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Accueil Nota Bene Cancer V2 Numéro 137 du 22 Mai 2012 Biologie

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Nota Bene Cancer Numéro 137 du 22 Mai 2012 RSS

Biologie

Aberrations chromosomiques

Menée sur 100 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude identifie des mutations "conductrices" dans plus de 40 gènes et met en évidence 73 combinaisons différentes de gènes mutés

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    Menée sur 100 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude identifie des mutations "conductrices" dans plus de 40 gènes et met en évidence 73 combinaisons différentes de gènes mutés

    “The landscape of cancer genes and mutational processes in breast cancer”

    • Stephens, Philip J.;Tarpey, Patrick S.;Davies, Helen;Van Loo, Peter;Greenman, Chris;Wedge, David C.;Zainal, Serena Nik;Martin, Sancha;Varela, Ignacio;Bignell, Graham R.;Yates, Lucy R.;Papaemmanuil, Elli;Beare, David;Butler, Adam;Cheverton, Angela;Gamble, John;Hinton, Jonathan;Jia, Mingming;Jayakumar, Alagu;Jones, David;Latimer, Calli;Lau, King Wai;McLaren, Stuart;McBride, David J.;Menzies, Andrew;Mudie, Laura;Raine, Keiran;Rad, Roland;Spencer Chapman, Michael;Teague, Jon;Easton, Douglas;Langerod, Anita;Osbreac,;Lee, Ming Ta Michael;Shen, Chen-Yang;Tee, Benita Tan Kiat;Huimin, Bernice Wong;Broeks, Annegien;Vargas, Ana Cristina;Turashvili, Gulisa;Martens, John;Fatima, Aquila;Miron, Penelope;Chin, Suet-Feung;Thomas, Gilles;Boyault, Sandrine;Mariani, Odette;Lakhani, Sunil R.;van de Vijver, Marc;van /`t Veer, Laura;Foekens, John;Desmedt, Christine;Sotiriou, Christos;Tutt, Andrew;Caldas, Carlos;Reis-Filho, Jorge S.;Aparicio, Samuel A. J. R.;Salomon, Anne Vincent;Borresen-Dale, Anne-Lise;Richardson, Andrea;Campbell, Peter J.;Futreal, P. Andrew;Stratton, Michael R.

    All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 ...


Mots clés : Sein; Biologie (Aberrations chromosomiques)

Menées sur 21 cas de cancer du sein, ces deux études analysent les processus mutationnels à l'oeuvre dans le développement tumoral et modélisent leur histoire naturelle

  • The Life History of 21 Breast Cancers
    Cell, sous presse, 2012 (résumé)
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    Menées sur 21 cas de cancer du sein, ces deux études analysent les processus mutationnels à l'oeuvre dans le développement tumoral et modélisent leur histoire naturelle

    “The Life History of 21 Breast Cancers”

    • Nik-Zainal, Serena;Van Loo, Peter;Wedge, David C;Alexandrov, Ludmil B;Greenman, Christopher D;Lau, King Wai;Raine, Keiran;Jones, David;Marshall, John;Ramakrishna, Manasa;Shlien, Adam;Cooke, Susanna L;Hinton, Jonathan;Menzies, Andrew;Stebbings, Lucy A;Leroy, Catherine;Jia, Mingming;Rance, Richard;Mudie, Laura J;Gamble, Stephen J;Stephens, Philip J;McLaren, Stuart;Tarpey, Patrick S;Papaemmanuil, Elli;Davies, Helen R;Varela, Ignacio;McBride, David J;Bignell, Graham R;Leung, Kenric;Butler, Adam P;Teague, Jon W;Martin, Sancha;Jönsson, Goran;Mariani, Odette;Boyault, Sandrine;Miron, Penelope;Fatima, Aquila;Langerød, Anita;Aparicio, Samuel A J. R.;Tutt, Andrew;Sieuwerts, Anieta M;Borg, Åke;Thomas, Gilles;Salomon, Anne Vincent;Richardson, Andrea L;Børresen-Dale, Anne-Lise;Futreal, P.  Andrew;Stratton, Michael R;Campbell, Peter J

    Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may ...


