ABSTRACT
BACKGROUND AIMS: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS: We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS: Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS: Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.
Subject(s)
Colorectal Neoplasms , Peritoneal Neoplasms , Receptors, Chimeric Antigen , Male , Animals , Carcinoembryonic Antigen , Peritoneal Neoplasms/therapy , T-Lymphocytes , Immunotherapy, Adoptive , Neoplasm Recurrence, Local , Colorectal Neoplasms/therapy , Colorectal Neoplasms/pathologyABSTRACT
The transmission of T-2 toxin and its metabolites into the edible tissues of poultry has potential effects on human health. The bile acid and xenobiotic system composes an intricate physiological network of chemoprotective and transporter-related functions, which ensures the detoxification and removal of harmful xenobiotic and endobiotic compounds from the body. This study revealed that cholic acid (CA), as one of the bile acids, promoted the metabolism of T-2 toxin in vivo by inducing the xenobiotic metabolism enzymes expression, thereby increasing the stress resistance and attenuating the oxidative stress. This study also indicated that dietary supplementation of 1% CA alleviated the mortality caused by T-2 toxin. Liver histology results demonstrated that CA supplementation significantly reduced inflammatory cell infiltration, sinusoidal expansion and congestion. Biochemistry results showed that the elevations of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and the increase in concentration of hydrogen peroxide (H2O2) in liver induced by the T-2 toxin were decreased by dietary supplementation of 1% CA. Additionally, CA supplementation led to the increase in superoxide dismutase (SOD) activity, but the decrease in catalase (CAT) activity in broiler chicken livers. Based on these findings, we propose that activation of FXR promotes T-2 toxin xenobiotic metabolism, and FXR plays a hepatoprotection role in liver injury induced by T-2 toxin.
Subject(s)
Cholic Acid/pharmacology , Liver/metabolism , Oxidative Stress/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , T-2 Toxin/toxicity , Xenobiotics/metabolism , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Catalase/metabolism , Chickens , Chromatography, High Pressure Liquid , Hydrogen Peroxide/metabolism , Inactivation, Metabolic , Liver/drug effects , Liver/pathology , Receptors, Cytoplasmic and Nuclear/agonists , Superoxide Dismutase/metabolism , T-2 Toxin/blood , T-2 Toxin/metabolism , Tandem Mass SpectrometryABSTRACT
Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats.