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Ma R.,Huazhong University of Science and Technology | Ji T.,Huazhong University of Science and Technology | Chen D.,Peking Union Medical College | Dong W.,Peking Union Medical College | And 10 more authors.
OncoImmunology | Year: 2016

ABSTRACT: Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages. © 2016, © Taylor & Francis Group, LLC.

Zhang J.,University of Southern California | Zhu L.,University of Southern California | Lu X.,University of Southern California | Feldman E.R.,University of Florida | And 12 more authors.
PLoS Pathogens | Year: 2015

Human gamma herpesviruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumors, particularly in in immune-compromised individuals. Due to the stringent host tropism, rodents are resistant to infection by human gamma herpesviruses, creating a significant barrier for the in vivo study of viral genes that contribute to tumorigenesis. The closely-related murine gamma herpesvirus 68 (γHV68) efficiently infects laboratory mouse strains and establishes robust persistent infection without causing apparent disease. Here, we report that a recombinant γHV68 carrying the KSHV G protein-coupled receptor (kGPCR) in place of its murine counterpart induces angiogenic tumors in infected mice. Although viral GPCRs are conserved in all gamma herpesviruses, kGPCR potently activated downstream signaling and induced tumor formation in nude mouse, whereas γHV68 GPCR failed to do so. Recombinant γHV68 carrying kGPCR demonstrated more robust lytic replication ex vivo than wild-type γHV68, although both viruses underwent similar acute and latent infection in vivo. Infection of immunosuppressed mice with γHV68 carrying kGPCR, but not wild-type γHV68, induced tumors in mice that exhibited angiogenic and inflammatory features shared with human Kaposi’s sarcoma. Immunohistochemistry staining identified abundant latently-infected cells and a small number of cells supporting lytic replication in tumor tissue. Thus, mouse infection with a recombinant γHV68 carrying kGPCR provides a useful small animal model for tumorigenesis induced by a human gamma herpesvirus gene in the setting of a natural course of infection. © 2015 Zhang et al.

Vacchelli E.,Gustave Roussy Cancer Campus | Vacchelli E.,French Institute of Health and Medical Research | Vacchelli E.,University of Paris Descartes | Vacchelli E.,University Pierre and Marie Curie | And 17 more authors.
OncoImmunology | Year: 2016

Several pattern recognition receptors including toll-like receptors and purinergic receptors are implicated in the anticancer immune response elicited by anthracyclines or oxaliplatin. Recently, formyl peptide receptor-1 (FPR1) has been involved in this response as well. FPR1 is required for the correct positioning of dendritic cells (DC) close to dying cancer cells. A genetic defect in FPR1 abrogates cross-presentation of tumor antigens by DC, thereby compromising therapy-elicited immunosurveillance. © 2016 Taylor & Francis Group, LLC.

Ci X.,Jilin University | Lv H.,Jilin University | Wang L.,Jilin University | Wang X.,Jilin University | And 9 more authors.
Chemico-Biological Interactions | Year: 2015

Abstract Farrerol, (S)-2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-6,8-dimethyl-4-benzopyrone, isolated from rhododendron, has been shown to have antioxidative potential, but the molecular mechanism underlying this activity remains unclear. The inducible expression of heme oxygenase-1 (HO-1), a potent antioxidative and cytoprotective enzyme, is known to play an important role in cytoprotection in a variety of pathological models. In this study, we evaluated the antioxidative potential of farrerol against oxidative damage and investigated its antioxidative mechanism in RAW 264.7 cells. The molecular mechanism underlying the cytoprotective function of farrerol was determined by analyzing intracellular signaling pathways, transcriptional activation and the inhibitory effect of HO-1 on ROS production. Farrerol induced antioxidant enzymes mRNA expression, HO-1 protein expression and nuclear translocation of NF-E2-related factor 2 in RAW 264.7 macrophage cells. Farrerol down-regulated the expression of the Keap1 protein and the thiol reducing agents attenuated farrerol-induced HO-1 expression. Further investigation utilizing Western blotting and specific inhibitors of Akt, p38, JNK and ERK demonstrated that Akt, p38, and ERK axis of signaling pathway mediates HO-1 expression. Moreover, tert-butyl hydroperoxide (t-BHP)-induced oxidative damage was ameliorated by farrerol treatment in a dose-dependent manner, which was abolished by Akt, p38, ERK and HO-1 inhibitors (Snpp). It is hence likely that farrerol inactivated KEAP-1 or activated the Akt, p38 and ERK to facilitate the release of Nrf2 from Keap1 and subsequent reduced the intracellular production of reactive oxygen species via the induction of HO-1 expression. These results support the central role of HO-1 in the cytoprotective effect of farrerol. © 2015 Elsevier Ireland Ltd.

Liu W.,Shanghai JiaoTong University | Liu W.,Suzhou Institute of Systems Medicine | Wu A.,Suzhou Institute of Systems Medicine | Wu A.,Chinese Institute of Basic Medical Sciences
Proceedings - 2015 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2015 | Year: 2015

Recent advances in proteomic technologies have enabled high-throughput binary data on protein-protein interactions of E. coli to be released into public domain, and many protein complexes have been identified by experimental methods. Although it has a long study history, a large-scale analysis of protein complex in binary PPI network of E. coli is still absent. We used a novel link clustering algorithm named ELPA to infer protein complexes and functional modules in E. coli PPI network. By mapping our results to 276 gold standard protein complexes and protein function annotations offered by EcoCyc, we found that 80.2% of predicted modules mapping well with one or more complexes, while 92.8% of predicted modules tally well with certain GO terms. Furthermore, we compare our results with MCL algorithm, and evaluated our results with several accuracy measures and biological relevance, the result shows that ELPA achieved an average 18.3% improvement over MCL based on the accuracy measures, which means our method will contributes to uncover the complexes of Ecoli. © 2015 IEEE.

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