  • Mutational Processes Molding the Genomes of 21 Breast Cancers
    Cell, sous presse, 2012 (résumé)
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    Menées sur 21 cas de cancer du sein, ces deux études analysent les processus mutationnels à l'oeuvre dans le développement tumoral et modélisent leur histoire naturelle

    “Mutational Processes Molding the Genomes of 21 Breast Cancers”

    • Nik-Zainal, Serena ; Alexandrov, Ludmil B ; Wedge, David C ; Van Loo, Peter ; Greenman, Christopher D ; Raine, Keiran ; Jones, David ; Hinton, Jonathan ; Marshall, John ; Stebbings, Lucy A ; Menzies, Andrew ; Martin, Sancha ; Leung, Kenric ; Chen, Lina ; Leroy, Catherine ; Ramakrishna, Manasa ; Rance, Richard ; Lau, King Wai ; Mudie, Laura J ; Varela, Ignacio ; McBride, David J ; Bignell, Graham R ; Cooke, Susanna L ; Shlien, Adam ; Gamble, John ; Whitmore, Ian ; Maddison, Mark ; Tarpey, Patrick S ; Davies, Helen R ; Papaemmanuil, Elli ; Stephens, Philip J ; McLaren, Stuart ; Butler, Adam P ; Teague, Jon W ; Jönsson, Göran ; Garber, Judy E ; Silver, Daniel ; Miron, Penelope ; Fatima, Aquila ; Boyault, Sandrine ; Langerød, Anita ; Tutt, Andrew ; Martens, John W M. ; Aparicio, Samuel A J. R. ; Borg, Åke ; Salomon, Anne Vincent ; Thomas, Gilles ; Børresen-Dale, Anne-Lise ; Richardson, Andrea L ; Neuberger, Michael S ; Futreal, P.  Andrew ; Campbell, Peter J ; Stratton, Michael R

    All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed kataegis, was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The ...


Mots clés : Sein; Biologie (Aberrations chromosomiques)

Menée sur 50 échantillons tumoraux prélevés à l'autopsie sur des patients ayant été lourdement traités pour un cancer métastatique de la prostate résistant à la castration et sur 11 échantillons tumoraux prélevés sur des patients avant un traitement pour un cancer localisé de haut grade de la prostate, cette étude de séquençage des exons dresse le paysage des mutations associées à ce cancer et identifie des nouveaux mécanismes de dérégulation de la signalisation du récepteur des androgènes

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    Menée sur 50 échantillons tumoraux prélevés à l'autopsie sur des patients ayant été lourdement traités pour un cancer métastatique de la prostate résistant à la castration et sur 11 échantillons tumoraux prélevés sur des patients avant un traitement pour un cancer localisé de haut grade de la prostate, cette étude de séquençage des exons dresse le paysage des mutations associées à ce cancer et identifie des nouveaux mécanismes de dérégulation de la signalisation du récepteur des androgènes

    “The mutational landscape of lethal castration-resistant prostate cancer”

    • Grasso, Catherine S.;Wu, Yi-Mi;Robinson, Dan R.;Cao, Xuhong;Dhanasekaran, Saravana M.;Khan, Amjad P.;Quist, Michael J.;Jing, Xiaojun;Lonigro, Robert J.;Brenner, J. Chad;Asangani, Irfan A.;Ateeq, Bushra;Chun, Sang Y.;Siddiqui, Javed;Sam, Lee;Anstett, Matt;Mehra, Rohit;Prensner, John R.;Palanisamy, Nallasivam;Ryslik, Gregory A.;Vandin, Fabio;Raphael, Benjamin J.;Kunju, Lakshmi P.;Rhodes, Daniel R.;Pienta, Kenneth J.;Chinnaiyan, Arul M.;Tomlins, Scott A.

    Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of ...


Mots clés : Prostate; Biologie (Aberrations chromosomiques)

Menée sur 112 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un cancer de la prostate, cette étude de séquençage des exons identifie des mutations fréquentes du gène SPOP et suggère qu'elles définissent un nouveau sous-type moléculaire de ce cancer

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    Menée sur 112 paires d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un cancer de la prostate, cette étude de séquençage des exons identifie des mutations fréquentes du gène SPOP et suggère qu'elles définissent un nouveau sous-type moléculaire de ce cancer

    “Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer”

    • Barbieri, Christopher E.;Baca, Sylvan C.;Lawrence, Michael S.;Demichelis, Francesca;Blattner, Mirjam;Theurillat, Jean-Philippe;White, Thomas A.;Stojanov, Petar;Van Allen, Eliezer;Stransky, Nicolas;Nickerson, Elizabeth;Chae, Sung-Suk;Boysen, Gunther;Auclair, Daniel;Onofrio, Robert C.;Park, Kyung;Kitabayashi, Naoki;MacDonald, Theresa Y.;Sheikh, Karen;Vuong, Terry;Guiducci, Candace;Cibulskis, Kristian;Sivachenko, Andrey;Carter, Scott L.;Saksena, Gordon;Voet, Douglas;Hussain, Wasay M.;Ramos, Alex H.;Winckler, Wendy;Redman, Michelle C.;Ardlie, Kristin;Tewari, Ashutosh K.;Mosquera, Juan Miguel;Rupp, Niels;Wild, Peter J.;Moch, Holger;Morrissey, Colm;Nelson, Peter S.;Kantoff, Philip W.;Gabriel, Stacey B.;Golub, Todd R.;Meyerson, Matthew;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.

    Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of ...


Mots clés : Prostate; Biologie (Aberrations chromosomiques)

Menée sur 77 patients atteints d'une forme rare de leucémie lymphocytaire T, cette étude identifie la présence fréquente de mutations du gène STAT3

  • Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia
    New England Journal of Medicine, Vol. 366 (20), pp. 1905-1913, 2012 (résumé)
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    Menée sur 77 patients atteints d'une forme rare de leucémie lymphocytaire T, cette étude identifie la présence fréquente de mutations du gène STAT3

    “Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia”

    • Koskela, Hanna L.M.;Eldfors, Samuli;Ellonen, Pekka;van Adrichem, Arjan J.;Kuusanmäki, Heikki;Andersson, Emma I.;Lagström, Sonja;Clemente, Michael J.;Olson, Thomas;Jalkanen, Sari E.;Majumder, Muntasir Mamun;Almusa, Henrikki;Edgren, Henrik;Lepistö, Maija;Mattila, Pirkko;Guinta, Kathryn;Koistinen, Pirjo;Kuittinen, Taru;Penttinen, Kati;Parsons, Alun;Knowles, Jonathan;Saarela, Janna;Wennerberg, Krister;Kallioniemi, Olli;Porkka, Kimmo;Loughran, Thomas P.;Heckman, Caroline A.;Maciejewski, Jaroslaw P.;Mustjoki, Satu

    Background: T-cell large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T lymphocytes (CTLs) and often associated with autoimmune disorders and immune-mediated cytopenias. Methods: We used next-generation exome sequencing to identify somatic mutations in CTLs from an index patient with large granular lymphocytic leukemia. Targeted resequencing was performed in a well-characterized cohort of 76 patients with this disorder, characterized by clonal T-cell–receptor rearrangements and increased numbers of large granular lymphocytes. Results: Mutations in the signal transducer and activator of transcription 3 gene (STAT3) were found in 31 of 77 patients (40%) with large granular lymphocytic leukemia. Among these 31 patients, recurrent mutational hot spots included Y640F in 13 (17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All mutations were located in exon 21, encoding the Src homology 2 (SH2) ...


Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome ou d'un cancer du sein, cette étude met én évidence le rôle joué par la protéine de choc thermique HSP27 dans le phénomène de dormance tumorale

  • Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome ou d'un cancer du sein, cette étude met én évidence le rôle joué par la protéine de choc thermique HSP27 dans le phénomène de dormance tumorale

    “Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer”

    • Straume, Oddbjørn;Shimamura, Takeshi;Lampa, Michael J. G.;Carretero, Julian;Øyan, Anne M.;Jia, Di;Borgman, Christa L.;Soucheray, Margaret;Downing, Sean R.;Short, Sarah M.;Kang, Soo-Young;Wang, Souming;Chen, Liang;Collett, Karin;Bachmann, Ingeborg;Wong, Kwok-Kin;Shapiro, Geoffrey I.;Kalland, Karl Henning;Folkman, Judah;Watnick, Randolph S.;Akslen, Lars A.;Naumov, George N.

    The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors ...


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

Menée in vitro et in vivo, cette étude suggère que le micro-ARN 16 joue un rôle de suppresseur de tumeurs dans les cancers du sein induits par une hormone progestative

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    Menée in vitro et in vivo, cette étude suggère que le micro-ARN 16 joue un rôle de suppresseur de tumeurs dans les cancers du sein induits par une hormone progestative

    “Downregulation of the tumor-suppressor miR-16 via progestin-mediated oncogenic signaling contributes to breast cancer development”

    • Rivas, Martin;Venturutti, Leandro;Huang, Yi-Wen;Schillaci, Roxana;Huang, Tim;Elizalde, Patricia

    INTRODUCTION:Experimental and clinical evidence points to a critical role of progesterone and the nuclear progesterone receptor (PR) in controlling mammary gland tumorigenesis. However, the molecular mechanisms of progesterone action in breast cancer still remain elusive. On the other hand, micro RNAs (miRNAs) are short ribonucleic acids which have also been found to play a pivotal role in cancer pathogenesis. The role of miRNA in progestin-induced breast cancer is poorly explored. In this study we explored progestin modulation of miRNA expression in mammary tumorigenesis.METHODS:We performed a genome-wide study to explore progestin-mediated regulation of miRNA expression in breast cancer. miR-16 expression was studied by RT-qPCR in cancer cell lines with silenced PR, signal transducer and activator of transcription 3 (Stat3) or c-Myc, treated or not with progestins. Breast cancer cells were transfected with the precursor of miR-16 and proliferation assays, Western blots or in vivo ...


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

Menée sur des lignées cellulaires et 360 échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude met en évidence la surexpression de la protéine CRKL en association avec un sous-groupe de patients

  • The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer
    Journal of Translational Medicine, Vol. 10 (1), pp. 97, 2012 (article en libre accès)
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    Menée sur des lignées cellulaires et 360 échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude met en évidence la surexpression de la protéine CRKL en association avec un sous-groupe de patients

    “The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer”

    • Natsume, Hiroko;Shinmura, Kazuya;Tao, Hong;Igarashi, Hisaki;Suzuki, Masaya;Nagura, Kiyoko;Goto, Masanori;Yamada, Hidetaka;Maeda, Matsuyoshi;Konno, Hrioyuki;Nakamura, Satoki;Sugimura, Haruhiko

    BACKGROUND:Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer. Methods and Results A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH), and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An ...


