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...
Background and Objectives: The Notch signaling pathway plays an important role both in the development of the ductal systems of the pancreas and the bile ducts as well as in cancer development and progression. The aim of this study was to examine the expression of central proteins of the Notch signaling pathway in pancreatobiliary tumors and its influence on patient survival. Materials and Methods: We compared the receptors (Notch1, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas via immunohistochemistry and ImageJ software-assisted analysis. An Immunohistochemistry (IHC)-score was determined by the percentage and intensity of stained (positive) cells (scale 0–7) and normal and malignant tissue was compared. In the IHC results, patients’ (gender, age) and tumor (TNM Classification of Malignant Tumors, Union Internationale contre le Cancer (UICC) stages, grading, and lymphangitic carcinomatosa) characteristics were correlated to patient survival. Results: For eCC, the expression of CD44 (p = 0.043, IHC-score 3.94 vs. 3.54) and for iCC, the expression of CD44 (p = 0.026, IHC-score 4.04 vs. 3.48) and Notch1 (p < 0.001, IHC-score 2.87 vs. 1.78) was significantly higher in the tumor compared to non-malignant tissue. For PDAC, the expression of ADAM17 (p = 0.008, IHC-score 3.43 vs. 1.73), CD44 (p = 0.012, IHC-score 3.64 vs. 2.27), Notch1 (p = 0.012, IHC-score 2.21 vs. 0.64), and Notch4 (p = 0.008, IHC-score 2.86 vs. 0.91) was significantly higher in the tumor tissue. However, none of the analyzed Notch-signaling related components showed an association to patient survival. Conclusion: A significant overexpression of almost all studied components of the Notch signaling pathway can be found in the tumor tissue, however, without a significant influence on patient survival. Therefore, further studies are warranted to draw conclusions on Notch pathway’s relevance for patient survival.
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