Adipose Tissue Wasting as a Determinant of Pancreatic Cancer-Related Cachexia

SIMPLE SUMMARY: Pancreatic cancer (PC) is one of the deadliest cancers in the US. The poor prognosis of PC is related to diagnostic delay and the presence of unintended weight loss (cachexia) that commonly presents in PC patients even before diagnosis. However, the current understanding of how PC mediates cachexia is limited, and there are few treatments clinically available for cachexia. Based on the current literature, we demonstrate that PC-related cachexia primarily results from the wasting of adipose tissue, once thought to be merely a storage depot but now appreciated as an instrumental metabolic organ in the body. In addition, poor survival in PC patients was found to be associated with adipose tissue loss at diagnosis and during treatment. Therefore, identifying potential mediators and molecular mechanisms underlying adipose tissue loss would promise to pave the way for the development of effective interventions for PC-related cachexia ABSTRACT: Pancreatic cancer (PC) is the third leading cause of cancer-related death in the US, and its 5-year survival rate is approximately 10%. The low survival rates largely stem from diagnostic delay and the presence of significant adipose tissue and muscle wasting, commonly referred to as cachexia. Cachexia is present in nearly 80% of PC patients and is a key cause of poor response to treatment and about 20% of death in PC patients. However, there are few clinical interventions proven to be effective against PC-related cachexia. Different cancer types feature distinct secretome profiles and functional characteristics which would lead to cachexia development differently. Therefore, here we discuss affected tissues and potential mechanisms leading to cachexia in PC. We postulate that the most affected tissue during the development of PC-related cachexia is adipose tissue, historically and still thought to be just an inert repository for excess energy in relation to cancer-related cachexia. Adipose tissue loss is considerably greater than muscle loss in quantity and shows a correlation with poor survival in PC patients. Moreover, we suggest that PC mediates adipose atrophy by accelerating adipocyte lipid turnover and fibroblast infiltration.