Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

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 tumour‐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 interleukin 6 (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 induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐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 tumour‐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. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). Conclusions Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer

“…In patients with advanced‐stage EOC, the performance status at baseline and at 3 months after adjuvant chemotherapy were associated OS, suggesting the relevance of optimal supportive care during cancer therapy . Lifestyle therapy and pharmacotherapy may also offer benefits for the management of body composition in patients with EOC; however, their effectiveness for advanced‐stage EOC remains unclear. Hence, future studies are warranted to determine if the effects of body composition on survival outcomes are both causal and, more importantly, reversible through intervention for advanced‐stage EOC.…”

Molecular mechanisms of cancer cachexia‑induced muscle atrophy (Review)

“…The inhibition of activin signaling reduced the production of il-6 in cancer cells and the ability of cancer cells to accelerate autophagy in non-cancerous cells in vivo, which reversed cachexia and counteracted the loss of all measured muscle groups (Fig. 2) (113). in addition, oxidative stress-induced expression of the autophagy-related gene aTG7 in the alP pathway was found to be temporally associated with activation of the p38 MaPK signaling pathway (Fig.…”

Dehydrodiisoeugenol Inhibits Colorectal Cancer Growth by Endoplasmic Reticulum Stress Induced Autophagic Pathways

“…Moreover, the traditional Chinese medicine is a potential way for the treatment of cancer in the light of its extremely low toxicity during its long course of application [39].…”