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Interleukin-6, C/EBP-beta and PPAR-gamma expression correlates with intramuscular liposarcoma growth in mice: The impact of voluntary physical activity levels

Abstract : IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anticancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited-6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-4 and PPAR-gamma expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-a and PPAR-gamma exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses.
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Submitted on : Tuesday, November 28, 2017 - 4:46:49 PM
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Mohamad Assi, Moussa Kenawi, Mickael Ropars, Amélie Rébillard. Interleukin-6, C/EBP-beta and PPAR-gamma expression correlates with intramuscular liposarcoma growth in mice: The impact of voluntary physical activity levels. Biochemical and Biophysical Research Communications, Elsevier, 2017, 490 (3), pp.1026--1032. ⟨10.1016/j.bbrc.2017.06.158⟩. ⟨hal-01585980⟩

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