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.

Figure 1. Desmoplastic reaction and pancreatic cancer

H&E (haematoxylin and eosin) and trichrome stains of normal pancreas and a human PDAC tumour. Note the increased fibrosis (blue staining) in the PDAC tumour compared with the normal pancreas.

Figure 2. MT1-MMP in three-dimensional collagen contributes to chemotherapy resistance by increasing ERK1/2 activity and HMGA2 levels

MT1-MMP through proteolytic processing of collagen or activation of growth factors modulates integrin and/or growth factor receptor signalling to enhance ERK1/2 phosphorylation and HMGA2 expression in pancreatic cancer cells. This signalling pathway functions to attenuate the effect of gemcitabine chemotherapy in the three-dimensional collagen microenvironment.

Figure 3. Collagen regulation of MT1-MMP mRNA expression

Pancreatic cancer cells in three-dimensional collagen up-regulate MT1-MMP through activation of the TGF-β/TβRI/Smad3/Snail pathway. MT1-MMP can also be induced in the collagen microenvironment through the β1-integrin/Src/Egr1 signalling pathway. Although β-catenin signalling can regulate MT1-MMP, it is not known whether collagen regulation of MT1-MMP also involves β-catenin signalling.

Figure 4. A feed-forward amplification loop involving collagen, MT1-MMP and TGF-β

(A) Pancreatic cancer cells in the collagen microenvironment up-regulate TGF-β signalling to induce MT1-MMP expression. (B) Expression of MT1-MMP in cancer cells can in turn cause stellate cell activation also through increased TGF-β signalling. (C) The activated stellate cells deposit more collagen, resulting in a further increase in MT1-MMP expression in the cancer cells. As detailed in the text, this forward amplification loop contributes to pancreatic cancer invasion and generation of the desmoplastic reaction. (D) MT1-MMP expression in the collagen microenvironment also contributes to chemoresistance, in part, through up-regulation of HMGA2 (see also Figure 2). An animated version of this Figure is available at http://www.BiochemJ.org/bj/441/0541/bj4410541add.htm.