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Accueil Nota Bene Cancer V2 Numéro 118 du 10 Janvier 2012 Biologie

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Nota Bene Cancer Numéro 118 du 10 Janvier 2012 RSS

Biologie

Aberrations chromosomiques

Menée sur un modèle murin, cette étude montre que, en combinaison avec la délétion du gène Pten, une mutation du gène PI3K est susceptible de déclencher une tumorigenèse ovarienne

  • An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Menée sur un modèle murin, cette étude montre que, en combinaison avec la délétion du gène Pten, une mutation du gène PI3K est susceptible de déclencher une tumorigenèse ovarienne

    “An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice”

    • Kinross, Kathryn M.;Montgomery, Karen G.;Kleinschmidt, Margarete;Waring, Paul;Ivetac, Ivan;Tikoo, Anjali;Saad, Mirette;Hare, Lauren;Roh, Vincent;Mantamadiotis, Theo;Sheppard, Karen E.;Ryland, Georgina L.;Campbell, Ian G.;Gorringe, Kylie L.;Christensen, James G.;Cullinane, Carleen;Hicks, Rodney J.;Pearson, Richard B.;Johnstone, Ricky W.;McArthur, Grant A.;Phillips, Wayne A.

    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous ...


Mots clés : Ovaire; Biologie (Aberrations chromosomiques)

Menée sur deux cohortes de patients atteints de lymphome, cette étude identifie des mutations du gène IDH2 en association avec les lymphomes T angio-immunoblastiques

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    Menée sur deux cohortes de patients atteints de lymphome, cette étude identifie des mutations du gène IDH2 en association avec les lymphomes T angio-immunoblastiques

    “IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma”

    • Cairns, Rob A;Iqbal, Javeed;Lemonnier, François;Kucuk, Can;de Leval, Laurence;Jais, Jean-Philippe;Parrens, Marie;Martin, Antoine;Xerri, Luc;Brousset, Pierre;Chan, Li Chong;Chan, Wing-Chung;Gaulard, Philippe;Mak, Tak W

    Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in most grade 2 and 3 gliomas, secondary glioblastomas, and a subset of acute myelogenous leukemias, but have not been detected in other tumor types. The mutations occur at specific arginine residues, and result in the acquisition of a novel enzymatic activity that converts 2-oxoglutarate to D-2-hydroxyglutarate. This study reports IDH1 and IDH2 genotyping results from a set of lymphomas which included a large set of peripheral T-cell lymphomas (PTCL). IDH2 mutations were identified in approximately 20% of angioimmunoblastic T-cell lymphomas (AITL), but not in other PTCL entities. These results were confirmed in an independent set of AITL patients, where the IDH2 mutation rate was approximately 45%. This is the second common genetic lesion identified in AITL after TET2, and extends the number of neoplastic diseases where IDH1 and IDH2 mutations may play a role.


Mots clés : Lymphome; Biologie (Aberrations chromosomiques)

Menée à l'aide d'inhibiteurs d'histone déacétylase sur des lignées cellulaires de cancer du côlon, cette étude analyse les effets de ces molécules sur la méthylation de l'ADN et l'expression de certains gènes, notamment le gène GFP

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    Menée à l'aide d'inhibiteurs d'histone déacétylase sur des lignées cellulaires de cancer du côlon, cette étude analyse les effets de ces molécules sur la méthylation de l'ADN et l'expression de certains gènes, notamment le gène GFP

    “DNA methylation does not stably lock gene expression but instead serves as a molecular mark for gene silencing memory”

    • Raynal, Noel J-M;si, Jiali;Taby, Rodolphe F;Gharibyan, Vazganush;Ahmed, Saira S;Jelinek, Jaroslav;Estecio, Marcos R;Issa, Jean-Pierre J

    DNA methylation is commonly thought of as a "molecular lock" that leads to permanent gene silencing. To investigate this notion, we tested 24 different HDAC inhibitors (HDACi) on colon cancer cells that harbor a GFP locus stably integrated and silenced by a hypermethylated CMV promoter. We found that HDACi efficiently reactivated expression of GFP and many other endogenous genes silenced by DNA hypermethylation. After treatment, all promoters were marked with active chromatin, yet DNA hypermethylation did not change. Thus, DNA methylation could not prevent gene reactivation by drug-induced resetting of the chromatin state. In evaluating the relative contribution of DNA methylation and histone modifications to stable gene silencing, we followed expression levels of GFP and other genes silenced by DNA hypermethylation over time after treatment with HDACi or DNA demethylating drugs. Reactivation of methylated loci by HDACi was detectable for only 2 weeks, whereas DNA demethylating drugs ...


