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Gastrointestinal cancer is one of the leading health problems worldwide, with a high morbidity and mortality. To date, harnessing both the innate and adaptive immune system against cancer provides a selective and effective therapeutic strategy for patients. As a first line defense against cancer, natural killer (NK) cells can swiftly target and lyse tumor cells without prior activation. In addition to its pivotal role in innate immunity, NK cells also play unique roles in the adaptive immune system as it enhance anti-tumor adaptive immune responses through secretion of cytokines and retaining an immunological memory. All these characteristics make NK cell a promising anti-cancer agent for patients. In spite of scarce infiltration and impaired function of NK cells in tumors, and the fact that tumors easily develop resistant mechanisms to evade the attacks from endogenous NK cells, multiple strategies have been developed to boost anti-tumor effect of NK cells and abolish tumor resistance. Some examples include adoptive transfer of NK cells after ex vivo activation and expansion; restoration of NK cell function using immune checkpoint inhibitors, and monoclonal antibody or cytokine treatment. Preclinical data have shown encouraging results, suggesting that NK cells hold great potential in cancer therapy. In this review, we discuss NK cells’ cytotoxicity and modulation function in GI cancer and the current application in clinical therapy.

Non-alcoholic fatty liver disease (NAFLD) is a continuous spectrum of diseases characterized by excessive lipid accumulation in hepatocytes. NAFLD progresses from simple liver steatosis to non-alcoholic steatohepatitis and, in more severe cases, to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Because of its growing worldwide prevalence, various animal models that mirror both the histopathology and the pathophysiology of each stage of human NAFLD have been developed. The selection of appropriate animal models continues to be one of the key questions faced in this field. This review presents a critical analysis of the histopathology and pathogenesis of NAFLD, the most frequently used and recently developed animal models for each stage of NAFLD and NAFLD-induced HCC, the main mechanisms involved in the experimental pathogenesis of NAFLD in different animal models, and a brief summary of recent therapeutic targets found by the use of animal models. Integrating the data from human disease with those from animal studies indicates that, although current animal models provide critical guidance in understanding specific stages of NAFLD pathogenesis and progression, further research is necessary to develop more accurate models that better mimic the disease spectrum, in order to provide both increased mechanistic understanding and identification/testing of novel therapeutic approaches. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases, which include simple liver steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). It is a burgeoning health problem worldwide in line with the trend towards unhealthy diet and increased prevalence of obesity and type 2 diabetes mellitus (T2DM). Many animal models that illustrate both the histology and pathology of human NAFLD have been established. It is important to choose an animal model that best conforms to the aim of the study. This chapter presents a critical analysis of the histopathology and pathogenesis of NAFLD and the most commonly used and recently developed animal models of hepatic steatosis, NASH and NAFLD-induced hepatocellular carcinoma (NAFLD-HCC). The main mechanisms involved in the experimental pathogenesis of NAFLD in various animal models were also discussed. This chapter also includes a brief summary of recent therapeutic targets found using animal models. Although current animal models provide important guidance in understanding the pathogenesis and development of NAFLD, future study is essential to develop more precise models that better mimic the disease spectrum for both improved mechanistic understanding and identification of novel therapeutic options.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases, which include simple liver steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). It is a burgeoning health problem worldwide in line with the trend towards unhealthy diet and increased prevalence of obesity and type 2 diabetes mellitus (T2DM). Many animal models that illustrate both the histology and pathology of human NAFLD have been established. It is important to choose an animal model that best conforms to the aim of the study. This chapter presents a critical analysis of the histopathology and pathogenesis of NAFLD and the most commonly used and recently developed animal models of hepatic steatosis, NASH and NAFLD-induced hepatocellular carcinoma (NAFLD-HCC). The main mechanisms involved in the experimental pathogenesis of NAFLD in various animal models were also discussed. This chapter also includes a brief summary of recent therapeutic targets found using animal models. Although current animal models provide important guidance in understanding the pathogenesis and development of NAFLD, future study is essential to develop more precise models that better mimic the disease spectrum for both improved mechanistic understanding and identification of novel therapeutic options.

Background & Aims: The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy in fibrosing steatohepatitis. Methods: Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6 wildtype mice fed high-fat/high-cholesterol (HFHC) or methionine-and choline-deficient (MCD) diet. Bone marrow transplantation (BMT) was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted by liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. Results: Macrophage infiltration is significantly induced in two mouse models of fibrosing steatohepatitis and human NASH-fibrosis patients. Bone marrow-derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Hepatic BMMs depletion by liposomal clodronate significantly attenuated fibrosing steatohepatitis. This effect was associated with reduced hepatic stellate cell (HSC) activation, collagen deposition and hepatic expression of key pro-fibrotic factors (TIMP1, TIMP2 and TGFβ1) and endoplasmic reticulum (ER) stress markers (GRP78, IRE1α and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; enhanced activation and proliferation (P