Abstract
Interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) play an important role in the progression of pancreatic cancer. Recent studies have shown that cellular senescence and senescence-associated secretory phenotype factors play roles in the progression of cancer. This study aimed to clarify the effects of senescence-induced PSCs on pancreatic cancer cells. Senescence was induced in primary-cultured human PSCs (hPSCs) through treatment with hydrogen peroxide or gemcitabine. Microarray and Gene Ontology analyses showed the alterations in genes and pathways related to cellular senescence and senescence-associated secretory phenotype factors, including the upregulation of C-X-C motif chemokine ligand (CXCL)-1, CXCL2, and CXCL3 through the induction of senescence in hPSCs. Conditioned media of senescent hPSCs increased the proliferation-as found in an assessment with a BrdU incorporation assay-and migration-as found in an assessment with wound-healing and two-chamber assays-of pancreatic cancer AsPC-1 and MIAPaca-2 cell lines. SB225002, a selective CXCR2 antagonist, and SCH-527123, a CXCR1/CXCR2 antagonist, attenuated the effects of conditioned media of senescent hPSCs on the proliferation and migration of pancreatic cancer cells. These results suggest a role of CXCLs as senescence-associated secretory phenotype factors in the interaction between senescent hPSCs and pancreatic cancer cells. Senescent PSCs might be novel therapeutic targets for pancreatic cancer.