Mots clés : Colon-rectum; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée sur des lignées cellulaires et des échantillons de tissus sains et tumoraux prélevés sur des patients atteints d'un cancer invasif de la vessie, cette étude suggère que le gène Nkx2.8 exerce une fonction de suppresseur de tumeurs

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    Menée sur des lignées cellulaires et des échantillons de tissus sains et tumoraux prélevés sur des patients atteints d'un cancer invasif de la vessie, cette étude suggère que le gène Nkx2.8 exerce une fonction de suppresseur de tumeurs

    “The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway”

    • Yu, Chunping;Zhang, Zhiling;Liao, Wenting;Zhao, Xiaohui;Liu, Liping;Wu, Yanheng;Liu, Zhuowei;Li, Yonghong;Zhong, Yi;Chen, Kun;Li, Jun;Zhou, Fangjian;Song, Libing

    Invasive bladder cancer is a lethal disease for which effective prognostic markers as well as potential therapy targets are still lacking. Nkx2.8 (Nk2 homeobox 8), a novel member of the the NK-2 gene family, was reported to play an important role in the development and progression of human cancer. Herein, we reported that Nkx2.8 was markedly reduced in bladder cancer tissues compared with matched adjacent normal urothelial tissues. Nkx2.8 levels were inversely correlated with advanced T classification, N classification, tumor multiplicity, high proliferation index (Ki-67) and poor survival of patients. Furthermore, we found that overexpression of Nkx2.8 in bladder cancer cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing Nkx2.8 dramatically enhanced cell proliferation. Moreover, we demonstrated that overexpression of Nkx2.8 resulted in G1/S phase arrest, accompanied by up-regulation of p27Kip1, down-regulation of cyclin D1 and p-FOXO3a, and ...


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

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle clé joué par le facteur HIF-1alpha dans la croissance d'une tumeur mammaire et dans le processus métastatique, notamment par la régulation de la population des cellules initiatrices de tumeurs

  • Hypoxia inducible factor-1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer
    Breast Cancer Research, Vol. 14 (1), pp. R6, 2012 (article en libre accès)
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    Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle clé joué par le facteur HIF-1alpha dans la croissance d'une tumeur mammaire et dans le processus métastatique, notamment par la régulation de la population des cellules initiatrices de tumeurs

    “Hypoxia inducible factor-1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer”

    • Schwab, Luciana;Peacock, Danielle;Majumdar, Debeshi;Ingels, Jesse;Jensen, Laura;Smith, Keisha;Cushing, Richard;Seagroves, Tiffany

    INTRODUCTION:Over-expression of the oxygen-responsive transcription factor hypoxia inducible factor (HIF)-1alpha correlates with poor prognosis in breast cancer patients. The MMTV-PyMT (polyoma virus middle T) mouse is a widely utilized pre-clinical mouse model that resembles luminal breast cancer and is highly metastatic. Prior studies in the PyMT model demonstrated that HIF-1 is essential to promote carcinoma onset and lung metastasis, although no differences in primary tumor endpoint size were observed. Using a refined model system, we investigated whether HIF-1 is directly implicated in regulation of tumor-initiating cells (TICs) in breast cancer.METHODS:Mammary tumor epithelial cells (MTECs) were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either denovirusbeta-galactosidase or Cre to generate wild type (WT) and HIF-1 null (KO) cells, respectively. The impact of HIF-1 deletion on tumor-initiating potential was ...


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

Menée in vitro et sur des échantillons tumoraux, cette étude met en évidence le rôle oncogénique d'une protéine 14-3-3 dans le sarcome stromal endométrial de haut grade

  • 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée in vitro et sur des échantillons tumoraux, cette étude met en évidence le rôle oncogénique d'une protéine 14-3-3 dans le sarcome stromal endométrial de haut grade

    “14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma”

    • Lee, Cheng-Han;Ou, Wen-Bin;Mariño-Enriquez, Adrian;Zhu, Meijun;Mayeda, Mark;Wang, Yuexiang;Guo, Xiangqian;Brunner, Alayne L.;Amant, Frédéric;French, Christopher A.;West, Robert B.;McAlpine, Jessica N.;Gilks, C. Blake;Yaffe, Michael B.;Prentice, Leah M.;McPherson, Andrew;Jones, Steven J. M.;Marra, Marco A.;Shah, Sohrab P.;van de Rijn, Matt;Huntsman, David G.;Dal Cin, Paola;Debiec-Rychter, Maria;Nucci, Marisa R.;Fletcher, Jonathan A.

    14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE–FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE–FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion ...


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

Cette étude met en évidence un mécanisme impliquant l'enzyme USP2a dans la régulation du gène c-Myc au sein des cellules de cancer de la prostate

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    Cette étude met en évidence un mécanisme impliquant l'enzyme USP2a dans la régulation du gène c-Myc au sein des cellules de cancer de la prostate

    “c-Myc is activated via USP2a-mediated modulation of microRNAs in prostate cancer”

    • Benassi, Barbara;Flavin, Richard;Marchionni, Luigi;Zanata, Silvio;Pan, Yunfeng;Chowdhury, Dipanjan;Marani, Marina;Strano, Sabrina;Muti, Paola;Blandino, Giovanni;Loda, Massimo

    Ubiquitin-Specific Protease 2a (USP2a) is over-expressed in almost half of human prostate cancers and c-Myc is amplified in a third of these tumour types. As a transgene c-Myc results in invasive adenocarcinomas in the murine prostate. We show that over-expression of USP2a, down-regulates a set of microRNAs (miRNAs) which collectively increase c-Myc, via Mdm2 de-ubiquitination and subsequent p53 inactivation. By establishing c-Myc as a target of miR-34b/c, we demonstrate that this cluster functions as a tumor suppressor in prostate cancer cells. We identify a distinct mRNA signature, which is enriched for c-Myc-regulated transcripts and transcription factor binding sites in USP2a over-expressing prostate cancer cells. We demonstrate that these genes are associated with an invasive phenotype in human prostate cancer, and that the proliferative and invasive properties of USP2a over-expressing cells are c-Myc-dependent. These results highlight an unrecognized mechanism of c-Myc ...


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

Menée sur des échantillons tumoraux et in vitro, cette étude montre qu'une enzyme du métabolisme, la glycine décarboxylase, favorise la prolifération des cellules initiatrices de tumeurs et la tumorigenèse dans le cancer du poumon non à petites cellules

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    Menée sur des échantillons tumoraux et in vitro, cette étude montre qu'une enzyme du métabolisme, la glycine décarboxylase, favorise la prolifération des cellules initiatrices de tumeurs et la tumorigenèse dans le cancer du poumon non à petites cellules

    “Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis”

    • Zhang, Wen Cai;Shyh-Chang, Ng;Yang, He;Rai, Amit;Umashankar, Shivshankar;Ma, Siming;Soh, Boon Seng;Sun, Li Li;Tai, Bee Choo;Nga, Min En;Bhakoo, Kishore Kumar;Jayapal, Senthil Raja;Nichane, Massimo;Yu, Qiang;Ahmed, Dokeu A;Tan, Christie;Sing, Wong Poo;Tam, John;Thirugananam, Agasthian;Noghabi, Monireh Soroush;Huei Pang, Yin;Ang, Haw Siang;Robson, Paul;Kaldis, Philipp;Soo, Ross Andrew;Swarup, Sanjay;Lim, Elaine Hsuen;Lim, Bing

    Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer ...


