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Stress response protein links inflammatory disease to colon cancer
(l-r) Hagar Lavon, Dr. Ruth Scherz-Shouval and Oshrat Levi-Galibov

The findings might help identify those at extra risk of this cancer and develop means of prevention

Inflammation promotes some of the deadliest cancers. In the colon, inflammatory bowel disease is well known to be associated with higher-than-average rates of malignancy. Nevertheless, the developing tumor is commonly diagnosed only when it has already advanced or even metastasized, possibly because the early symptoms of malignancy are often mistakenly ascribed to a flare-up of intestinal inflammation. Weizmann Institute of Science researchers have now revealed a molecular missing link between chronic gut inflammation and cancer. This revelation may help develop ways of preventing colon cancers in people with inflammatory diseases of the intestines.

Lining of mouse gut under a microscope. That of regular mice (top left) becomes disorganized as chronic inflammation progresses (top, second and third from left), facilitating the development of cancer (top right). In mice lacking HSF1 (bottom left), inflammation fails to develop (bottom, second and third from left, and right)

Dr. Ruth Scherz-Shouval of the Biomolecular Sciences Department hypothesized that the path from chronic bowel disease to cancer winds through the stress response to inflammation within the intestinal cells. She focused on heat shock factor 1, or HSF1, a protein that triggers cellular changes in just such instances of stress and strain on the cells. In earlier work she had found that HSF1 causes supporting cells called fibroblasts to start assisting the progression of cancer in their vicinity. In the new research, Scherz-Shouval and her team asked whether this process begins even before cancer is seen – in colon inflammation that eventually leads to colon cancer.

Doctoral student Oshrat Levi-Galibov led a series of experiments in which the scientists observed changes in mice that exhibited symptoms of chronic inflammation of the gut, resulting some two months later in colon tumors. At different stages in the course of the inflammatory disease, the researchers examined the gut tissue of the mice, using advanced two-photon microscopy, and analyzed the protein composition of this tissue, using mass spectrometry and other methods. They found that starting in the early stages of inflammation, the extra-cellular matrix that is generated by fibroblasts – the network of collagen and other large molecules providing support to surrounding cells – underwent abnormal changes that later facilitated cancerous growth.

To ascertain whether these changes had been triggered by HSF1, they silenced this protein in mice through genetic engineering. The fibroblasts then created a normal extracellular matrix, and the mice failed to develop chronic inflammation and did not grow colon tumors.

Next, the researchers established that their findings were relevant to human disease by examining tissue samples from patients who had been treated for inflammation-related colon cancer at the Sheba Medical Center in Tel HaShomer and at Memorial Sloan Kettering Cancer Center in New York City. HSF1 was found to be activated in the tissues of these patients, and their extracellular matrix and protein composition had undergone abnormal changes similar to those observed in mice in the Weizmann study.

Finally, the scientists experimented with a small molecule that blocks HSF1 activity. When they exposed fibroblasts isolated from inflamed tissue to this molecule, these cells failed to create an extracellular matrix. In other words, the molecule put an end to the fibroblasts’ cancer-facilitating activity.

The extracellular matrix (red) in the colon of regular mice (top left) was disrupted by inflammation (top, center and right), whereas mice lacking HSF1 (bottom left) failed to develop inflammation under the same conditions, and their matrix remained normal over time (bottom, center and right)

In the future, these findings may lead to a drug that will help prevent inflammation-related colon cancer by selectively blocking the effects of HSF1 on fibroblasts. This research may also one day make it possible to identify people among those with inflammatory bowel disease who are at an increased risk of colon cancer, so that these high-risk individuals can receive the preventive treatment long before the cancer gets a chance to form.

Study participants included Hagar Lavon, Dr. Rina Wassermann-Dozorets, Dr. Meirav Pevsner-Fischer, Shimrit Mayer, Yaniv Stein, Gil Friedman and Dr. Reinat Nevo of Weizmann’s Biomolecular Sciences Department; Dr. Esther Wershof and Prof. Erik Sahai of the Francis Crick Institute, London; Dr. Lauren E. Brown, Dr. Wenhan Zhang and Prof. John A. Porco of Boston University; Ofra Golani of Weizmann’s Life Sciences Core Facilities Department; Dr. Lior H. Katz, Dr. Ido Laish and Dr. Dror S. Shouval of Sheba Medical Center; and Dr. Rona Yaeger and Dr. David Kelsen of Memorial Sloan Kettering Cancer Center.

 

Dr. Ruth Scherz-Shouval’s research is supported by the Moross Integrated Cancer Center; the Dr. Barry Sherman Institute for Medicinal Chemistry; the Laura Gurwin Flug Family Fund; the Rising Tide Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Sklare Family Foundation; and the estate of Aliza Yemini. Dr. Scherz-Shouval is the incumbent of the Ernst and Kaethe Ascher Career Development Chair in Life Sciences. 
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