Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells.
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.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Alisha M
AM
Mendonsa
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Madeleine C
MC
Chalfant
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Lee D
LD
Gorden
Department of Surgery, Division of Surgical Oncology, University of Miami, Sylvester Cancer Center, Miami, Florida, United States of America.
Michael N
MN
VanSaun
D050154:Adiposity / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D059305:Diet, High-Fat; D055785:Gene Knockdown Techniques; D006801:Humans; D020738:Leptin / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D054411:Receptors, Leptin / Q000378:metabolism*
D020738:Leptin; D054411:Receptors, Leptin