Cancer Associated Fibroblasts Derived from Pancreatic Adenocarcinoma and Their Role in Cell Migration

Abstract

Background/Aim: Pancreatic ductal adenocarcinoma (PDAC) shows poor survival and early systemic dissemination. Cancer associated fibroblasts (CAFs) enhance migration and invasion of cancer cells. We aimed to investigate the role of CAFs in cell migration and their underlying paracrine effects. Materials and Methods: Using Transwell ® migration assays, PDAC cells (PANC-1) and three distinct types of fibroblasts were analyzed: CAFs, genetically transformed human foreskinfibroblasts (BJeLR), and non-transformed human foreskinfibroblasts (VH7). IL6 in the culture supernatant was measured to investigate paracrine communication in monocultures and direct/indirect cocultures. Results: CAFs showed a significantly higher capacity to migrate in vitro when compared to benign fibroblasts (p=0.009). They also facilitated the migration of PDAC cells in coculture (p=0.001). Neither BJeLR, nor VH7 displayed such features. This was accompanied by a significant increase in IL-6 when CAFs were cocultured with PANC-1 (p=0.009). Conclusion: CAFs are a key element of intra-tumoral migration and should be further investigated as a potential therapeutic target.Patients with pancreatic ductal adenocarcinoma (PDAC) display poor 5-year survival rates of approximately 9%, concomitant with steadily increasing incidence rates (1). In addition, pancreatic carcinoma cells tend to metastasize at a very early stage (2) and when diagnosed, about 53% of the patients with PDAC present with systemic dissemination (3). Early metastasis limits surgical treatment options and due to greatly ineffective chemotherapies, the patient's overall survival drops significantly (4). Therefore, underlying mechanisms that cause early metastasis are of major interest.A dense and fibrotic desmoplastic stroma is characteristic of the PDAC. The pancreatic tumor microenvironment largely consists of inflammatory and immune cells, extracellular matrix and foremost cancer-associated fibroblasts (CAFs) (5, 6), which all play a significant role in tumor spread and therapy resistance (7-11). Each of the cell types have multiple functions, some of which help the pancreatic cancer cells sustain and enhance their malignant potential. Here, CAFs are of particular interest, exhibiting functions that enable and enhance the migration of cancer cells and promote a proinvasive tumor environment (5,(12)(13)(14)(15).CAFs originate from various pancreatic cell types, such as pancreatic stellate cells, resident fibroblasts, bone marrow derived cells (BMDC) and epithelial cells (5). Even in the early stages of pancreatic cancer development/carcinogenesis, carcinoma cells establish a specific cancer microenvironment, which activates fibroblasts (16)(17)(18)(19). Activated CAFs are characterized by unique expression of α-SMA, in addition to Vimentin and GFAP (11,20).CAFs are able to communicate with the cells in their direct tumor microenvironment by direct cell-cell contact as well as in a paracrine manner (21). Hereto, CAFs can secrete pro-inflammatory cytokines such as IL1β, IL6, IL10, and...

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer

“…The pro-tumourigenic properties of CAFs can be exerted through extracellular matrix (ECM) remodelling, direct cell-cell interactions, as well as secretion of soluble factors [19]. In PDAC, effects of CAFs on tumour cells include increased proliferation, migration and invasion, for instance via indirect interleukin (IL)-6 signalling [20,21]. These interactions between CAFs and tumour cells contribute to the formation of distant metastasis.…”