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Accueil Nota Bene Cancer V2 Numéro 139 du 05 June 2012 Biologie

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Nota Bene Cancer Numéro 139 du 05 June 2012 RSS

Biologie

Oncogènes et suppresseurs de tumeurs

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine SPRY2, en régulant la voie de signalisation PI3K/AKT, joue un rôle de suppresseur de tumeurs dans le cancer de la prostate

  • SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis
    EMBO Molecular Medicine, sous presse, 2012 (article en libre accès)
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    Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine SPRY2, en régulant la voie de signalisation PI3K/AKT, joue un rôle de suppresseur de tumeurs dans le cancer de la prostate

    “SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis”

    • Gao, Meiling;Patel, Rachana;Ahmad, Imran;Fleming, Janis;Edwards, Joanne;McCracken, Stuart;Sahadevan, Kanagasabai;Seywright, Morag;Norman, Jim;Sansom, Owen;Leung, Hing Y.

    Loss of SPRY2 and activation of receptor tyrosine kinases are common events in prostate cancer (PC). However, the molecular basis of their interaction and clinical impact remains to be fully examined. SPRY2 loss may functionally synergize with aberrant cellular signalling to drive PC and to promote treatment-resistant disease. Here, we report evidence for a positive feedback regulation of the ErbB-PI3K/AKT cascade by SPRY2 loss in in vitro as well as pre-clinical in vivo models and clinical PC. Reduction in SPRY2 expression resulted in hyper-activation of PI3K/AKT signalling to drive proliferation and invasion by enhanced internalization of EGFR/HER2 and their sustained signalling at the early endosome in a PTEN-dependent manner. This involved p38 MAPK activation by PI3K to facilitate clathrin-mediated ErbB receptor endocytosis. Finally, in vitro and in vivo inhibition of PI3K suppressed proliferation and invasion, supporting PI3K/AKT as a target for therapy particularly in patients ...


Mots clés : Prostate; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro et in vivo, cette étude suggère que, dans les cancers de l'ovaire, le ganglioside GD3 (un glycolipide acide) joue un rôle essentiel dans le mécanisme d'échappement au système immunitaire

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    Menée in vitro et in vivo, cette étude suggère que, dans les cancers de l'ovaire, le ganglioside GD3 (un glycolipide acide) joue un rôle essentiel dans le mécanisme d'échappement au système immunitaire

    “Molecular identification of GD3 as a suppressor of the innate immune response in ovarian cancer”

    • Webb, Tonya J.;Li, Xiangming;Giuntoli, Robert L.;Lopez, Pablo H. H.;Heuser, Christoph;Schnaar, Ronald L.;Tsuji, Moriya;Kurts, Christian;Oelke, Mathias;Schneck, Jonathan P.

    Tumors often display mechanisms to avoid or suppress immune recognition. One such mechanism is the shedding of gangliosides into the local tumor microenvironment, and a high concentration of circulating gangliosides is associated with poor prognosis. In this study, we identify ganglioside GD3, which was isolated from the polar lipid fraction of ovarian cancer-associated ascites, as an inhibitory factor that prevents innate immune activation of natural killer T (NKT) cells. Purified GD3 displayed a high affinity for both human and mouse CD1d, a molecule involved in the presentation of lipid antigens to T cells. Purified GD3, as well as substances within the ascites, bound to the CD1d antigenic binding site and did not require additional processing for its inhibitory effect on NKT cells. Importantly, in vivo administration of GD3 inhibited α-GalCer- induced NKT cell activation in a dose dependent manner. These data therefore indicate that ovarian cancer tumors may use GD3 to inhibit ...


Mots clés : Ovaire; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par des récepteurs inhibiteurs de l'activité immunitaire dans la différenciation des cellules leucémiques

  • Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development
    Nature, Vol. 485 (7400), pp. 656-660, 2012 (résumé)
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    Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par des récepteurs inhibiteurs de l'activité immunitaire dans la différenciation des cellules leucémiques

    “Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development”

    • Zheng, Junke;Umikawa, Masato;Cui, Changhao;Li, Jiyuan;Chen, Xiaoli;Zhang, Chaozheng;Hyunh, HoangDinh;Kang, Xunlei;Silvany, Robert;Wan, Xuan;Ye, Jingxiao;Canto, Alberto Puig;Chen, Shu-Hsia;Wang, Huan-You;Ward, E. Sally;Zhang, Cheng Cheng

    How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered ‘orphan ligands’ because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that ...


Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'expression du récepteur RACK1 dans la croissance d'une tumeur hépatique et l'apparition d'une résistance à la chimiothérapie

  • Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'expression du récepteur RACK1 dans la croissance d'une tumeur hépatique et l'apparition d'une résistance à la chimiothérapie

    “Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma”

    • Ruan, Yuanyuan;Sun, Linlin;Hao, Yuqing;Wang, Lijing;Xu, Jiejie;Zhang, Wen;Xie, Jianhui;Guo, Liang;Zhou, Lei;Yun, Xiaojing;Zhu, Hongguang;Shen, Aiguo;Gu, Jianxin

    Coordinated translation initiation is coupled with cell cycle progression and cell growth, whereas excessive ribosome biogenesis and translation initiation often lead to tumor transformation and survival. Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. We found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in HCC. Aberrant expression of RACK1 contributed to in vitro chemoresistance as well as in vivo tumor growth of HCC. These effects depended on ribosome localization of RACK1. Ribosomal RACK1 coupled with PKCβII to promote the phosphorylation of eukaryotic initiation factor 4E (eIF4E), which led to preferential translation of the potent factors involved in growth and survival. Inhibition of PKCβII or depletion of eIF4E abolished RACK1-mediated chemotherapy resistance of HCC in vitro. Our results ...


Mots clés : Foie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro, cette étude montre que deux gènes de récepteurs à activité tyrosine kinase, ATM et MET, sont en interaction synthétique létale avec le suppresseur de tumeurs p53

  • ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53
    Nature Chemical Biology, sous presse, 2012 (résumé)
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    Menée in vitro, cette étude montre que deux gènes de récepteurs à activité tyrosine kinase, ATM et MET, sont en interaction synthétique létale avec le suppresseur de tumeurs p53

    “ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53”

    • Sullivan, Kelly D.;Padilla-Just, Nuria;Henry, Ryan E.;Porter, Christopher C.;Kim, Jihye;Tentler, John J.;Eckhardt, S. Gail;Tan, Aik Choon;DeGregori, James;Espinosa, Joaquín M.

    The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small-molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a genome-wide short hairpin RNA screen for genes that are lethal in combination with p53 activation by Nutlin-3, which showed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors also enable Nutlin-3 to kill tumor spheroids. These results identify new pathways controlling the cellular response to p53 ...


Mots clés : Cancer (général); Biologie (Oncogènes et suppresseurs de tumeurs)

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