Exploring Biomarkers for Weight Loss in Cancer Cachexia: The Prognostic Value of Serum sP-selectin, Activin A and Autophagy-stimulatory Activity

Abstract

Cancer cachexia is an extremely devastating wasting syndrome that adversely influences treatment response, quality of life and survival rates of patients. It involves severe metabolic imbalance resulting in progressive weight loss from reduction of skeletal muscle mass and adipose tissues. The development of effective prediction method, prevention and treatment are hampered by the multifactorial nature of the pathological mechanisms underlying cachexia. Consequently, the clinical demand for diagnostic biomarkers/therapeutic targets for this multidimensional problem still remained unmet. In this study, ELISA-based detection of serum/plasma concentrations of activin A and sP-selectin were conducted and the association of the protein levels with weight loss examined in cancer patient samples obtained from the European Pharmacogenetic Study (EPOS) and the Central Norway Lung Cancer Biobank. Besides the role of autophagy in cell survival and recycling mechanism, its impact on excessive body weight loss in cancer-induced cachexia was evaluated. The screening of patient samples was investigated in an autophagy flux reporter cell system based on monitoring GFP-p62 turnover. Significant correlation between activin A/sP-selectin levels and weight loss was not observed despite significantly higher concentrations obtained in patients compared to controls. The severity of weight loss was found to be uninfluenced by the mean levels of the measured proteins. In the autophagy assay, 33% and 82% of patients displayed an enhanced level of autophagy stimulation in EPOS and lung cancer biobank samples, respectively. The autophagy-stimulating capacity did not, however, correlate with the extent of weight loss. Moreover, the statistically derived predictive model for weight loss in cancer cachexia incorporating diverse clinical parameters was capable of explaining only 20% of the differences in the weight loss. Better insight into the role of autophagy in cancer-related skeletal muscle and adipose tissue wasting may contribute to future development of therapeutic targets for this lethal wasting disorder.