Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients

Abstract

BackgroundIn order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.MethodsOne hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time–polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581–1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively.ResultsCancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008).ConclusionsThe present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

“…94,95 Such factors include for instance leptin, 96 ghrelin, 97 and obestatin 98 which are all thought to play a major role in cancer cachexia. These emerging biomarkers were MMP-generated degradation fragment of collagen 6 (C6M) 68 Type VI collagen N-terminal globular domain epitope (IC6) 68 N-terminal propeptide of type III procollagen (P3NP) 69 C-terminal agrin fragment (CAF) 69 Methyl-d 3 -Methylhistidine (D-3MH) 70 Growth differentiating factor-15 (GDF-15) 71 Follistatin (FST) 72 Irisin 72 Ghrelin 73 Leptin 73 β-Dystroglycan 74 Dystrophin 74 Tartrate-resistant acid phosphatase 5a (TRACP5a) [75][76][77][78] MMP, matrix metalloproteinase. investigated in oncologic patients as diagnostic and/or predictive markers, as well as their impact on patient survival.…”

“…73 Furthermore, in a recently published study, in which a large number of putative biomarker candidates were tested, with a cohort of upper gastrointestinal cancer patients, β-dystroglycan was identified as a potential biomarker for weight-loss and myosin heavy chain or dystrophin as survival biomarkers. 74 As mentioned before, inflammatory cytokines are used for prognosis of cancer cachexia. A new promising chronic inflammatory marker was found recently and is suggested to play a prognostic role in cancer cachexia: the tartrateresistant acid phosphatase 5a (TRACP5a).…”

Impaired regeneration: A role for the muscle microenvironment in cancer cachexia

“…Importantly, these same patients demonstrated a significant post-feeding increase in protein synthesis following curative tumor resection, providing clear evidence that tumors do alter muscle protein synthesis, at least in response to feeding. Consistent with the controversy about changes in muscle protein synthesis in patients with cancer, the Akt signaling pathway is commonly believed to be either downregulated or dysfunctional in patients with cancer, but the evidence for changes in this pathway is not compelling [24–26]. …”

Searching for the Ideal Therapy for Cancer Cachexia

“…Biomarkers could detect the changes before any clinical manifestations arouse, facilitating treatment and, possibly, improving prognosis. Progress has certainly been made concerning biomarkers [2] but more research is needed in this field to find an easy measurable --either blood or urine present and specific muscle wasting biomarker. Third, since cancer cachexia leads to decrease potential for muscle regeneration due to the fact that satellite cells are not able to differentiate into myocells, one new revolutionary concept that will, no doubt, involve further research is that of cell reprogramming to muscle.…”