Abstract
Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to identify perturbations in pancreatic cancer patient samples. Thus, we utilized a mass spectrometry-based lipidomic approach, focused towards the sphingolipid class of lipids, to quantify changes in human pancreatic cancer tumor and plasma specimens. Subgroup analysis revealed that patients with positive lymph node metastasis have a markedly higher level of ceramide species (C16:0 and C24:1) in their tumor specimens compared to pancreatic cancer patients without nodal disease or to patients with pancreatitis. Also of interest, ceramide metabolites, including phosphorylated (sphingosine- and sphinganine-1-phosphate) and glycosylated (cerebroside) species were elevated in the plasma, but not the pancreas, of pancreatic cancer patients with nodal disease. Analysis of plasma level of cytokine and growth factors revealed that IL-6, IL-8, CCL11 (eotaxin), EGF and IP10 (interferon inducible protein 10, CXCL10) were elevated in patients with positive lymph nodes metastasis, but that only IP10 and EGF directly correlated with several sphingolipid changes. Taken together, these data indicate that sphingolipid metabolism is altered in human pancreatic cancer and associated with advanced disease. Assessing plasma and/or tissue sphingolipids could potentially risk stratify patients in the clinical setting.
Highlights
Pancreatic cancer is one of the leading causes of cancer related deaths with a five-year survival rate of approximately 5% [1]
The biological activity of sphingolipids has been extensively explored in cell culture and animal models, it remains unclear what the exact “in vivo” roles of sphingolipids are in human cancers
The data demonstrate that specific species of ceramide and cerebroside are significantly and selectively altered in the cancerous tissue comparing to the non-cancerous pancreatic tissue
Summary
Pancreatic cancer is one of the leading causes of cancer related deaths with a five-year survival rate of approximately 5% [1]. A myriad of molecular and pharmacological studies have validated the role of ceramide species and metabolites to regulate tumor growth, migration, or metastasis. These studies have largely focused on in vitro cell lines and xenograft/syngeneic mouse models. The role of, and regulation of, altered sphingolipid metabolism in cancer development, progression and metastasis remains largely undefined in human patient populations. To address this deficiency, a mass spectrometry-based targeted analysis of sphingolipids in human pancreatic cancer clinical specimens was initiated
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