Curbing Side Effects

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New approach may help reduce treatment-related skin fibrosis in cancer patients.
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Fibrosis is often a late side effect of radiotherapy for cancer and can occur years after the original treatment. Skin fibrosis leads to thickening of the skin (similar to what happens when a scar forms after an injury) and can cause pain, severe itching and sensitivity.

A team of researchers and clinicians specializing in head-and-neck cancer has identified a way to manipulate metabolism to potentially prevent skin fibrosis—a common side effect of radiotherapy affecting quality of life of cancer survivors.

The findings, from the laboratory of Princess Margaret Cancer Centre Senior Scientist Dr. Fei-Fei Liu, were published online today in Nature Metabolism.

First author Dr. Xiao Zhao, a resident in head-and- neck surgery who completed his PhD studies with Dr. Liu, says the research team wanted to find a way to reduce radiation-induced fibrosis, a condition where normal tissue progressively thickens causing pain and dysfunction. The underlying problem is the excess buildup of the extracellular matrix, a supporting structure for all tissues. There is currently no effective treatment to reduce this accumulation.

The team used human tissues with radiation-induced fibrosis and pre-clinical experiments to identify metabolic processes as key triggers and promoters of fibrosis. Metabolic processes are responsible for breaking down fats, proteins and sugars to provide cellular energy. Dr. Zhao explains, “We were surprised to see that metabolic abnormalities were predominant and consistently found in patients with skin fibrosis, even years after their original radiotherapy. Our question was: ‘Can we manipulate metabolism to reduce fibrosis?’”

The team identified two metabolic pathways that were consistently altered in skin with fibrosis: one pathway involved in the breakdown of fats was less active relative to healthy skin; and a second pathway involved in the breakdown of sugar was more active than in healthy skin.

Through uncovering this metabolic model of extracellular matrix regulation, the team also identified several metabolic drug compounds and potential cell therapy techniques that reduced fibrosis in pre-clinical models.

“We’re highlighting fibrosis from this new perspective, thereby opening the door to metabolic regulation as a way to treat this side effect of radiation,” says Dr. Zhao.


Xiao Zhao, Pamela Psarianos, Laleh Soltan Ghoraie, Kenneth Yip, David Goldstein, Ralph Gilbert, Ian Witterick, Hilary Pang, Ali Hussain, Ju Hee Lee, Justin Williams, Scott V. Bratman, Laurie Ailles, Benjamin Haibe-Kains and Fei-Fei Liu. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nature Metabolism, 2019; 1 (1): 147 DOI: 10.1038/s42255-018-0008-5

This work was supported by Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, Physicians Services Incorporated Foundation, the Harry Barberian Research Grant, the Jessie & Julie Rasch Foundation, the Strategic Training in Transdisciplinary Radiation Science for the 21st Century (STARS21), the Campbell Family Cancer Research Institute, the Ontario Ministry of Health and Long-Term Care, and The Princess Margaret Cancer Foundation.