Senescent Human Pancreatic Stellate Cells Secrete CXCR2 Agonist CXCLs to Promote Proliferation and Migration of Human Pancreatic Cancer AsPC-1 and MIAPaCa-2 Cell Lines

by Selleckchem | Aug 07 2023

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.

Comments:

The study you mentioned aimed to investigate the effects of senescence-induced pancreatic stellate cells (PSCs) on pancreatic cancer cells and clarify the role of senescence-associated secretory phenotype (SASP) factors in this interaction. PSCs are cells in the pancreas that play a critical role in the development and progression of pancreatic cancer.

The researchers induced senescence in primary-cultured human PSCs (hPSCs) using hydrogen peroxide or gemcitabine, which are known inducers of cellular senescence. They then analyzed the gene expression changes in senescent hPSCs using microarray and Gene Ontology analyses. The results showed alterations in genes and pathways related to cellular senescence and SASP factors.

One of the notable findings was the upregulation of C-X-C motif chemokine ligand (CXCL)-1, CXCL2, and CXCL3 in senescent hPSCs. These chemokines are known to be involved in various cellular processes, including inflammation and cell migration. The researchers further investigated the effects of senescent hPSCs on pancreatic cancer cells.

They collected conditioned media from senescent hPSCs and treated pancreatic cancer cell lines (AsPC-1 and MIAPaca-2) with it. The conditioned media from senescent hPSCs promoted the proliferation and migration of pancreatic cancer cells, as observed in BrdU incorporation, wound-healing, and two-chamber assays.

To understand the mechanism underlying these effects, the researchers used selective antagonists of chemokine receptors CXCR1 and CXCR2 (SB225002 and SCH-527123, respectively). By blocking these receptors, they found that the effects of conditioned media from senescent hPSCs on pancreatic cancer cells' proliferation and migration were attenuated. This suggests that the upregulated CXCLs in senescent hPSCs contribute to the interaction between senescent PSCs and pancreatic cancer cells.

Overall, the study highlights the importance of cellular senescence and SASP factors in the interaction between pancreatic cancer cells and PSCs. The findings suggest that senescent PSCs and the associated secreted factors, such as CXCLs, could be potential therapeutic targets for pancreatic cancer. Further research is needed to explore the underlying mechanisms in more detail and develop effective strategies for targeting senescent PSCs in pancreatic cancer treatment.