Loss of peripheral fat and muscle occurs early in development of pancreatic cancer

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    In mouse models, loss of muscle and fat in early pancreatic cancer may be caused in part by a tumor-related decrease in production of pancreatic enzymes, report scientists from Dana-Farber Cancer Institute and Massachusetts Institute of Technology. Additionally, muscle and fat tissue wasting was common in a large cohort of patients with newly diagnosed pancreatic cancer, highlighting the potential for tissue wasting to serve as a marker for early detection.

    Reporting in the journal Nature, the researchers determined that peripheral tissue wasting in pancreatic cancer occurs early during the development of the disease, in addition to the syndrome of dramatic weight loss and fatigue often seen in cancer patients with advanced disease and known as cancer-related cachexia. Interestingly, when the researchers examined records of a large number of patients with pancreatic cancer, they found that the early loss of muscle and fat was not associated with shortened survival compared with patients who did not experience early tissue wasting.

    “It remains to be determined whether early tissue wasting is the same phenomenon as cachexia associated with advanced disease or whether these entities may be biologically distinct,” said Brian Wolpin, M.D., MPH, Director of the Gastrointestinal Cancer Center and the Hale Center for Pancreatic Cancer Research at Dana-Farber. He is senior author of the report along with Matthew G. Vander Heiden, MD, PhD, a specialist in cancer metabolism at Dana-Farber and the Massachusetts Institute of Technology.

    Pancreatic cancer is associated with wasting of peripheral tissues such as muscle and body fat. To investigate the cause of this metabolic change, the researchers used mouse models of pancreatic cancer, driven by alterations in the Kras oncogene and the tumor suppressor gene Trp53. In these models, the scientists observed that peripheral tissue wasting in pancreatic cancer is initiated early in the development of the cancer, before the onset of other signs of the disease.

    Further experiments showed that the tissue wasting wasn’t caused by some cancer-related substance circulating in the bloodstream, but resulted from the growth of the tumor in the pancreas. Tumor growth was found to decrease the mouse pancreas’ production of enzymes that help the body absorb fats and proteins, creating a starvation-like state that in turn causes a breakdown of fat and muscle tissues. To prove the connection, the wasting of body tissue was reduced when the mice were given supplemental pancreatic enzymes. Surprisingly, the researchers noted that the mice that experienced less tissue loss due to enzyme supplementation had worse survival.

    The scientists then looked at the association between tissue wasting and survival in human pancreatic cancer patients. They studied records of 782 patients at five cancer centers who had undergone CT scans when they were diagnosed, and before they were treated. Using the scans to measure muscle mass, the investigators found that 65 percent of the patients had muscle loss when they were diagnosed and their survival was similar to those without muscle loss. Interestingly, this high rate of muscle depletion was seen among patients with localized pancreatic cancer, suggesting that, “assessing peripheral tissue loss before overt disease onset may help to identify pancreatic cancer at earlier stages,” according to the report authors.

    To explore the potential of peripheral tissue wasting to serve as part of early-detection strategies, researchers at Dana-Farber and the Kaiser Permanente health care system are conducting a large study of pancreatic cancer patients who underwent CT scans during the five years before their cancer diagnosis. “We would like to know the time frame in which this tissue wasting occurs,” Wolpin said. “Is this something that can be detected a year before the cancer diagnosis, or several years before – if that is true, then understanding this biology becomes important for its potential utility in early detection strategies.”

    Clary Clish, director of the Metabolomics Platform at the Broad Institute, and members of his research group also contributed to this work. The patients included in the study were treated at the cancer centers at Dana-Farber, Massachusetts General Hospital, Mayo Clinic, Stanford University, and University of North Carolina-Chapel Hill.  

    Major funding for the research was provided by the Lustgarten Foundation, the Robert T. and Judith B. Hale Fund for Pancreatic Cancer Research, the National Institutes of Health Ruth Kirschstein Fellowship (F32CA210421); P50CA127003; F32CA213810; the Damon Runyon Cancer Research Foundation (DRG-2299-17); NIH/NCI U01CA210171, Department of Defense (CA130288); Pancreatic Cancer Action Network, Stand Up To Cancer; Noble Effort Fund; Peter R. Leavitt Family Fund; Wexler Family Fund, Promises for Purple; Howard Hughes Medical Institute; The Ludwig Center at MIT; the Koch Institute Frontier Awards; the MIT Center for Precision Cancer Medicine, and NIH (R01CA168653 and P30CA14051).

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