Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma

Abstract

Abstract. Background: Obesity is an established risk factor for the development of pancreatic ductal adenocarcinoma (PDACPancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, with a 5-year survival rate of less than 6% in the United States (1). The low survival rate is due to the late stage at which patients are usually diagnosed, with only 20% of patients being eligible for tumor resection at the time of diagnosis (1). Several risk factors for PDAC are firmly established, such as chronic pancreatitis (2), cigarette smoking (3), family history of pancreatic cancer (4), and diabetes mellitus (5).Both epidemiological and experimental studies have also linked obesity to the development of PDAC. In a large casecontrol study, Silverman et al. (6) showed obesity portends a 50-60% increased risk of PDAC in both men and women. Similarly, a pooled case-control analysis using data from the Pancreatic Cancer Cohort Consortium (PanScan) comparing 2170 PDAC cases to 2209 controls showed a positive association between increasing body mass index (BMI) and risk of PDAC [adjusted odds ratio (aOR) for the highest vs. lowest BMI quartile=1.33, 95% confidence interval (CI)= 1.12-1.58, p<0.001 (7).The mechanism of how obesity increases PDAC risk is poorly understood. Previous studies have shown that increased peritumoral fat density promotes metastasis and increases mortality in patients with PDAC (8). Adipose triglyceride lipase (ATGL) is a lipase in adipose tissue that catabolizes the first step in triglyceride hydrolysis and is responsible for the release of free fatty acids. Another lipase called monoacylglycerol lipase has been shown to be overexpressed in human cancer cell lines and to promote in vivo tumor growth via 'feeding' cancer cells with free fatty acids (9). Previous studies of breast cancer demonstrated increased peritumoral ATGL expression in fat cells of obese 699 Τhis article is freely accessible online.

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

“…ATGL depletion leads to growth inhibition in several cancer cell lines [ 190 , 191 ], suggesting a pro-tumourigenic role for the enzyme. Additionally, recent studies suggest that ATGL activity in both tumours and neighbouring adipose tissue contributes to the adipocyte-induced metabolic reprogramming and aggressiveness of breast, pancreatic, and ovarian cancer [ 102 , 103 , 104 , 192 ]. Activated lipolysis in omental fat adipocytes provides lipids for energy production in ovarian cancer cells and promotes their growth at the metastatic site [ 103 ].…”

Hints on ATGL implications in cancer: beyond bioenergetic clues

“…Interestingly, ATGL upregulation in breast cancer was associated with a tumour microenvironment enriched in adipocytes, contributing to aggressiveness of high-grade tumours 43 . Similarly, pancreatic ductal adenocarcinoma with elevated levels of ATGL were characterised by higher adiposity and stromal proliferation (desmoplasia) 44 .…”

Drosophila melanogaster: A Model Organism to Study Cancer

“…In this context, a recent role was identified for adipose triglyceride lipase (ATGL) whereby it hydrolyzes triacylglycerols into fatty acids (FAs) that may act as signaling molecules to induce growth both cell autonomously and in neighboring cells (Walther and Farese, 2012). The contribution of ATGL to cancer growth is controversial, indeed several studies showed that its depletion reduced proliferation in colorectal cancer cells and in non-small-cell lung carcinoma (Ou et al, 2014; Zagani et al, 2015), and in breast and pancreatic carcinoma its upregulation contributed to tumorigenesis (Grace et al, 2017; Wang et al, 2017). On the contrary, lack of ATGL favored pulmonary neoplasia in mice, and in few human tumors ATGL expression was found reduced highlighting the complex role of lipids in tumorigenesis (Al-Zoughbi et al, 2016).…”