Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression

Abstract

PDAC (pancreatic ductal adenocarcinoma) is among the most deadly of human malignances. A hallmark of the disease is a pronounced collagen-rich fibrotic extracellular matrix known as the desmoplastic reaction. Intriguingly, it is precisely these areas of fibrosis in which human PDAC tumours demonstrate increased expression of a key collagenase, MT1-MMP [membrane-type 1 MMP (matrix metalloproteinase); also known as MMP-14]. Furthermore, a cytokine known to mediate fibrosis in vivo, TGF-β1 (transforming growth factor-β1), is up-regulated in human PDAC tumours and can promote MT1-MMP expression. In the present review, we examine the regulation of PDAC progression through the interplay between type I collagen (the most common extracellular matrix present in human PDAC tumours), MT1-MMP and TGF-β1. Specifically, we examine the way in which signalling events through these pathways mediates invasion, regulates microRNAs and contributes to chemoresistance.

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…20,[44][45][46] In addition, the detection of aligned collagen signatures in routine histopathology slides can predict disease 16 In pancreatic ductal adenocarcinoma, cancer cells in contact with collagen type I show enhanced migratory capabilities through upregulation of Snail, a regulator of epithelial-to-mesenchymal transition. [47][48][49][50][51] Epithelial-to-mesenchymal transition is a process that dissemination-competent cells undergo. It has been shown to be prevalent in pancreatic ductal adenocarcinoma tissue and to negatively impact patient prognosis.…”

BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo

“…Compared with adjacent normal pancreatic tissue, PDAC tumors demonstrate increased fibrosis and increased numbers of activated myofibroblasts in the fibrotic microenvironment (6)(7)(8). As a recent report showed that the BET family protein BRD4 mediates the profibrotic response in activated liver stellate cells (13), we evaluated human PDAC tumors for BRD4 expression.…”

“…Pancreatic stellate cells (PSCs) are the predominant fibroblasts present in the pancreas and the key regulators of fibrosis in vivo (7,12). In the quiescent state, PSCs demonstrate cytoplasmic lipid droplets and produce minimal amounts of collagen I and other extracellular matrix (ECM) proteins (12).…”

“…However, the success of current drug therapies is limited (2,3), frequently only extending survival of PDAC patients by a few months at most (4,5). As fibrotic reaction is a characteristic feature of the majority of PDAC tumors (6)(7)(8), there has been increasing interest in understanding the role and regulation of the stroma in PDAC progression and in mediating response to therapy. While ablating the stroma results in worse outcomes in mouse models of PDAC (9), remodeling and normalizing the stroma can improve survival in transgenic mouse models (10,11).…”

Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion

“…This is particularly relevant in pancreatic cancer, where cancer progression is marked by the fibrotic nature of the ECM surrounding and throughout the tumor [26]. This fibrotic ECM is dense and stiff and requires high pericellular MMP activity in order for cells to invade through it suggesting that this disease might be sensitive to specific MMP-14 inhibition as an approach to block invasion and metastasis.…”