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

Menée in vitro et in vivo, ainsi que sur des échantillons tumoraux prélevés sur des patients atteints d'un carcinome pulmonaire, cette étude suggère que le gène CBX7 exerce une fonction de suppresseur de tumeurs

  • CBX7 is a tumor suppressor in mice and humans
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Menée in vitro et in vivo, ainsi que sur des échantillons tumoraux prélevés sur des patients atteints d'un carcinome pulmonaire, cette étude suggère que le gène CBX7 exerce une fonction de suppresseur de tumeurs

    “CBX7 is a tumor suppressor in mice and humans”

    • Forzati, Floriana;Federico, Antonella;Pallante, Pierlorenzo;Abbate, Adele;Esposito, Francesco;Malapelle, Umberto;Sepe, Romina;Palma, Giuseppe;Troncone, Giancarlo;Scarfò, Marzia;Arra, Claudio;Fedele, Monica;Fusco, Alfredo

    The CBX7 gene encodes a polycomb group protein that is known to be downregulated in many types of human cancers, although the role of this protein in carcinogenesis remains unclear. To shed light on this issue, we generated mice null for Cbx7. Mouse embryonic fibroblasts derived from these mice had a higher growth rate and reduced susceptibility to senescence compared with their WT counterparts. This was associated with upregulated expression of multiple cell cycle components, including cyclin E, which is known to play a key role in lung carcinogenesis in humans. Adult Cbx7-KO mice developed liver and lung adenomas and carcinomas. In in vivo and in vitro experiments, we demonstrated that CBX7 bound to the CCNE1 promoter in a complex that included HDAC2 and negatively regulated CCNE1 expression. Finally, we found that the lack of CBX7 protein expression in human lung carcinomas correlated with CCNE1 overexpression. These data suggest that CBX7 is a tumor suppressor and that its loss ...


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

Menée à l'aide d'un modèle murin, cette étude suggère que des cellules dendritiques de l'épiderme, les cellules de Langerhans, sont susceptibles de favoriser le développement d'un carcinome épidermoïde induit par une substance chimique cancérigène

  • Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma
    Science, Vol. 335 (6064), pp. 104-108, 2012 (résumé)
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    Menée à l'aide d'un modèle murin, cette étude suggère que des cellules dendritiques de l'épiderme, les cellules de Langerhans, sont susceptibles de favoriser le développement d'un carcinome épidermoïde induit par une substance chimique cancérigène

    “Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma”

    • Modi, Badri G.;Neustadter, Jason;Binda, Elisa;Lewis, Julia;Filler, Renata B.;Roberts, Scott J.;Kwong, Bernice Y.;Reddy, Swapna;Overton, John D.;Galan, Anjela;Tigelaar, Robert;Cai, Lining;Fu, Peter;Shlomchik, Mark;Kaplan, Daniel H.;Hayday, Adrian;Girardi, Michael

    Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between ...


Mots clés : Peau (hors mélanome); Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des échantillons tumoraux et des lignées cellulaires, cette étude montre que trois micro-ARNs, miR-200c, MiR-205 et miR-211, exercent une fonction de suppresseur de tumeurs dans les mélanomes

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    Menée sur des échantillons tumoraux et des lignées cellulaires, cette étude montre que trois micro-ARNs, miR-200c, MiR-205 et miR-211, exercent une fonction de suppresseur de tumeurs dans les mélanomes

    “Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors”

    • Xu, Y.;Brenn, T.;Brown, E. R. S.;Doherty, V.;Melton, D. W.

    Background:The incidence of malignant melanoma is increasing faster than that for any other cancer. Histological examination of skin excision biopsies remains the standard method for melanoma diagnosis and prognosis. Significant morphological overlap between benign and malignant lesions complicates diagnosis, and tumour thickness is not always an accurate predictor of prognosis. Methods:To identify improved molecular markers to support histological examination, we used microarray analysis of formalin-fixed and paraffin-embedded samples from different stages of melanomagenesis to identify differentially expressed microRNAs (miRNAs). Differential expression was validated by qRT–PCR, and functional studies were carried out after transfection of miRNA precursors or inhibitors into melanoma cells to modulate miRNA expression. Results:In all, 20 miRNAs showed highly significant differential expression between benign naevi and either primary or metastatic melanomas, the majority being ...


