MMP12 knockout prevents weight and muscle loss in tumor-bearing mice.

BACKGROUND

Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. Apc mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the Apc mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when Apc mice were crossed with MMP12 mice, indicating that MMP12 has a role in age-related Apc-associated weight loss. As a control, the weight of MMP12 mice on a weekly basis, their weight were not significantly different from those of WT mice.

METHODS

Apc; MMP12 mice were obtained by crossing Apc mice with MMP12 knockout (MMP12 ) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of Apc mice.

RESULTS

MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in Apc mice, while inhibiting MMP12 could suppress weight loss in Apc mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of Apc mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage.

CONCLUSIONS

MMP12 is essential for controlling body weight of Apc mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.