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Accueil Nota Bene Cancer V2 Numéro 130 du 03 April 2012 Biologie

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Biologie

Aberrations chromosomiques

Menée à l'aide d'anticorps anti-phosho-tyrosine sur des lignées cellulaires et des échantillons tumoraux de sarcome, cette étude met en évidence divers récepteurs dont l'activité tyrosine kinase est essentielle à la survie des cellules cancéreuses

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    Menée à l'aide d'anticorps anti-phosho-tyrosine sur des lignées cellulaires et des échantillons tumoraux de sarcome, cette étude met en évidence divers récepteurs dont l'activité tyrosine kinase est essentielle à la survie des cellules cancéreuses

    “Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors”

    • Bai, Yun;Li, Jiannong;Fang, Bin;Edwards, Arthur;Zhang, Guolin;Bui, Marilyn;Eschrich, Steven;Altiok, Soner;Koomen, John;Haura, Eric B

    Driver tyrosine kinase mutations are rare in sarcomas and patterns of tyrosine phosphorylation are poorly understood. To better understand the signaling pathways active in sarcoma, we examined global tyrosine phosphorylation in sarcoma cell lines and human tumor samples. Anti-phospho-tyrosine antibodies were used to purify tyrosine-phosphorylated peptides, which were then identified using liquid chromatography and tandem mass spectrometry. The findings were validated using RNA interference, rescue, and small molecule tyrosine kinase inhibitors. We identified 1,936 unique tyrosine phosphorylated peptides, corresponding to 844 unique phospho-tyrosine proteins. In sarcoma cells alone, peptides corresponding to 39 tyrosine kinases were found. Four of ten cell lines demonstrated dependence on tyrosine kinases for growth and/or survival, including PDGFR , MET, insulin receptor/IGF1R signaling, and SRC family kinase signaling. Rhabdomyosarcoma samples demonstrated over-expression of PDGFR in ...


Mots clés : Sarcome; Biologie (Aberrations chromosomiques)

Menée sur 4 patients ayant subi une prostatectomie radicale, cette étude de séquençage des exons met en évidence l'hétérogénéité du profil mutationnel des divers échantillons tumoraux prélevés sur chaque patient

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    Menée sur 4 patients ayant subi une prostatectomie radicale, cette étude de séquençage des exons met en évidence l'hétérogénéité du profil mutationnel des divers échantillons tumoraux prélevés sur chaque patient

    “Exome Sequencing of Prostate Cancer Supports the Hypothesis of Independent Tumour Origins”

    • Johan, Lindberg;Daniel, Klevebring;Wennuan, Liu;Mårten, Neiman;Jianfeng, Xu;Peter, Wiklund;Fredrik, Wiklund;Ian, Mills;Lars, Egevad;Henrik, Grönberg

    Background: Prostate cancer (PCa) is a clinically and pathologically heterogeneous disease. The rapid development of sequencing technology has the potential to deliver new biomarkers with emphasis on aggressive disease and to revolutionise personalised cancer treatment. However, a prostate harbouring cancer commonly contains multiple separate tumour foci, with the potential to aggravate tumour sampling. The level of intraprostatic tumour heterogeneity remains to be determined. Objective: To determine the level of intraprostatic tumour heterogeneity through genome-wide, high-resolution profiling of multiple tumour samples from the same individual. Design, settings, and participants: Multiple tumour samples were obtained from four individuals following radical prostatectomy. One individual (SWE-1) contained >70% cancer cells in all tumour samples, whereas the other three (SWE-2 to SWE-4) required the use of laser capture microdissection for tumour cell enrichment. Subsequently, DNA was ...


