The musculoskeletal cost of metastatic colorectal cancer

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

PROJECT SUMMARY Colorectal cancer (CRC), in particular metastatic CRC is frequently accompanied by the development of cachexia, a multi-organ wasting syndrome affecting musculoskeletal health. Cachexia is directly responsible for worsened quality of life in cancer patients and for over 30% of all cancer-related deaths. We and others have shown that cancer is accompanied by metabolic and genomic perturbations of the liver, and further, that CRC liver metastases (LM) exacerbate musculoskeletal wasting. Unfortunately, there is no available cure for cachexia, and investigations into how metastatic disease exacerbates musculoskeletal wasting are sparse; hence, there is a critical need to identify targetable mediators of skeletal muscle and bone loss in advanced CRC. In this regard, our preliminary findings suggest that FGF21, an endocrine hormone belonging to the fibroblast growth factor (FGF) family of proteins, plays a causative role in cancer-induced musculoskeletal wasting. In our preliminary studies, circulating FGF21 was elevated in CRC patients and in MC38 tumor hosts, which present with losses of skeletal muscle and bone. Deletion of FGF21 from MC38 cells reduced myotube atrophy and osteoclastogenesis in vitro and preserved musculoskeletal health in vivo. Though suggestive that FGF21 is largely tumor-derived in CRC cachexia, we also found elevations of hepatic FGF21 in tumor hosts. Supporting a causative role for host-FGF21 in the development of cachexia, muscle mass, muscle torque, bone mass and bone strength were protected in FGF21 knockout mice bearing CRC. Of interest, mice bearing CRC LM, which display exacerbated musculoskeletal wasting, also have heightened circulating FGF21, further linking FGF21 to the development of cachexia. Follow-up studies also revealed greater FGF21 in hepatocyte-CRC mixed cultures and in the livers of mice with advanced CRC, suggesting a role of FGF21 in tumor metastasization. Altogether, these observations suggest a novel role of FGF21 in the development of cachexia in advanced CRC. The objective of this proposal is to interrogate the FGF21-dependent effects in metastatic CRC-associated muscle and bone loss. Our central hypothesis is that metastatic CRC exacerbates FGF21 production, which in turn mediates musculoskeletal wasting in advanced CRC. In Aim 1, we will investigate the FGF21-dependent effects on bone loss in advanced CRC. The working hypothesis is that FGF21 determines bone loss in advanced CRC, by promoting osteoclastogenesis. In Aim 2, we will determine the mechanism(s) by which FGF21 triggers muscle wasting in advanced CRC. The working hypothesis is that FGF21 is participates in the development of muscle atrophy. In Aim 3, we will examine the metastatic niche and its role in exacerbating CRC cachexia. The working hypothesis is that tumor metastasization to the liver alters hepatocyte and cancer cell gene expression, consistent with elevated pro-cachectic signaling and aberrant expression of FGF21. Completion of this study will identify FGF21 as a novel therapeutic target for the treatment of musculoskeletal wasting in CRC and will facilitate new avenues for cachexia research.