Pancreatic cancer-induced cachexia is Jak2-dependent in mice.

Cancer cachexia syndrome is observed in 80% of patients with advanced-stage cancer, and it is one of the most frequent causes of death. Severe wasting accounts for more than 80% in patients with advanced pancreatic cancer. Here we wanted to define, by using an microarray approach and the Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) mice model, the pathways involved in muscle, liver, and white adipose tissue wasting. These mice, which develop systematically pancreatic cancer, successfully reproduced many human symptoms afflicted with this disease, and particularly cachexia. Using the profiling analysis of pancreatic cancer-dependent cachectic tissues we found that Jak2/Stat3 pathways, p53 and NFkB results activated. Thus, our interest was focused on the Jak2 pathways because it is pharmacologically targetable with low toxicity and FDA approved drugs are available. Therefore, Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) mice were treated with the Jak2 inhibitor AG490 compound daily starting at 7 weeks old and for a period of 3 weeks and animals were sacrificed at 10 weeks old. Body weight for control mice was 27.84 ± 2.14 g, for untreated Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) was 14.97 ± 1.99 g, whereas in animals treated with the AG490 compound the weight loss was significantly less to 24.53 ± 2.04 g. Treatment with AG490 compound was efficient since phosphorylation of Jak2 and circulating interleukin-6 (IL6) levels were significantly reduced in cachectic tissues and in mice respectively. In conclusion, we found that Jak2/Stat3-dependent intracellular pathway plays an essential role since its pharmacological inhibition strongly attenuates cachexia progression in a lethal transgenic pancreatic cancer model.

Gilabert M ，Calvo E ，Airoldi A ，Hamidi T ，Moutardier V ，Turrini O ，Iovanna J ... -  《-》

Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

Miller A ，McLeod L ，Alhayyani S ，Szczepny A ，Watkins DN ，Chen W ，Enriori P ，Ferlin W ，Ruwanpura S ，Jenkins BJ ... -  《-》

Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response.

Guo D ，Wang C ，Wang Q ，Qiao Z ，Tang H ... -  《-》

IL-6 regulates MMP-10 expression via JAK2/STAT3 signaling pathway in a human lung adenocarcinoma cell line.

Zhang X ，Yin P ，DI D ，Luo G ，Zheng L ，Wei J ，Zhang J ，Shi Y ，Zhang J ，Xu N ... -  《-》

Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy.

Beckles DL ，Mascareno E ，Siddiqui MA 《-》