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

Menée in vitro, cette étude met en évidence un mécanisme par lequel, en interagissant avec p53, la protéine RASSF3 exerce une fonction de suppresseur de tumeurs

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    Menée in vitro, cette étude met en évidence un mécanisme par lequel, en interagissant avec p53, la protéine RASSF3 exerce une fonction de suppresseur de tumeurs

    “The RASSF3 Candidate Tumor Suppressor Induces Apoptosis and G1–S Cell-Cycle Arrest via p53”

    • Kudo, Takumi;Ikeda, Mitsunobu;Nishikawa, Misa;Yang, Zeyu;Ohno, Kikuo;Nakagawa, Kentaro;Hata, Yutaka

    RASSF3 is the smallest member of the RASSF family of proteins that function as tumor suppressors. Unlike other members of this important family, the mechanisms through which RASSF3 suppresses tumor formation remain unknown. Here, we show that RASSF3 expression induces p53-dependent apoptosis and its depletion attenuates DNA damage–induced apoptosis. We found that RASSF3-induced apoptosis depended upon p53 expression. Exogenous expression of RASSF3 induced G1–S arrest, which was also p53 dependent. In contrast, loss of RASSF3 promoted cell-cycle progression, abrogated UVB- and VP-16–induced G1–S arrest, decreased p53 protein and target gene expression, and prevented DNA repair. RASSF3 was shown to directly interact with and facilitate the ubiquitination of MDM2, the E3 ligase that targets p53 for degradation, thereby increasing p53 stabilization. Together, our findings show the tumor suppressor activity of RASSF3, which occurs through p53 stabilization and regulation of ...


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

Menée in vitro, cette étude met en évidence un mécanisme par lequel la kinase Aurora B régule l'expression du gène suppresseur de tumeurs p53

  • Aurora B kinase phosphorylates and instigates degradation of p53
    Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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    Menée in vitro, cette étude met en évidence un mécanisme par lequel la kinase Aurora B régule l'expression du gène suppresseur de tumeurs p53

    “Aurora B kinase phosphorylates and instigates degradation of p53”

    • Gully, Chris P.;Velazquez-Torres, Guermarie;Shin, Ji-Hyun;Fuentes-Mattei, Enrique;Wang, Edward;Carlock, Colin;Chen, Jian;Rothenberg, Daniel;Adams, Henry P.;Choi, Hyun Ho;Guma, Sergei;Phan, Liem;Chou, Ping-Chieh;Su, Chun-Hui;Zhang, Fanmao;Chen, Jiun-Sheng;Yang, Tsung-Ying;Yeung, Sai-Ching J.;Lee, Mong-Hong

    Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly interacts with p53 at different subcellular localizations and during different phases of the cell cycle (for instance, at the nucleus in interphase and the centromeres in prometaphase of mitosis). We show that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination–proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic ...


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

Progression et métastases

Menée sur des lignées cellulaires, des modèles murins et des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel, en régulant l'expression des gènes DAPK et KLF4, les micro-ARNs 103 et 107 favorisent le processus métastatique

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    Menée sur des lignées cellulaires, des modèles murins et des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un mécanisme par lequel, en régulant l'expression des gènes DAPK et KLF4, les micro-ARNs 103 et 107 favorisent le processus métastatique

    “miR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4”

    • Chen, Ruey-Hwa;Chen, Hsin-Yi;Lin, Yu-Min;Chung, Hsiang-Ching;Lang, Yaw-Dong;Lin, Ching-Jung;Huang, John;Wang, Wei-Chi;Lin, Feng-Mao;Chen, Zhen;Huang, Hsien-Da;Shyy, John Y-J;Liang, Jin-Tung

    Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of microRNAs (miRNAs) to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in CRC patients. We demonstrated that miR-103/107 targeted the known metastasis suppressors DAPK and KLF4 in CRC cells, resulting in increased cell motility and cell-matrix adhesion and decreased cell-cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis, effects which were suppressed by re-expression of DAPK or KLF4. miR-103/107-mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a ...