Mots clés : Prostate; Biologie (Aberrations chromosomiques)

Menée sur 76 patients atteints d'une leucémie lymphocytaire chronique et 35 témoins, cette étude évalue l'association entre un mécanisme épigénétique régulant l'expression d'un gène de l'horloge circadienne, CRY1, et le pronostic de la maladie

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    Menée sur 76 patients atteints d'une leucémie lymphocytaire chronique et 35 témoins, cette étude évalue l'association entre un mécanisme épigénétique régulant l'expression d'un gène de l'horloge circadienne, CRY1, et le pronostic de la maladie

    “Epigenetic Silencing of the Circadian Clock Gene CRY1 is Associated with an Indolent Clinical Course in Chronic Lymphocytic Leukemia”

    • Hanoun, Maher;Eisele, Lewin;Suzuki, Masako;Greally, John M.;Hüttmann, Andreas;Aydin, Semra;Scholtysik, René;Klein-Hitpass, Ludger;Dührsen, Ulrich;Dürig, Jan

    Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) unmutated patients as compared to low-risk (LR) CD38−/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 ...


Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Cet article passe en revue les travaux récents faisant appel à une approche évolutionniste pour étudier le génome des cancers

  • Evolution of the cancer genome
    Trends in Genetics, Vol. 28 (4), pp. 155-163, 2012 (résumé)
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    Cet article passe en revue les travaux récents faisant appel à une approche évolutionniste pour étudier le génome des cancers

    “Evolution of the cancer genome”

    • Podlaha, Ondrej;Riester, Markus;De, Subhajyoti;Michor, Franziska

    Human tumors result from an evolutionary process operating on somatic cells within tissues, whereby natural selection operates on the phenotypic variability generated by the accumulation of genetic, genomic and epigenetic alterations. This somatic evolution leads to adaptations such as increased proliferative, angiogenic, and invasive phenotypes. In this review we outline how cancer genomes are beginning to be investigated from an evolutionary perspective. We describe recent progress in the cataloging of somatic genetic and genomic alterations, and investigate the contributions of germline as well as epigenetic factors to cancer genome evolution. Finally, we outline the challenges facing researchers who investigate the processes driving the evolution of the cancer genome.


Mots clés : Cancer (général); Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée sur un modèle murin, cette étude met en évidence le rôle joué par HER3 dans l'épithélium mammaire avant, pendant et après la formation d'une tumeur HER2+

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    Menée sur un modèle murin, cette étude met en évidence le rôle joué par HER3 dans l'épithélium mammaire avant, pendant et après la formation d'une tumeur HER2+

    “HER3 is required for HER2-induced pre-neoplastic changes to the breast epithelium and tumor formation”

    • Vaught, David B;Stanford, Jamie C;Young, Christian;Hicks, Donna J;Wheeler, Frank;Rinehart, Cammie;Sánchez, Violeta;Koland, John;Muller, William J.;Arteaga, Carlos L.;Cook, Rebecca S

    Increasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breast epithelial transformation remains unknown. Using mouse mammary-specific models of Cre-mediated ErbB3 ablation, we show that ErbB3 loss prevents the progressive transformation of HER2-overexpressing mammary epithelium. Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu mammary glands lacking ErbB3, thus inhibiting premalignant HER2-induced hyperplasia. Using a transgenic model in which HER2 and Cre are expressed from a single polycistronic transcript, we showed that palpable tumor penetrance decreased from 93.3% to 6.7% upon ErbB3 ablation. Penetrance of ductal carcinomas in situ was also decreased. In addition, loss of ErbB3 impaired Akt and p44/42 phosphorylation in pre-neoplastic HER2-overexpressing mammary glands and in tumors, decreased growth of ...


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

Menée sur divers modèles murins, cette étude met en évidence le rôle joué par l'interleukine 17 dans la formation et la croissance d'un adénocarcinome de la prostate

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    Menée sur divers modèles murins, cette étude met en évidence le rôle joué par l'interleukine 17 dans la formation et la croissance d'un adénocarcinome de la prostate

    “Interleulin-17 Promotes Formation and Growth of Prostate Adenocarcinoma in Mouse Models”

    • Zhang, Qiuyang;Liu, Sen;Ge, Dongxia;Zhang, Qingsong;Xue, Yun;Xiong, Zhenggang;Abdel-Mageed, Asim B;Myers, Leann;Hill, Steven M;Rowan, Brian G;Sartor, Oliver;Melamed, Jonathan;Chen, Zhenbang;You, Zongbing

