Cancer-Associated Fibroblasts Enhance Survival and Progression of the Aggressive Pancreatic Tumor Via FGF-2 and CXCL8

Pancreatic ductal adenocarcinoma remains one of the most challenging human cancers. Desmoplasia is predominant in this disease exhibiting a strong stromal reaction with an abundance of the cancer-associated fibroblasts (CAFs). We aimed in this study to investigate the reciprocal interaction between the tumor cells and the CAFs and its effect on tumor cells survival. We hypothesized that the survival of pancreatic cancer cell with aggressive phenotype is modulated by the Interactions between malignant pancreatic tumor cells and surrounding CAFs. To examine this, we utilized co-culture methods where tumor cells with different malignant potentials, HPAF (low) HPAF-CD11 (moderate/high) co-cultured with CAFs. CAFs-conditioned media increased the growth of HPAF-CD11 but not HPAF cells and increased CXCL8 levels highly in HPAF-CD11 and slightly in HPAF. The growth stimulatory effect and elevated CXCL8 level caused by CAFs-conditioned media were diminished by neutralizing the fibroblast growth factor-2 (FGF-2). In addition, conditioned media of HPAF-CD11 increased CAFs cell number whereas that of HPAF did not, and these effects were suppressed by neutralizing CXCL8. Furthermore, data from gene expression microarray study exhibited different expression profiles between HPAF and HPAF-CD11 when co-culture with CAFs. A significant increase in CXCL8 and FGF-2 expression was observed with HPAF-CD11/CAFs co-culture and to a lower extent with HPAF/CAFs co-culture. Together, these data demonstrate a paracrine bi-directional interaction between pancreatic tumor cells and the CAFs through CXCL8 and FGF-2 that helps the tumor growth. Future in-depth study of these pathways will assist in obtaining diagnostic and therapeutic tools for pancreatic ductal adenocarcinoma.