Mots clés : Colon-rectum; Biologie (Progression et métastases)

Cette étude met en évidence un mécanisme par lequel la formation de protrusions cellulaires analogues à des filopodes favorise le processus métastatique

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    Cette étude met en évidence un mécanisme par lequel la formation de protrusions cellulaires analogues à des filopodes favorise le processus métastatique

    “The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions”

    • Shibue, Tsukasa;Brooks, Mary W.;Inan, M. Fatih;Reinhardt, Ferenc;Weinberg, Robert A

    Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix (ECM) components in order to survive, proliferate and form macroscopic metastases. The biochemical and cell-biological mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated, integrin β1-containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase (FAK). These plaques originate in and appear only after the formation of filopodium-like protrusions (FLPs) that harbor integrin β1 along their shafts. The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to the formation of these protrusions and thereby enable the proliferation of extravasated cancer cells. Hence, the formation of FLPs represents a critical rate-limiting step for the subsequent development of macroscopic metastases.


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

Cet article passe en revue les travaux récents sur le rôle des cellules souches mésenchymateuses dans la progression tumorale et la résistance thérapeutique

  • The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression
    British Journal of Cancer, sous presse, 2012 (article en libre accès)
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    Cet article passe en revue les travaux récents sur le rôle des cellules souches mésenchymateuses dans la progression tumorale et la résistance thérapeutique

    “The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression”

    • Houthuijzen, J. M.;Daenen, L. G. M.;Roodhart, J. M. L.;Voest, E. E.

    It is becoming increasingly clear that the tumour microenvironment has a very important role in tumour progression and drug resistance. Many different cell types within the tumour stroma have an effect on tumour progression either in a positive or in a negative way. Mesenchymal stem cells (MSCs) are a distinct population of cells that have been linked with tumour growth. Mesenchymal stem cells can home to tumours where they modulate the immune system and facilitate tumour growth, angiogenesis and metastasis. Recent studies have shown that MSCs also have an important role in the resistance to various anti-cancer drugs. This mini-review provides an overview of the functional properties of MSCs in tumour progression and drug resistance.


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

Ressources et infrastructures (Biologie)

A partir de travaux portant sur 909 échantillons, cette étude démontre la faisabilité d'une méthode de séquençage à faible taux de couverture pour améliorer la puissance des études d'association sur le génome entier

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    A partir de travaux portant sur 909 échantillons, cette étude démontre la faisabilité d'une méthode de séquençage à faible taux de couverture pour améliorer la puissance des études d'association sur le génome entier

    “Extremely low-coverage sequencing and imputation increases power for genome-wide association studies”

    • Pasaniuc, Bogdan;Rohland, Nadin;McLaren, Paul J.;Garimella, Kiran;Zaitlen, Noah;Li, Heng;Gupta, Namrata;Neale, Benjamin M.;Daly, Mark J.;Sklar, Pamela;Sullivan, Patrick F.;Bergen, Sarah;Moran, Jennifer L.;Hultman, Christina M.;Lichtenstein, Paul;Magnusson, Patrik;Purcell, Shaun M.;Haas, David W.;Liang, Liming;Sunyaev, Shamil;Patterson, Nick;de Bakker, Paul I. W.;Reich, David;Price, Alkes L.

    Genome-wide association studies (GWAS) have proven to be a powerful method to identify common genetic variants contributing to susceptibility to common diseases. Here, we show that extremely low-coverage sequencing (0.1–0.5×) captures almost as much of the common (>5%) and low-frequency (1–5%) variation across the genome as SNP arrays. As an empirical demonstration, we show that genome-wide SNP genotypes can be inferred at a mean r2 of 0.71 using off-target data (0.24× average coverage) in a whole-exome study of 909 samples. Using both simulated and real exome-sequencing data sets, we show that association statistics obtained using extremely low-coverage sequencing data attain similar P values at known associated variants as data from genotyping arrays, without an excess of false positives. Within the context of reductions in sample preparation and sequencing costs, funds invested in extremely low-coverage sequencing can yield several times the effective sample size of GWAS ...


Mots clés : Cancer (général); Biologie (Ressources et infrastructures (Biologie))

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