    The contributions of interleukin-17 (IL-17) to cancer remain unclear and somewhat controversial. We took a genetic approach to explore its role in prostate cancers by interbreeding IL-17 receptor C (IL-17RC) deficient mice with mice that are conditionally mutant for PTEN, one established preclinical model for prostate cancer. Mice that were IL-17RC deficient (IL-17RC-) displayed prostates that were smaller than mice that maintained IL-17RC expression (IL-17RC+). Additionally, IL-17RC- mice developed a reduced number of invasive prostate adenocarcinomas with lower rates of cellular proliferation and higher apoptosis, compared to IL-17RC+ mice. Moreover, the fibromuscular stroma surrounding prostatic glands was relatively thicker in IL-17RC- mice and was associated with decreased Mmp7 expression and increased Timp1,2,4 expression, whereas administration of recombinant mouse IL-17 induced prostatic expression of Mmp7. Taken together, our results suggested that IL-17 promotes the ...


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

Menée sur un modèle murin et 30 échantillons prélevés sur des patients atteints de lymphomes présentant des mutations du gène BCL6, cette étude met en évidence un mécanisme impliquant une coopération entre les gènes PIM1 et BCL6 dans le développement de la maladie

  • PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée sur un modèle murin et 30 échantillons prélevés sur des patients atteints de lymphomes présentant des mutations du gène BCL6, cette étude met en évidence un mécanisme impliquant une coopération entre les gènes PIM1 et BCL6 dans le développement de la maladie

    “PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas”

    • Baron, Beverly W.;Anastasi, John;Hyjek, Elizabeth M.;Bies, Juraj;Reddy, Poluru L.;Dong, Jingfang;Joseph, Loren;Thirman, Michael J.;Wroblewski, Kristen;Wolff, Linda;Baron, Joseph M.

    Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. ...


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

Menée sur un modèle murin de leucémie avec réarrangement MLL, cette étude met en évidence le rôle joué par l'enzyme KDM1A dans la régulation des cellules souches leucémiques

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    Menée sur un modèle murin de leucémie avec réarrangement MLL, cette étude met en évidence le rôle joué par l'enzyme KDM1A dans la régulation des cellules souches leucémiques

    “The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells”

    • Harris, William J;Huang, Xu;Lynch, James T;Spencer, Gary J;Hitchin, James R;Li, Yaoyong;Ciceri, Filippo;Blaser, Julian G;Greystoke, Brigit F;Jordan, Allan M;Miller, Crispin J;Ogilvie, Donald J;Somervaille, Tim C P.

    Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect. º KDM1A is a key effector of the differentiation block in MLL leukemia º KDM1A sustains expression of the MLL-AF9 oncogenic program º Nanomolar KDM1A inhibitor concentrations induce ...


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

Menée sur un modèle murin, cette étude montre que l'activation de la protéine kinase mTORC1 favorise la formation d'un carcinome hépatocellulaire

  • Chronic Activation of mTOR Complex 1 Is Sufficient to Cause Hepatocellular Carcinoma in Mice
    Science Signaling, Vol. 5 (217), pp. ra24-, 2012 (résumé)
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    Menée sur un modèle murin, cette étude montre que l'activation de la protéine kinase mTORC1 favorise la formation d'un carcinome hépatocellulaire

    “Chronic Activation of mTOR Complex 1 Is Sufficient to Cause Hepatocellular Carcinoma in Mice”

    • Menon, Suchithra;Yecies, Jessica L.;Zhang, Hui H.;Howell, Jessica J.;Nicholatos, Justin;Harputlugil, Eylul;Bronson, Roderick T.;Kwiatkowski, David J.;Manning, Brendan D.

    The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been linked to environmental factors that affect mTORC1 activity, including diet. Ablation of the gene encoding TSC1 (tuberous sclerosis complex 1), which as part of the TSC1-TSC2 complex is an upstream inhibitor of mTORC1, results in constitutively increased mTORC1 signaling, an effect on this pathway similar to that of obesity. We found that mice with liver-specific knockout of Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological and biochemical features. The spontaneous development of hepatocellular carcinoma in this mouse model was preceded by a series of pathological changes that accompany the primary etiologies of this cancer in humans, ...


