The hepatic pre-metastatic niche in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies to date, largely because it is associated with high metastatic risk. Pancreatic tumors have a characteristic tendency to metastasize preferentially to the liver. Over the past two decades, it has become evident that the otherwise hostile milieu of the liver is selectively preconditioned at an early stage to render it more conducive to the engraftment and growth of disseminated cancer cells, a concept defined as pre-metastatic niche (PMN) formation. Pancreatic cancer cells exploit components of the tumor microenvironment to facilitate their migration out of the primary tumor, which often involves conversion of pancreatic cancer cells from an epithelial to a mesenchymal phenotype via the epithelial-to-mesenchymal transition. Pancreatic stellate cells and matrix stiffness have been put forward as major drivers of invasiveness in PDAC. Even before the onset of pancreatic cancer cell dissemination, soluble factors and extracellular vesicles secreted by the primary tumor, and possibly even premalignant lesions, help shape a supportive niche in the liver by providing vascular docking sites for circulating tumor cells, enhancing vascular permeability, remodeling the extracellular matrix and recruiting immunosuppressive inflammatory cells. Emerging evidence suggests that some of these tumor-derived factors may represent powerful diagnostic or prognostic biomarkers. Though our understanding of the mechanisms driving PMN formation in PDAC has expanded considerably, many outstanding questions and challenges remain. Further studies dissecting the molecular and cellular events involved in hepatic PMN formation in PDAC will likely improve diagnosis and open new avenues from a therapeutic standpoint.

Keywords: Metastasis; Niche; Pancreatic cancer; Stroma.

Fig. 1

Molecular and cellular events involved in PMN formation in PDAC. PSCs and matrix stiffness, part of the tumor-associated stroma, assist invasion and intravasation of pancreatic cancer cells, for example by inducing EMT. Meanwhile in the hepatic microenvironment, platelet activation and thrombus formation in response to microparticle-associated TF secreted by the primary tumor facilitates the arrest of disseminated pancreatic cancer cells. Opening of the endothelial barrier by activated platelets then facilitates their extravasation. Exosomes enriched in MIF shed by pancreatic cancer cells interact with Kupffer cells, which activate HSCs via the release of TGFβ. The deposition of fibronectin by activated HSCs provides docking sites for metastasis-promoting bone marrow-derived cells such as macrophages and MDSCs. MDSCs impose immune tolerance by inhibiting NK cells and cytotoxic T cells and by promoting the development of Treg. Pancreatic cancer cell-derived TIMP-1 activates HSCs via its cognate receptor CD63 and induces the secretion of SDF-1, a chemoattractant for bone marrow-derived neutrophils. HSCs are also activated in response to MAM-derived granulin, which induces the production of periostin and collagen by HSCs. MAMs also inhibit anti-tumor immune responses by taking on an immunosuppressive M2 phenotype. PSC, pancreatic stellate cell; EMT, epithelial-to-mesenchymal transition; TF, tissue factor; MIF, macrophage inhibitory factor; HSC, hepatic stellate cell; TGFβ, transforming growth factor β; MDSC, myeloid-derived suppressor cell; NK cell, natural killer cell; Treg, regulatory T cell; TIMP-1, tissue inhibitor of metalloproteinases-1; CD63, cluster of differentiation 63; SDF-1, stromal-derived factor-1; MAM, metastasis-associated macrophage