2 research outputs found
Lipopolysaccharideâinduced hypothalamic inflammation in cancer cachexiaâanorexia is amplified by tumourâderived prostaglandin E2
Abstract Background Cachexiaâanorexia syndrome is a complex metabolic condition characterized by skeletal muscle wasting, reduced food intake and prominent involvement of systemic and central inflammation. Here, the gut barrier function was investigated in pancreatic cancerâinduced cachexia mouse models by relating intestinal permeability to the degree of cachexia. We further investigated the involvement of the gutâbrain axis and the crosstalk between tumour, gut and hypothalamus in vitro. Methods Two distinct mouse models of pancreatic cancer cachexia (KPC and 4662) were used. Intestinal inflammation and permeability were assessed through fluorescein isothiocyanate dextran (FITCâdextran) and lipopolysaccharide (LPS), and hypothalamic and systemic inflammation through mRNA expression and plasma cytokines, respectively. To simulate the tumourâgutâbrain crosstalk, hypothalamic (HypoEâN46) cells were incubated with cachexiaâinducing tumour secretomes and LPS. A synthetic mimic of C26 secretome was produced based on its secreted inflammatory mediators. Each component of the mimic was systematically omitted to narrow down the key mediator(s) with an amplifying inflammation. To substantiate its contribution, cyclooxygenaseâ2 (COXâ2) inhibitor was used. Results In vivo experiments showed FITCâdextran was enhanced in the KPC group (362.3 vs. sham 111.4 ng/mL, P < 0.001). LPS was increased to 140.9 ng/mL in the KPC group, compared with sham and 4662 groups (115.8 and 115.8 ng/mL, P < 0.05). Hypothalamic inflammatory gene expression of Ccl2 was upâregulated in the KPC group (6.3 vs. sham 1, P < 0.0001, 4662 1.3, P < 0.001), which significantly correlated with LPS concentration (r = 0.4948, P = 0.0226). These data suggest that intestinal permeability is positively related to the cachexic degree. Prostaglandin E2 (PGE2) was confirmed to be present in the plasma and PGE2 concentration (log10) in the KPC group was much higher than in 4662 group (1.85 and 0.56 ng/mL, P < 0.001), indicating a role for PGE2 in pancreatic cancerâinduced cachexia. Parallel to in vivo findings, in vitro experiments revealed that the cachexiaâinducing tumour secretomes (C26, LLC, KPC and 4662) amplified LPSâinduced hypothalamic ILâ6 secretion (419%, 321%, 294%, 160%). COXâ2 inhibitor to the tumour cells reduced PGE2 content (from 105 to 102 pg/mL) in the secretomes and eliminated the amplified hypothalamic ILâ6 production. Moreover, results could be reproduced by addition of PGE2 alone, indicating that the increased hypothalamic inflammation is directly related to the PGE2 from tumour. Conclusions PGE2 secreted by the tumour may play a role in amplifying the effects of bacteriaâderived LPS on the inflammatory hypothalamic response. The cachexiaâinducing potential of tumour mice models parallels the loss of intestinal barrier function. Tumourâderived PGE2 might play a key role in cancerârelated cachexiaâanorexia syndrome via tumourâgutâbrain crosstalk