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

Menée sur un modèle murin transgénique, cette étude montre que l'ablation du gène Tpl2 favorise un mécanisme inflammatoire et la formation d'adénomes intestinaux

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    Menée sur un modèle murin transgénique, cette étude montre que l'ablation du gène Tpl2 favorise un mécanisme inflammatoire et la formation d'adénomes intestinaux

    “Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation”

    • Serebrennikova, Oksana B.;Tsatsanis, Christos;Mao, Changchuin;Gounaris, Elias;Ren, Wenying;Siracusa, Linda D.;Eliopoulos, Aristides G.;Khazaie, Khashayarsha;Tsichlis, Philip N.

    To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apcmin/+ genetic background. Here, we show that Apcmin/+/Tpl2−/− mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2−/− mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2. The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and ...


Mots clés : Colon-rectum; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle de suppresseur de tumeurs joué par Lrig1 dans les cellules souches de l'intestin

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    Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle de suppresseur de tumeurs joué par Lrig1 dans les cellules souches de l'intestin

    “The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor”

    • Powell, Anne E;Wang, Yang;Li, Yina;Poulin, Emily J;Means, Anna L;Washington, Mary K;Higginbotham, James N;Juchheim, Alwin;Prasad, Nripesh;Levy, Shawn E;Guo, Yan;Shyr, Yu;Aronow, Bruce J;Haigis, Kevin M;Franklin, Jeffrey L;Coffey, Robert J

    Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1+ colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5+ colonic stem cells; genes upregulated in the Lrig1+ population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1+ cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by ...


Mots clés : Colon-rectum; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des modèles murins transgéniques surexprimant le gène PTEN, cette étude met en évidence un mécanisme par lequel PTEN, en régulant un processus métabolique, joue un rôle de suppresseur de tumeurs

  • Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State
    Cell, Vol. 149 (1), pp. 49-62, 2012 (résumé)
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    Menée sur des modèles murins transgéniques surexprimant le gène PTEN, cette étude met en évidence un mécanisme par lequel PTEN, en régulant un processus métabolique, joue un rôle de suppresseur de tumeurs

    “Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State”

    • Garcia-Cao, Isabel;Song, Min Sup;Hobbs, Robin M;Laurent, Gaelle;Giorgi, Carlotta;de Boer, Vincent C J.;Anastasiou, Dimitrios;Ito, Keisuke;Sasaki, Atsuo T;Rameh, Lucia;Carracedo, Arkaitz;Vander Heiden, Matthew G;Cantley, Lewis C;Pinton, Paolo;Haigis, Marcia C;Pandolfi, Pier Paolo

    Decremental loss of PTEN results in cancer susceptibility and tumor progression. PTEN elevation might therefore be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with PTEN expression elevated to varying levels by taking advantage of bacterial artificial chromosome (BAC)-mediated transgenesis. The Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake and increased mitochondrial oxidative phosphorylation and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and -independent pathways and negatively impacting two of the most pronounced ...


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

Cet article passe en revue les travaux récents sur le rôle du gène MYC dans le développement des cancers

  • MYC on the Path to Cancer
    Cell, Vol. 149 (1), pp. 22-35, 2012 (article en libre accès)
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    Cet article passe en revue les travaux récents sur le rôle du gène MYC dans le développement des cancers

    “MYC on the Path to Cancer”

    • Dang, Chi V

    The MYC oncogene contributes to the genesis of many human cancers. Recent insights into its expression and function have led to therapeutic opportunities. MYC's activation by bromodomain proteins could be inhibited by drug-like molecules, resulting in tumor inhibition in vivo. Tumor growth can also be curbed by pharmacologically uncoupling bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced cellular biomass accumulation. Other approaches to halt Myc on the path to cancer involve targeting Myc-Max dimerization or Myc-induced microRNA expression. Here the richness of our understanding of MYC is reviewed, highlighting new biological insights and opportunities for cancer therapies.


