Neuroendocrine proteins (GDF-15, PTHrP) have multiple levels of influence in promotion of cancer cachexia*

Abstract Introduction Cancer cachexia is well-recognized in pancreatic cancer, explained by cytokines, prostaglandins and hormones. Recently, neuroendocrine factors as PTHrP and GDF-15 are also proposed as important mediators behind cachexia in animal models. Therefore, our aim was to evaluate how EGFR, PTHrP and GDF-15 may relate to tumour progression and cachexia in patients with PDAC tumours. Method Blood PTHrP and GDF-15 were quantified by Elisa analyses (n=175). Tumour expression of EGFR, PTHrP and GDF-15 was quantified by Immunohistochemistry (n=33). Blood and tumour levels were compared to clinical variables (standard laboratory tests, food diaries, energy expenditure, body composition, exercise-capacity and Health Related Quality of Life (SF-36, HAD-scales). Simple- and multivariate analyses were used to evaluate statistical inferences. Result Blood PTHrP and GDF-15 levels were related to altered whole body metabolism, positively correlated to fat oxidation (p<0.001) and negatively to carbohydrate oxidation (p<0-02). Multivariate regressions on tumour tissue proteins imply EGFR as a primary driver of tumour growth (p<0.04), counteracted by PTHrP and GDH-15 in tumour tissue. Statistical inference on blood analyses implies that PTHrP may induce fat browning which promotes energy expenditure, while blood GDF-15 is not a primary statistical factor behind cachexia but may promote anorexia secondarily to systemic inflammation (p<0.001), with insulin resistance. Discussion Tumour tissue EGFR is a driver of PDAC growth, while tumour PTHrP- and GDF-15 may rather be counteracting factors. However, blood PTHrP and GDF-15 are produced in several tissues and thereby affect whole body oxidative metabolism and negative energy balance, within networks of systemic inflammation. *Published, submitted and unpublished results.