Cancer-Associated Fibroblasts in Pancreatic Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most highly malignant tumors with a very poor prognosis. In addition to the cancer cells, the stroma of tumor can expand by 50% and influence cancer cell growth. Cancer-associated fibroblasts (CAFs) are important components of tumor stroma. Cancer cells, normal fibroblasts, normal epithelial cells as well as bone marrow-derived myofibroblasts contribute to the emergence of CAFs through various cytokines (e.g., TGF-β, SHH, PDGF) and epithelial-to-mesenchymal transition. CAFs affect cancer growth, survival, metastasis, angiogenesis and immunosurveillance through the secretion of various cytokines, such as CXCL12 and secreted protein acidic and rich in cystein. Also, CAFs correlate to the prognosis and chemoresistance of PDAC patients. As novel therapeutic targets, CAFs, and their relative factors, represent an important role in PDAC therapy.

Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

“…These studies have focused on extracellular matrix components, including collagen 1, rather than cell subsets of the tumour microenvironment (Dangi-Garimella et al , 2011, 2013). Notably, in PDAC and AAC the tumour stroma is a major part of the total tumour mass (Lunardi et al , 2014a; Rucki and Zheng, 2014; Pan et al , 2015). Our study provides experimental and correlative findings that link PDGFR β -defined fibroblasts to HMGA2 status in malignant cells.…”

“…A massive desmoplastic reaction and stroma formation are characteristics for PDAC and AAC (Lunardi et al , 2014; Rucki and Zheng, 2014; Pan et al , 2015) and can also act as a physical barrier preventing proper delivery of chemotherapeutic agents (Wang et al , 2016). One major component of the reactive tumour stroma are cancer-associated fibroblasts (CAFs) and in vitro and in vivo studies have shown that CAFs have tumour-promoting functions, including support of growth and metastasis as well as suppression of immunosurveillance (Ostman and Augsten, 2009; Strell et al , 2012; Weiland et al , 2012; Lunardi et al , 2014; Pan et al , 2015).…”

“…One major component of the reactive tumour stroma are cancer-associated fibroblasts (CAFs) and in vitro and in vivo studies have shown that CAFs have tumour-promoting functions, including support of growth and metastasis as well as suppression of immunosurveillance (Ostman and Augsten, 2009; Strell et al , 2012; Weiland et al , 2012; Lunardi et al , 2014; Pan et al , 2015). In PDAC, SDF-1 α (Li et al , 2012) and Nodal/Activin (Lonardo et al , 2011) have been identified as CAF-derived factors that affect EMT and stem cell properties in cancer cells.…”

Hepatitis C virus–induced tumor‐initiating cancer stem–like cells activate stromal fibroblasts in a xenograft tumor model

“…Interestingly, TGF‐β is markedly up‐regulated in pancreatic ductal adenocarcinoma . Cancer cells and normal fibroblasts contribute to the emergence of TAFs through TGF‐β and EMT . On the other hand, the enhanced bone resorption in multiple myeloma bone lesions causes a marked increase in the release and activation of TGF‐β .…”

Chemotherapy and tumor microenvironment of pancreatic cancer

“…CAFs promote EMT of pancreatic cancer cells via IL-6/PI-3 signal pathway [156]1. CAFs potentially induce angiogenesis by CXCL12/CXCR4 axis and SPARC [157]1. CAFs induce immunosuppressive environment to dampen the effects of antibodies against CTLA-4 and PD-L1 by CXCL12 [12]2.…”