Conference Proceeding

How can we improve on treatment of cancer cachexia?

Dr. Thomas E. Adrian,
Uni Of Arab Emirates, Dubai

Thomas E. Adrian carried out his postdoctoral research in University of London in London city. Later he started working as Professor, Physiology Division Head, and Director of Cancer Research, Creighton University School of Medicine, United States. He has many honors and awards; presently he is working as Professor, Department of Physiology, College of Medicine and Health Sciences, UAE University.

Cachexia is a major complication of cancer and most patients are cachectic towards the end of life. Unlike starvation, cachexia is characterized by the selective loss of muscle mass with relative preservation of visceral organs and adipose tissue. Cachexia causes one third of cancer-related deaths and contributes to that of many others. Despite intensive research, the mechanisms of cancer cachexia are still poorly understood. It is clear that it involves tumor derived factors, but is exacerbated by anorexia, inflammation, chemotherapy and inactivity. Unfortunately, cancer cachexia is rarely managed actively, partly due to inadequate understanding of clinical nutrition in oncology, but also due to the lack of an adequate evidence base for therapy. We investigated the entire transcriptome, using next-generation sequencing to identify altered expression of genes in muscle and visceral fat samples from GI cancer patients exhibiting 5-10% weight loss prior to surgery, compared with stable-weight patients. Selected differentially expressed genes were confirmed using real-time RT-PCR and western blotting. In muscle, down regulated genes included 7 involved with metabolism (5 mitochondrial); 4 with signaling; 4 with ubiquitination; and 3 with intracellular trafficking. Multiple genes involved in glycogen metabolism were down regulated, correlating with the lack of glycogen, muscle weakness, and fatigue; characteristic of cachexia. The 5 up regulated genes include 2 involved with calcium signaling and 2 with cell matrix interactions. Expression of genes previously thought to be important in cachexia, including several inflammatory cytokines, was not significantly different. No transcripts for the dermicidin gene, coding for proteolysis-inducing factor, were detected. Expression of myostatin and its receptor (ACTR2B) were significantly decreased, possibly reflecting end organ adaptation to tumor produced myostatin. In visceral fat, expression of 6 genes were down regulated and 10 up regulated with high statistical significance (P<0.001-0.0002). Several of these encode metabolic enzymes. Of genes in fat previously implicated with cachexia, such as hormone sensitive lipase and triglyceride lipase, were unchanged. In contrast, leptin was significantly down regulated and the zinc-α-2-glycoprotein was significantly up regulated as expected. These studies explain some documented evidence in cachexia pathogenesis, highlight ambiguous data from animal models, and reveal unexpected changes in gene expression that underlie the pathophysiology of the cachectic state in cancer. Using information from transcriptome analysis it should be possible to develop appropriate therapies for cancer cachexia. However management should also address the inflammatory response and provide nutritional support and exercise.

Published: 11 May 2017