Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival

Abstract

BackgroundCancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia.MethodsMorphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided. ResultsSkeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P = .0016, r = 0.672), was increased in patients with lymph node metastasis (P = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P = .042), infiltration of CD68+ macrophages (63.6 cells/mm2 vs 233.8 cells/mm2, P = .0238), calcium deposition (0.21% vs 2.51%, P = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects.ConclusionsTo our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

“…This reduced expression of mitochondria‐related genes in the DIA of PDAC‐PDX mice aligns with published studies, which show mitochondrial deficits in cachectic tumour‐bearing hosts including altered mitochondrial biogenesis, fission/fusion, mitophagy, and mitochondrial function . Importantly, our findings are also consistent with repression of mitochondrial‐related genes in the skeletal muscle of cachectic PDAC patients …”

“…However, we found disrupted muscle architecture in the ABD and DIA, including increased extracellular space, irregularly shaped muscle fibres, increased number of mononuclear cells within the muscle, and necrotic fibres ( Figure C; Figure ). Importantly, these features are consistent with morphological pathologies identified in the RA of cachectic PDAC patients …”

“…Furthermore, expression of IL‐33, predominantly secreted by FAPs in skeletal muscle, is also increased in PDX DIA . An increase in the intramuscular FAP population along with infiltration of leukocytes would be consistent with that observed in PDAC patient RA …”

“…Indeed, as mentioned previously, many categories related to the immune response are enriched from genes increased in the DIA of PDX mice, and many of these same categories are enriched from genes increased in the RA of cachectic PDAC patients, including the host patient. Moreover, the morphology of the DIA and ABD of PDX mice showed characteristics consistent with that of PDAC muscle ( Figure C) . Critically, these findings imply that pancreatic tumour burden could elicit varying responses in different skeletal muscles in cancer patients, the future investigation of which could aid in the development of effective clinical therapies.…”

IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy

“…Interestingly "Oxidative Phosphorylation" was the most enriched GO category, which is highly relevant to pancreatic cancer cachexia. Indeed, recently published microarray data from our lab identified mitochondrial clusters as by far the most enriched clusters for genes downregulated in the skeletal muscle of cachectic pancreatic cancer patients compared to non-cancer controls [30].…”