Characterization of human skeletal muscle in weight-losing pancreatic cancer patients

Abstract

9571 Background: Decreased body mass (cachexia) is a common cause of functional decline in pancreas carcinoma (PC) and other malignancies. The etiology is unknown. Characterization of human PC skeletal muscle, in regard to proteolysis and gene expression, compared to control muscle may reveal information about pathophysiology. Methods: Biopsies of rectus abdominus muscle were performed in weight-losing PC patients all stages (A) during cancer-related surgery and in cancer-free controls undergoing ventral hernia repair (B). Caspase-3, pAkt, and urinary 3-methylhistidine (u3-MH) were assessed by Western blot and high-performance liquid chromatography. Fat-free mass (FFM), body mass index (BMI), and time to progression were recorded. Muscle from five patients (median weight loss 21%) and five controls were analyzed for gene expression patterns using Affymetrix Human Genome U133 A 2.0 array chip. Two hundred differentially over- and under-expressed genes were examined in group A for potential association with cachexia. RT-PCR confirmation of six candidate genes was performed. Results: Thirty-eight patients were enrolled. Median weight loss in group A (N=27) was 14.5% (5% - 34%). No differences were noted between groups in caspase-3 and pAkt expression. Baseline u3-MH (p=0.86) and FFM (p= 0.28) did not differ; baseline BMI was lower in group A (p=0.04). BMI follow-up measurements (N=17) were significantly decreased (p=0.0005). In 65% patients, progressive disease was noted within median time of 3 months. RT-PCR established up-regulation of CHRNA1 and LMO7, but not GDF8. mRNA down-regulation for TRIM63, IGF-BP6, and MYH-1 was confirmed. Conclusions: Muscle proteolysis in human PC skeletal muscle was not demonstrated, perhaps due to unmeasurable proteolysis or use of non-informative endpoints. BMI decreased in group A with PD; further studies need tight control of BMI variables. New hypotheses about cachexia include neuromuscular junction dysfunction, as CHRNA1 has specific role in ion channel gating; this is disrupted in the paraneoplastic Eaton-Lambert syndrome. This is first study analyzing human muscle in weight-losing PC and proves symptom management multidisciplinary research is feasible in academic setting. Supported by American Cancer Society pilot grant. No significant financial relationships to disclose.