Modulation of the Leptin Receptor Mediates Tumor Growth and Migration of Pancreatic Cancer Cells

Abstract

Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.

Leptin-Notch signaling axis is involved in pancreatic cancer progression

“…These observations were further assessed in diet induced obesity (DIO) mice hosting orthotopic syngeneic PC xenografts [12]. DIO-mice showed increased body and pancreatic weights, and size of peripancreatic adipocytes.…”

Obesity, Inflammation, and Cancer

“…Human and murine pancreatic cancer cells express both the short and long forms of the leptin receptor, but loss of the long isoform results in increased growth and metastasis of murine pancreatic cancer cells (152), suggesting an antitumor effect. Recently, however, leptin receptor expression was shown to potentiate tumor growth independent of tumor cell proliferation (153). Obesity-related adipocytokines IL-6 and TNFα likely augment leptin signaling through STAT3 and/or PI3K pathways (154).…”

Pancreatic Cancer and Obesity: Some Molecular Perspectives

“…Leptin increases proliferation and migration of human and murine PC cell lines expressing the OB-R long and short isoforms. shRNA knockdown of OB-R partially abrogated the enhanced obesity-mediated growth of orthotopic PC tumors in obese mice [23]. Moreover, the effects of obesity through leptin signaling on cancer growth seem to be involved in chemoresistance developed by other cancer types.…”