pci-32765 and Carcinogenesis

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients

Topics: Adenine; Animals; Biopsy; Carcinogenesis; CRISPR-Cas Systems; Drug Design; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Mice; Multiprotein Complexes; Mutation; Myeloid Differentiation Factor 88; NF-kappa B; Piperidines; Proteomics; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Toll-Like Receptor 9; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Increasing reports show noninflammation underlying HCC, challenging our understanding of the roles of the immune system in hepatocarcinogenesis. By exploring a mouse model of hepatic tumor induced by hepatocyte-specific expression of the Hras12V oncogene without obvious inflammation, we found that the proportion of B cells, but not T cells, progressively and significantly decreased in 3, 5-month-old transgenic mice (Tg) compared with non-transgenic mice. Notably, the proportions of total and activated B and T cells all significantly decreased in 9-month-old Tg with multiple massive hepatic tumors. Together with the decreased B cell proportion, serum IgG1/2 also significantly decreased in 5, 9-month-old Tg. Interestingly, homozygous Tg showed significantly higher B cell proportion and IgG2 levels, accompanied by significantly lower incidences of liver nodules but not adenomas and carcinomas compared with heterozygous Tg. Treatment of Tg with PCI-32765, a potent Bruton's tyrosine kinase (BTK) inhibitor for suppressing B cell proliferation and activation, significantly decreased the B cell proportion and IgG2 levels, accompanied by a significantly higher incidence of liver nodules, but had no effects on adenoma and carcinoma. Treatment of Tg with insulin-like growth factor 1 (IGF-1) significantly increased the B cell proportion and IgG2 levels, accompanied by a significantly lower incidence of liver nodules and carcinoma, but had no effects on adenoma. Conclusively, B cells and IgG2 may play important roles in suppressing hepatic tumorigenesis, but not development. In addition, hepatocyte-specific expression of the ras oncogene may play roles in suppressing B cells, while developed hepatic tumors suppress both B and T cells.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; Carcinogenesis; Immunoglobulin G; Insulin-Like Growth Factor I; Liver Neoplasms, Experimental; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oncogene Proteins; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; ras Proteins