Abstract
Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.
Highlights
Pancreatic cancer (PC) represents only 3% of the new cancer cases diagnosed in USA, but it has been the fourth cancer-related cause of death, with a five year survival rate of less than 5% for the last decade [1]
We investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptinNotch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC)
Present data assess that PC cells express OB-R, and show for the first time that leptin is secreted by PC cells and tumorspheres enriched in PCSC
Summary
Pancreatic cancer (PC) represents only 3% of the new cancer cases diagnosed in USA, but it has been the fourth cancer-related cause of death, with a five year survival rate of less than 5% for the last decade [1]. A variety of risk factors have been linked to PC, including smoking, diabetes, history of chronic pancreatitis and infection with H. pylori [3]. ABO blood types and genetic variants may influence pancreatic cancer risk [4]. Obesity (BMI > 30) is pandemic in the US and has been associated with poor prognosis of several malignancies, including prostate, colon and breast cancer [5]. Overweight is associated with shortened survival in patients with advanced PC, independently www.impactjournals.com/oncotarget of known prognostic factors, including high CA19-9 serum concentration, disease stage [6], and increased lymph node metastasis in patients with resected PC [7]. The mechanisms involved in the association between elevated BMI and decreased PC survival are still poorly understood
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