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

Progression et métastases

Menée à partir d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude montre qu'à l'intérieur d'une même tumeur, il existe plusieurs types de cellules dotées de caractéristiques de cellules souches

  • Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity
    Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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    Menée à partir d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude montre qu'à l'intérieur d'une même tumeur, il existe plusieurs types de cellules dotées de caractéristiques de cellules souches

    “Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity”

    • Kim, Jiyoung;Villadsen, René;Sørlie, Therese;Fogh, Louise;Grønlund, Signe Z.;Fridriksdottir, Agla J.;Kuhn, Irene;Rank, Fritz;Wielenga, Vera Timmermans;Solvang, Hiroko;Edwards, Paul A. W.;Børresen-Dale, Anne-Lise;Rønnov-Jessen, Lone;Bissell, Mina J.;Petersen, Ole William

    The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without ...


Mots clés : Sein; Biologie (Progression et métastases)

Menée sur des modèles murins, cette étude met en évidence un mécanisme par lequel le micro-ARN 23a favorise la transformation d'un cancer colorectal d'une forme indolente en une forme invasive

  • miR-23a Promotes the Transition from Indolent to Invasive Colorectal Cancer
    Cancer Discovery, sous presse, 2012 (résumé)
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    Menée sur des modèles murins, cette étude met en évidence un mécanisme par lequel le micro-ARN 23a favorise la transformation d'un cancer colorectal d'une forme indolente en une forme invasive

    “miR-23a Promotes the Transition from Indolent to Invasive Colorectal Cancer”

    • Jahid, Sohail;Sun, Jian;Edwards, Robert A;Dizon, Diana;Panarelli, Nicole C.;Milsom, Jeffrey W.;Sikandar, Shaheen S.;Gümüş, Zeynep H.;Lipkin, Steven M

    Colorectal cancer (CRC) is a classic example of a tumor that progresses through multiple distinct stages in its evolution. To understand the mechanisms regulating the transition from indolent to invasive disease, we profiled somatic copy number alterations in non-invasive adenomas and invasive adenocarcinomas from Apc and DNA mismatch repair (MMR) mutant mouse models. We identified a recurrent amplicon on mouse chromosome 8 that encodes microRNAs (miRs) 23a and 27a. miRs-23a and 27a levels are upregulated in mouse intestinal adenocarcinomas, primary tumors from stage I/II CRC patients, as well as in human CRC cell lines and cancer stem cells. Functionally, miR-23a promotes CRC cells and stem cells migration and invasion, while miR- 27a primarily promotes proliferation. We computationally and experimentally validated that Metastasis Suppressor 1 (MTSS1) is a direct miR-23a target and similarly validated that the ubiquitin ligase FBXW7 is a direct miR-27a target. Analyses of ...


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

Ressources et infrastructures (Biologie)

Cet article passe en revue les travaux récents sur le génome, les modèles animaux et les cellules souches des gliomes

  • Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells
    Cell, Vol. 149 (1), pp. 36-47, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le génome, les modèles animaux et les cellules souches des gliomes

    “Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells”

    • Chen, Jian;McKay, Renée M;Parada, Luis F

    Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-ºB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells and explore how the integration of new molecular data allows for the generation of more informative animal models to advance our knowledge of glioma's origin, progression, and treatment.


Mots clés : Système nerveux central; Biologie (Ressources et infrastructures (Biologie))

Cet article passe en revue les travaux récents sur les échanges entre le système immunitaire, inné et adaptatif, et les cellules tumorales

  • Cancer and the Immune System
    Cell, Vol. 149 (1), pp. 5-7, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur les échanges entre le système immunitaire, inné et adaptatif, et les cellules tumorales

    “Cancer and the Immune System”

    The immune system interacts with developing cancer in ways that can protect the host against hyperproliferation but that may also contribute to malignancy. Understanding the mechanisms behind the protective and harmful effects of the innate and adaptive immune systems in their exchanges with tumor cells will help to unravel how to harness our natural defenses with targeted therapeutics. This issue's Select delves into cancer immunoediting, T cell therapy, and how the goodies can become the baddies during tumor growth.


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

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