title: Liver metastases: Microenvironments and ex-vivo models.
abstract: The liver is a highly metastasis-permissive organ, tumor seeding of which usually portends mortality. Its unique and diverse architectural and cellular composition enable the liver to undertake numerous specialized functions, however, this distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells. The particular focus for this perspective is the bidirectional interactions between the disseminated tumor cells and the unique resident cell populations of the liver; notably, parenchymal hepatocytes and non-parenchymal liver sinusoidal endothelial, Kupffer, and hepatic stellate cells. Understanding the early steps in the metastatic seeding, including the decision to undergo dormancy versus outgrowth, has been difficult to study in 2D culture systems and animals due to numerous limitations. In response, tissue-engineered biomimetic systems have emerged. At the cutting-edge of these developments are ex vivo 'microphysiological systems' (MPS) which are cellular constructs designed to faithfully recapitulate the structure and function of a human organ or organ regions on a milli- to micro-scale level and can be made all human to maintain species-specific interactions. Hepatic MPSs are particularly attractive for studying metastases as in addition to the liver being a main site of metastatic seeding, it is also the principal site of drug metabolism and therapy-limiting toxicities. Thus, using these hepatic MPSs will enable not only an enhanced understanding of the fundamental aspects of metastasis but also allow for therapeutic agents to be fully studied for efficacy while also monitoring pharmacologic aspects and predicting toxicities. The review discusses some of the hepatic MPS models currently available and although only one MPS has been validated to relevantly modeling metastasis, it is anticipated that the adaptation of the other hepatic models to include tumors will not be long in coming.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Clark
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA University of Pittsburgh Cancer Institute, University of Pittsburgh, PA 15213, USA.
authors.forename: D Lansing
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Griffith
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA Pittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA wellsa@upmc.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Wells
mesh_terms: D032701:Biomimetics; D055166:Hepatic Stellate Cells / Q000473:pathology; D006801:Humans; D007728:Kupffer Cells / Q000473:pathology; D008099:Liver / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D059016:Tumor Microenvironment / Q000502:physiology*
keywords: Liver metastasis; hepatic niche; metastatic models; microphysiological; tumor microenvironment