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

Menée sur des lignées cellulaires de mélanome, cette étude suggère que les molécules du complexe majeur d'histocompatibilité de classe I sont susceptibles de jouer un rôle de suppresseur de tumeurs

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    Menée sur des lignées cellulaires de mélanome, cette étude suggère que les molécules du complexe majeur d'histocompatibilité de classe I sont susceptibles de jouer un rôle de suppresseur de tumeurs

    “MHC class I molecules act as tumor suppressor genes regulating the cell cycle gene expression, invasion, and intrinsic tumorigenicity of melanoma cells”

    • Garrido, Cristina;Paco, Laura;Romero, Irene;Berruguilla, Enrique;Stefansky, Julia;Collado, Antonia;Algarra, Ignacio;Garrido, Federico;Garcia-Lora, Angel M.

    The alteration of MHC class I (MHC-I) expression is a frequent event during cancer progression, allowing tumor cells to evade the immune system. We report that the loss of one MHC haplotype in human melanoma cells not only allowed them to evade immunosurveillance but also increased their intrinsic oncogenic potential. A second successive defect in MHC-I expression, MHC-I total downregulation, gave rise to melanoma cells that were more oncogenic per se in vivo and showed a higher proliferation rate and greater migratory and invasive potential in vitro. All of these processes were reversed by restoring MHC-I expression via HLA-A2 gene transfection. MHC-I cell surface expression was inversely correlated with intrinsic oncogenic potential. Modifications in the expression of various cell cycle genes were correlated with changes in MHC-I expression; the most important differences among the melanoma cell lines were in the transcriptional level of AP2-alpha, cyclin A1, and p21WAF1/CIP1. ...


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

Cet article passe en revue les travaux récents sur le rôle du suppresseur de tumeurs TET2 dans les hémopathies malignes

  • TET2, a tumor suppressor in hematological disorders
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le rôle du suppresseur de tumeurs TET2 dans les hémopathies malignes

    “TET2, a tumor suppressor in hematological disorders”

    • Mercher, Thomas;Quivoron, Cyril;Couronné, Lucile;Bastard, Christian;Vainchenker, William;Bernard, Olivier A.

    The TET family of proteins has been described a few years ago. Only recently, their roles in DNA modification, through the oxydation of methyl-cytosine, and in normal and malignant development, through the description of TET2 as a tumor suppressor have been documented. The conjunction of these findings has prompted large efforts to understand the biology of these novel entities. Here, we summarize the recent results implicating TET2 in hematological malignancies suggesting that further studies are required to fully understand the role of DNA methylation alterations during transformation.


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

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel le gène Ku80, impliqué dans la réparation de l'ADN, exerce une fonction de suppresseur de tumeurs hépatiques

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    Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel le gène Ku80, impliqué dans la réparation de l'ADN, exerce une fonction de suppresseur de tumeurs hépatiques

    “Ku80 functions as a tumor suppressor in hepatocellular carcinoma by inducing S-phase arrest through a p53-dependent pathway”

    • Wei, Shuang;Zhan, Da-qian;Xiong, Min;Liang, Bin-yong;Wang, Yang-yang;Gutmann, David H.;Chen, Xiao-ping;Huang, Zhi-yong

    Ku80 is a component of the protein complex called DNA-dependent Protein Kinase (DNA-PK), which is involved in DNA double-strand break repair and multiple other functions. Previous studies revealed that Ku80 haplo-insufficient and Poly (ADP-ribose) polymerase-null transgenic mice developed HCC at a high frequency. The role of Ku80 has never been investigated in human HCC. Ku80 expressions in HCC and adjacent liver tissue were investigated by using immunohistochemical staining and western blot. Ku80 was transfected into a Ku80-deficient HCC cell line SMMC7721 cells, and the growth features of the Ku80-expressing cells and vector-transfected cells were studied both in vitro and in vivo. Cell cycle analysis and RNA interference were employed to investigate the mechanisms underlying the growth regulation associated with Ku80 expression. Ku80 was found frequently downregulated in HCC compared with adjacent liver tissue. Ku80 downregulation was significantly correlated with elevated HBV-DNA ...


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

Cette étude met en évidence le rôle essentiel joué par une glutaminase (GAC) d'origine mitochondriale dans le métabolisme tumoral

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    Cette étude met en évidence le rôle essentiel joué par une glutaminase (GAC) d'origine mitochondriale dans le métabolisme tumoral

    “Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism”

    • Cassago, Alexandre;Ferreira, Amanda P. S.;Ferreira, Igor M.;Fornezari, Camila;Gomes, Emerson R. M.;Greene, Kai Su;Pereira, Humberto M.;Garratt, Richard C.;Dias, Sandra M. G.;Ambrosio, Andre L. B.

    Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls, known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization-induced lifting of a “gating loop” as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. ...


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

Progression et métastases

Menée sur des échantillons de tumeurs primitives et métastatiques prélevés sur des patientes atteintes d'un cancer du sein ER+, cette étude met en évidence une plasticité des mécanismes de liaison au récepteur des estrogènes en association avec différentes évolutions cliniques de la maladie

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    Menée sur des échantillons de tumeurs primitives et métastatiques prélevés sur des patientes atteintes d'un cancer du sein ER+, cette étude met en évidence une plasticité des mécanismes de liaison au récepteur des estrogènes en association avec différentes évolutions cliniques de la maladie

    “Differential oestrogen receptor binding is associated with clinical outcome in breast cancer”

    • Ross-Innes, Caryn S.;Stark, Rory;Teschendorff, Andrew E.;Holmes, Kelly A.;Ali, H. Raza;Dunning, Mark J.;Brown, Gordon D.;Gojis, Ondrej;Ellis, Ian O.;Green, Andrew R.;Ali, Simak;Chin, Suet-Feung;Palmieri, Carlo;Caldas, Carlos;Carroll, Jason S.

    Oestrogen receptor- α (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. Here we map genome-wide ER-binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, but that ER binding is a dynamic process, with the acquisition of unique ER-binding regions in tumours from patients that are likely to relapse. The acquired ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive disease exclusively. We find that the differential ER-binding programme observed in tumours from patients with poor ...


Mots clés : Sein; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle des cellules souches cancéreuses dans le cancer du sein et propose un modèle d'évolution de ces cellules au cours du développement tumoral

  • Breast-cancer stem cells-beyond semantics
    The Lancet Oncology, Vol. 13 (1), pp. e43-e48, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le rôle des cellules souches cancéreuses dans le cancer du sein et propose un modèle d'évolution de ces cellules au cours du développement tumoral

    “Breast-cancer stem cells-beyond semantics”

    • Badve, Sunil;Nakshatri, Harikrishna

    Intratumoral heterogeneity in breast cancer is well documented. Although the mechanisms leading to this heterogeneity are not understood, a subpopulation of cancer cells, cancer stem cells (CSCs), that have some phenotypic similarities with adult tissue stem cells, has been suggested to contribute to tumour heterogeneity. It has been postulated that these CSCs are dormant, and by virtue of their low proliferative activity and ability to exclude intracellular toxins, are resistant to chemotherapy and radiation therapy. These cells were initially isolated based on the presence of markers such as CD44, CD24, and ALDH1, with further characterisation using mammosphere assay and transplantation into immunodeficient mice. The CSC hypothesis raises several theoretical and practical questions. Does cancer arise in normal mammary stem cells or do some malignant cells acquire a CSC phenotype through clonal evolution? Are CSCs in different molecular (intrinsic) subtypes of breast cancer similar, ...


Mots clés : Sein; Biologie (Progression et métastases)

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel l'expression du gène DJ-1, impliqué dans la régulation de la mort cellulaire, favorise les processus invasif et métastatique d'un carcinome canalaire du pancréas

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    Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel l'expression du gène DJ-1, impliqué dans la régulation de la mort cellulaire, favorise les processus invasif et métastatique d'un carcinome canalaire du pancréas

    “DJ-1 Promotes Invasion and Metastasis of Pancreatic Cancer Cells by Activating SRC/ERK/uPA”

    • He, Xiangyi;Zheng, Zhong;Li, Jianfang;Liu, Bingya;Ben, Qiwen;Liu, Jun;Zhang, Jianian;Ji, Jun;Yu, Beiqin;Xuehua, Chen;Liping, Su;Lin, Zhou;Yaozong, Yuan

