Despite decades of effort in understanding pancreatic ductal
adenocarcinoma (PDAC), there is still a lack of innovative targeted
therapies for this devastating disease. Herein, we report the expression of
apelin and its receptor, APJ, in human pancreatic
adenocarcinoma and its protumoral function.
Apelin and APJ
protein expression in
tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry.
Apelin signaling function in
tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions,
apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage,
apelin and APJ were co-expressed by
tumor cells. In human
tumor cells,
apelin induced a long-lasting activation of PI3K/Akt, upregulated β-
catenin and the oncogenes c-myc and
cyclin D1 and promoted proliferation, migration and
glucose uptake.
Apelin receptor blockades reduced
cancer cell proliferation along with a reduction in pancreatic
tumor burden. These findings identify the
apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.