25 research outputs found
Diffusion coefficients of sodium dodecyl sulfate in water swollen cross-linked polyacrylamide membranes
http://www.sciencedirect.com/science/article/B6TWW-4603M7T-5/1/856606240860bfc6cbe86dfc5f5b4bf
Investigation on the formation mechanisms of hydrogels made by combination of Îł-ray irradiation and freeze-thawing
Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia
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 tumourâderived 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 (ILâ6) 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 ILâ6 in the cachexiaâinducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete ILâ6 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 ILâ6 from the cancer cells was determined in both culture and tumourâbearing mice by a speciesâspecific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagyâinducing activities, and muscle mass changes were evaluated in tumourâbearing mice.
Results
We show that activin A acts in an autocrine manner to promote the synthesis and secretion of ILâ6 from cancer cells. By inhibiting activin A signalling, the production of ILâ6 from the cancer cells is reduced by 40â50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced ILâ6 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 nonâcancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an antiâactivin receptor 2 antibody in cachectic tumourâbearing mice reduces serum levels of cancer cellâderived ILâ6 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 ILâ6 signalling pathways and indicate that interference with activin Aâinduced ILâ6 secretion from the tumour has therapeutic potential for cancerâinduced cachexia