    A major hallmark of pancreatic ductal adenocarcinoma (PDAC) is extensive local tumor invasion and early systemic dissemination. DJ-1 has been shown to prevent cell death via the Akt pathway, thereby playing an important role in cancer progression and Parkinson's disease development. Here, we investigated the role of DJ-1 in tumor invasion and metastasis of pancreatic cancer, and showed that DJ-1 is up-regulated in 68.5% of pancreatic cancer specimens, correlated with tumor stage, and predictive of short overall survival. Knockdown of DJ-1 expression in two PDAC cell lines reduced cell migration and invasion potential in vitro and inhibited metastasis in vivo. Knockdown of DJ-1 led to cytoskeleton disruption and diminished uPA activity and expression, without affecting PAI-1 and uPAR expression. All of these effects were reversed by restoration of DJ-1 expression. In determining the pathway through which DJ-1 regulated cell migration and invasion, DJ-1 was found not to regulate Akt ...


Mots clés : Pancréas; Biologie (Progression et métastases)

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 83 patients atteints d'un cancer du poumon, cette étude met en évidence le rôle joué par le récepteur DDR1 de liaison au collagène dans le développement de métastases osseuses

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    Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur 83 patients atteints d'un cancer du poumon, cette étude met en évidence le rôle joué par le récepteur DDR1 de liaison au collagène dans le développement de métastases osseuses

    “Inhibition of collagen receptor Discoidin Domain Receptor-1 (DDR1) Reduces Cell Survival, Homing and Colonization in Lung Cancer Bone Metastasis”

    • Valencia, Karmele;Ormazábal, Cristina;Zandueta, Carolina;Luis-Ravelo, Diego;Antón, Iker;Pajares, Maria Jose;Agorreta, Jackeline;Montuenga, Luis M;Martínez-Canarias, Susana;Leitinger, Birgit;Lecanda, Fernando

    Purpose: We investigated the role of the collagen binding receptor, discoidin domain receptor-1 (DDR1), in the initiation and development of bone metastasis. Experimental Design:We performed westernblot analysis and phosphorylation status in a panel of human lung cancer cell lines and immunohistochemical analysis in a cohort of 83 lung cancer specimens. Adhesion, chemotaxis, invasiveness, metalloproteolytic, osteoclastogenic and apoptotic assays were performed in DDR1 silenced cells. In vivo, metastatic osseous homing and colonization was assessed in a murine model of metastasis. Results:DDR1 was expressed in a panel of human lung cancer cell lines and high DDR1 levels in human lung tumors were associated with poor survival. Knock-down (shDDR1) cells displayed unaltered growth kinetics in vitro and in vivo. In contrast, shDDR1 cells showed reduced invasiveness in collagen matrices and increased basal and induced apoptosis in vitro. More importantly, conditioned media of DDR1 knock ...


Mots clés : Os; Biologie (Progression et métastases)

Menée sur divers modèles murins, cette étude met en évidence le rôle central joué par des petites molécules appelées époxy-eicosanoides, des modulateurs de la signalisation lipidique, dans la croissance tumorale et le processus métastatique

  • Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice
    The Journal of Clinical Investigation, Vol. 122 (1), pp. 178-191, 2012 (article en libre accès)
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    Menée sur divers modèles murins, cette étude met en évidence le rôle central joué par des petites molécules appelées époxy-eicosanoides, des modulateurs de la signalisation lipidique, dans la croissance tumorale et le processus métastatique

    “Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice”

    • Panigrahy, Dipak;Edin, Matthew L.;Lee, Craig R.;Huang, Sui;Bielenberg, Diane R.;Butterfield, Catherine E.;Barnés, Carmen M.;Mammoto, Akiko;Mammoto, Tadanori;Luria, Ayala;Benny, Ofra;Chaponis, Deviney M.;Dudley, Andrew C.;Greene, Emily R.;Vergilio, Jo-Anne;Pietramaggiori, Giorgio;Scherer-Pietramaggiori, Sandra S.;Short, Sarah M.;Seth, Meetu;Lih, Fred B.;Tomer, Kenneth B.;Yang, Jun;Schwendener, Reto A.;Hammock, Bruce D.;Falck, John R.;Manthati, Vijaya L.;Ingber, Donald E.;Kaipainen, Arja;D’Amore, Patricia A.;Kieran, Mark W.;Zeldin, Darryl C.

    Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET ...


Mots clés : Cancer (général); Biologie (Progression et métastases)

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