Pettersen, Kristine, Andersen, Sonja, van der Veen, Anna, Nonstad, Unni, Hatakeyama, Shinji, Lambert, Christian, Trifilieff, Estelle, Moestue, Ilver, Cebulla, Jana, Grønberg, Bjørn Henning, Schilb, Alain, Jacobi, Carsten and Bjørkøy, Geir (2019) Autocrine activin A signaling in cancer cells controls secretion of IL-6 and autophagy in cancer cachexia. Journal of Cachexia, Sarcopenia and Muscle. ISSN 2190-59912190-6009

Abstract

Background - The majority of patients with advanced cancer develop cachexia, a
weight loss syndrome that severely reduces quality of life and limits survival. Our
understanding of the underlying mechanisms that cause the condition is limited, and
there are currently no treatment options that can completely reverse cachexia. Several
tumor-derived factors and inflammatory mediators have been suggested to contribute
to weight loss in cachectic patients. However, inconsistencies between studies are
recurrent. Activin A and IL-6 are among the best studied factors that seem to be
important, and several studies support their individual role in cachexia development.
Methods – We investigated the interplay between activin A and IL-6 in the cachexia
inducing TOV21G cell line both in culture and in tumours in mice. We previously found
that the human TOV21G cells secrete IL-6 that induce autophagy in reporter cells and
cachexia in mice. Using this established cachexia cell model, we targeted autocrine
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activin A by genetic, chemical and biological approaches. The secretion of IL-6 from
the cancer cells was determined both in culture and tumor-bearing mice by a species
specific ELISA. Autophagy reporter cells were used to monitor the culture medium for
autophagy inducing activities and muscle mass changes were evaluated in tumor
bearing mice.
Results – We show that activin A acts in an autocrine manner to promote the synthesis
and secretion of IL-6 from cancer cells. We find that this is important for the ability of
the cancer cells to accelerate autophagy in non-cancerous cells. Consistently,
interfering with activin A signaling in cachectic tumor-bearing mice reduces serum
levels of cancer cell-derived IL-6 and reverses cachexia. Thus, our data support a
functional link between activin and IL-6 signaling pathways, and indicate that
interference with activin A-induced IL-6 secretion from the tumor has therapeutic
potential for cancer-induced cachexia.

Item Type:	Article
Date Deposited:	06 Sep 2019 00:45
Last Modified:	06 Sep 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38709