCL1 can be detrimental. 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 tumor development. "The regulation of this protein is like walking a tightrope," warns 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."


Story Source:

Materials provided by University of Zurich. Note: Content may be edited for style and length.


Journal Reference:

  1. Marc E. Healy, Yannick Boege, Michael C. Hodder, Friederike Böhm, Mohsen Malehmir, Anna-Lena Scherr, Jasna Jetzer, Lap Kwan Chan, Rossella Parrotta, Kurt Jacob, Laure-Alix Clerbaux, Susanne Kreutzer, Andrew Campbell, Ella Gilchrist, Kathryn Gilroy, Ann-Katrin Rodewald, Hanna Honcharova-Biletska, Roman Schimmer, Karelia Vélez, Simone Büeler, Patrizia Cammareri, Gabriela Kalna, Anna S. Wenning, Kathy D. McCoy, Mercedes Gomez de Agüero, Henning Schulze-Bergkamen, Christoph Klose, Kristian Unger, Andrew J. Macpherson, Andreas E. Moor, Bruno Köhler, Owen J. Sansom, Mathias Heikenwalder, Achim Weber. MCL1 is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice. Gastroenterology, 2020; DOI: 10.1053/j.gastro.2020.03.017

Cite This Page:

University of Zurich. "Loss of protein disturbs intestinal homeostasis and can drive cancer." ScienceDaily. ScienceDaily, 18 March 2020. <www.sciencedaily.com/releases/2020/03/200318104435.htm>.
University of Zurich. (2020, March 18). Loss of protein disturbs intestinal homeostasis and can drive cancer. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2020/03/200318104435.htm
University of Zurich. "Loss of protein disturbs intestinal homeostasis and can drive cancer." ScienceDaily. www.sciencedaily.com/releases/2020/03/200318104435.htm (accessed March 28, 2024).

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