Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer

Abstract

There is growing evidence that metabolic alterations play an important role in cancer development and progression. The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation. Elevated fatty acid synthesis is one of the most important aberrations of cancer cell metabolism. An enhancement of fatty acids synthesis is required both for carcinogenesis and cancer cell survival, as inhibition of key lipogenic enzymes slows down the growth of tumor cells and impairs their survival. Based on the data that serum fatty acid synthase (FASN), also known as oncoantigen 519, is elevated in patients with certain types of cancer, its serum level was proposed as a marker of neoplasia. This review aims to demonstrate the changes in lipid metabolism and other metabolic processes associated with lipid metabolism in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic neoplasm, characterized by high mortality. We also addressed the influence of some oncogenic factors and tumor suppressors on pancreatic cancer cell metabolism. Additionally the review discusses the potential role of elevated lipid synthesis in diagnosis and treatment of pancreatic cancer. In particular, FASN is a viable candidate for indicator of pathologic state, marker of neoplasia, as well as, pharmacological treatment target in pancreatic cancer. Recent research showed that, in addition to lipogenesis, certain cancer cells can use fatty acids from circulation, derived from diet (chylomicrons), synthesized in liver, or released from adipose tissue for their growth. Thus, the interactions between de novo lipogenesis and uptake of fatty acids from circulation by PDAC cells require further investigation.

Keywords: Pancreatic cancer, Lipid metabolism, Fatty acid synthase, Monounsaturated fatty acids, Farnesylation, Hypoxia inducible factor 1α, Cyclooxygenase-2, Oncogenes, Tumor suppressors, Lipogenic enzymes inhibitors

Core tip: Metabolic alterations associated with mutation in oncogenes and tumor suppressor genes play an important role in cancer development and progression. One of the most important aberrations of metabolism in cancer cells is an elevated synthesis of lipids, which are building blocks for cell membrane formation during cell proliferation and signalling molecules. This review aims to demonstrate the changes in lipid metabolism in pancreatic ductal adenocarcinoma, the most common pancreatic neoplasm, with very high mortality. The potential role of elevated lipid synthesis in diagnosis, prognosis and therapy of pancreatic cancer is also discussed.