Liver metastases: Microenvironments andex-vivomodels

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 (LSEC), Kupffer (KC), and hepatic stellate cells (HSC). 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 region 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 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 for relevantly modeling metastasis, it is anticipated that the adaptation of the other hepatic models to include tumors will not be long in coming.

Similarity between Some Biological Systems, Organotropism and Metastatic Process: Active Role Played By Secondary Organ?

“…"We recently showed that the simultaneous targeting of glucose and glutamine under calorie restriction could signi icantly reduce systemic metastatic cancer in the VM-M2 mouse model" [17]. "The liver is a highly metastasis-permissive organ" [20]. "This distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells" [20].…”

“…"The liver is a highly metastasis-permissive organ" [20]. "This distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells" [20]. "Cancer metastasis is a highly complex process that involves aberrations in gene expression by cancer cells leading to transformation, growth, angiogenesis, invasion, and dissemination, survival in the circulation, and subsequent attachment and growth in the organ of metastasis.…”

“…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 also for therapeutic agents to be studied" [20].…”

3D Miniaturization of Human Organs for Drug Discovery

“…A very interesting approach to model the complex sinusoid-like structures using 3D perfused hepatic co-cultures in a microfluidic system has been developed by Griffith and co-workers. [74][75][76][77] This microfluidic model includes key features such as adjustable flow rates based on oxygen consumption and long-term steady maintenance of the oxygen gradient. This comprehensive system, using co-cultures of diverse heterogeneous cells, forms liver …”

“…[53] In these multicellular aggregates, the need for supporting gels or matrices is eliminated, the adverse effects 3D culture approach for generating a laminated cerebral cortex like structure from pluripotent stem cells. [57,58] Microfabrication Neuroprogenitor cells Microfluidic culture platform containing a relief pattern of soma and axonal compartments connected by microgrooves to direct, isolate, lesion, and biochemically analyze CNS axons [67,68] 3D bioprinting Primary human cortical neurons Discrete layers of primary neutrons in a RGD peptide-modified gellan gum [118][119][120] Intestine (Gut) Self-assembled Stem cells Identified intestinal stem cells and differentiated cells in vitro [59,60] Microfabrication Human epithelial cells Mimic contractility by using mechanochemical actuator [11,19,27,72] Liver Self-assembled Human stem cells 3D culture of self-renewing human liver tissue [61,62] Microfabrication Hepatocytes and fibroblasts Microengineered hepatic microtissues containing hepatocytes and fibroblasts [73][74][75][76][77] 3D bioprinting HepG2 and HUVEC Multilayered organ tissue model [96,[155][156][157] Vessel Microfabrication Rat brain endothelial cells 3D culture in microfluidic device [63][64][65][66] 3D bioprinting HUVECs and HUVSMCs Scaffold-less vessel formation using spheroid fusion [84][85][86][87][88][89][90][91]…”