Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment
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Elena Zoico1, Elena Darra1, Vanni Rizzatti1, Simona Budui1, Guido Franceschetti1, Gloria Mazzali1, Andrea P. Rossi1, Francesco Fantin1, Marta Menegazzi2, Saverio Cinti3, Mauro Zamboni1
1Department of Medicine, Geriatrics Section, University of Verona, Verona, Italy
2Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy
3Department of Experimental and Clinical Medicine, Center of Obesity-University of Ancona (Politecnica delle Marche), Ancona, Italy
Elena Zoico, e-mail: [email protected]
Keywords: pancreatic cancer, adipocytes, tumor microenvironment, cell dedifferentiation, WNT5a
Received: August 09, 2015 Accepted: February 06, 2016 Published: March 06, 2016
A significant epidemiological association between obesity and pancreatic ductal adenocarcinoma (PDAC) has previously been described, as well as a correlation between the degree of pancreatic steatosis, PDAC risk and prognosis. The underlying mechanisms are still not completely known.
After co-culture of 3T3-L1 adipocytes and MiaPaCa2 with an in vitro transwell system we observed the appearance of fibroblast-like cells, along with a decrease in number and size of remaining adipocytes. RT-PCR analyses of 3T3-L1 adipocytes in co-culture showed a decrease in gene expression of typical markers of mature adipocytes, in parallel with an increased expression of fibroblast-specific and reprogramming genes. We found an increased WNT5a gene and protein expression early in MiaPaCa2 cells in co-culture. Additionally, EMSA of c-Jun and AP1 in 3T3-L1 demonstrated an increased activation in adipocytes after co-culture. Treatment with WNT5a neutralizing antibody completely reverted the activation of c-Jun and AP1 observed in co-cultured adipocytes.
Increasing doses of recombinant SFRP-5, a competitive inhibitor for WNT5a receptor, added to the co-culture medium, were able to block the dedifferentiation of adipocytes in co-culture.
These data support a WNT5a-mediated dedifferentiation process with adipocytes reprogramming toward fibroblast-like cells that might profoundly influence cancer microenvironment.
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