Hunting hidden pieces of signaling pathways in hepatocellular carcinoma

Advanced hepatocellular carcinoma(HCC)has a poor prognosis with limited treatment options.During the last decade,sorafenib,a multi-tyrosine kinase inhibitor(TKI),has been the only available systemic agent for first-line treatment of unresectable HCC(1).Recently,another multi-TKI,lenvatinib,was added to the list of first-line treatment alternatives based on the results of the phase III RREFLECT trial.For second-line treatment,two multi-TKIs,regorafenib and cabozantinib,were approved in 2016 and 2018,respectively.Among other targeted therapies,ramucirumab and an anti-PD-1 antibody,nivolumab,will soon be added in a second-line setting to the therapeutic armamentarium.These agents,however,generally lead to disease stabilization rather than tumor shrinkage.Achievement of complete remission with available systemic treatments still remains rare,however,and therapeutic breakthroughs are still needed.

Immunotherapy for colorectal cancer

The incidence of colorectal cancer(CRC)is on the rise,and the prognosis for patients with recurrent or metastatic disease is extremely poor.Although chemotherapy and radiation therapy can improve survival rates,it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC.In this review,we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials,including peptide vaccines,dendritic cell-based cancer vaccines,whole tumor cell vaccines,viral vector-based cancer vaccines,adoptive cell transfer therapy,antibody-based cancer immunotherapy,and cytokine therapy.The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.

Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses

Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses.However,when human peripheral blood mononuclear cells(PBMCs)are transferred into NOG(NOD/Shi-scid,IL-2rg null)mice,severe graft versus host disease(GVHD)hinders long term detailed analysis.Administration of human PBMCs into newly developed murine MHC class I-and class II-deficient NOG(NOG-dKO;NOG-Iab,B2m-double-knockout)mice showed sufficient engraftment of human immune cells with little sign of GVHD.Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab,indicating induction of antigen-specific B cells in the NOG-dKO mice.Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells,indicating the induction of antigen-specific T cells in the NOG-dKO mice.Adoptive cell therapies(ACTs)using melanoma antigen recognized by T cells(MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells.ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice,in which changes in human cancer phenotypes by immune intervention,such as increased CD271 expression,could be evaluated.Therefore,NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.

miR-23a promotes invasion of glioblastoma via HOXD10-regulated glial-mesenchymal transition

Glioblastoma is the most aggressive and invasive brain tumor and has a poor prognosis;elucidating the underlying molecular mechanisms is essential to select molecular targeted therapies.Here,we investigated the effect of microRNAs on the marked invasiveness of glioblastoma.U373 glioblastoma cells were infected with 140 different microRNAs from an OncomiR library,and the effects of the invasion-related microRNAs and targeted molecules were investigated after repeated Matrigel invasion assays.Screening of the OncomiR library identified miR-23a as a key regulator of glioblastoma invasion.In six glioblastoma cell lines,a positive correlation was detected between the expression levels of miR-23a and invasiveness.A luciferase reporter assay demonstrated that homeobox D10(HOXD10)was a miR-23a-target molecule,which was verified by high scores from both the PicTar and miRanda algorithms.Forced expression of miR-23a induced expression of invasion-related molecules,including uPAR,RhoA,and RhoC,and altered expression of glial-mesenchymal transition markers such as Snail,Slug,MMP2,MMP9,MMP14,and E-cadherin;however,these changes in expression levels were reversed by HOXD10 overexpression.Thus,miR-23a significantly promoted invasion of glioblastoma cells with polarized formation of focal adhesions,while exogenous HOXD10 overexpression reversed these phenomena.Here,we identify miR-23a-regulated HOXD10 as a pivotal regulator of invasion in glioblastoma,providing a novel mechanism for the aggressive invasiveness of this tumor and providing insight into potential therapeutic targets.