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Accueil Nota Bene Cancer V2 Numéro 135 du 10 May 2012 Biologie

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Nota Bene Cancer Numéro 135 du 10 May 2012 RSS

Biologie

Aberrations chromosomiques

Menée sur des échantillons de tumeurs et de tissus sains prélevés sur 8 patients atteints d'un cholangiosarcome associé au parasite Opisthorchis viverrini, cette étude de séquençage des exons identifie des gènes dont les mutations sont associées au développement de cette forme de cancer

  • Exome sequencing of liver fluke-associated cholangiocarcinoma
    Nature Genetics, sous presse, 2012 (résumé)
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    Menée sur des échantillons de tumeurs et de tissus sains prélevés sur 8 patients atteints d'un cholangiosarcome associé au parasite Opisthorchis viverrini, cette étude de séquençage des exons identifie des gènes dont les mutations sont associées au développement de cette forme de cancer

    “Exome sequencing of liver fluke-associated cholangiocarcinoma”

    • Ong, Choon Kiat;Subimerb, Chutima;Pairojkul, Chawalit;Wongkham, Sopit;Cutcutache, Ioana;Yu, Willie;McPherson, John R.;Allen, George E.;Ng, Cedric Chuan Young;Wong, Bernice Huimin;Myint, Swe Swe;Rajasegaran, Vikneswari;Heng, Hong Lee;Gan, Anna;Zang, Zhi Jiang;Wu, Yingting;Wu, Jeanie;Lee, Ming Hui;Huang, DaChuan;Ong, Pauline;Chan-on, Waraporn;Cao, Yun;Qian, Chao-Nan;Lim, Kiat Hon;Ooi, Aikseng;Dykema, Karl;Furge, Kyle;Kukongviriyapan, Veerapol;Sripa, Banchob;Wongkham, Chaisiri;Yongvanit, Puangrat;Futreal, P. Andrew;Bhudhisawasdi, Vajarabhongsa;Rozen, Steve;Tan, Patrick;Teh, Bin Tean

    Opisthorchis viverrini–related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini–related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8–3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of ...


Mots clés : Voies biliaires; Biologie (Aberrations chromosomiques)

A partir d'échantillons tumoraux prélevés sur 69 patientes chinoises atteintes d'un cancer de l'ovaire, cette étude identifie 4 tumeurs dans lesquelles la kinase ALK est surexprimée

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    A partir d'échantillons tumoraux prélevés sur 69 patientes chinoises atteintes d'un cancer de l'ovaire, cette étude identifie 4 tumeurs dans lesquelles la kinase ALK est surexprimée

    “Identification of Anaplastic Lymphoma Kinase as a Potential Therapeutic Target in Ovarian Cancer”

    • Ren, Hong;Tan, Zhi-Ping;Zhu, Xin;Crosby, Katherine;Haack, Herbert;Ren , Jian-Min;Beausoleil, Sean;Moritz, Albrecht;Innocenti, Gregory;Rush , John;Zhang, Yi;Zhou, Xin-Min;Gu, Ting-Lei;Yang, Yi-Feng;Comb, Michael J

    Ovarian cancer is the leading cause of death from gynecological cancer. Improvement in the clinical outcome of patients is likely to be achieved by the identification of molecular events that underlie the oncogenesis of ovarian cancer. Here we show that the anaplastic lymphoma kinase (ALK) is aberrantly activated in ovarian cancer. Using an unbiased and global phospho-proteomic approach, we profiled 69 Chinese primary ovarian tumor tissues and found ALK to be aberrantly expressed and phosphorylated in 4 tumors. Genetic characterization of these ALK positive tumors indicated that full length ALK expression in two serous carcinoma patients is consistent with ALK gene copy number gain while a stromal sarcoma patient carries a novel trans-membrane ALK fusion gene: FN1-ALK. Biochemical and functional analysis demonstrated that both full length ALK and FN1-ALK are oncogenic and tumors expressing ALK or FN1-ALK are sensitive to ALK kinase inhibitors. Furthermore, immunohistochemical analysis ...


Mots clés : Ovaire; Biologie (Aberrations chromosomiques)

Menée sur un modèle murin de carcinome hépatocellulaire, cette étude évalue la pertinence d'un modèle alternatif à l'hypothèse du double événement pour rendre compte de l'inactivation des gènes suppresseurs de tumeurs

  • A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée sur un modèle murin de carcinome hépatocellulaire, cette étude évalue la pertinence d'un modèle alternatif à l'hypothèse du double événement pour rendre compte de l'inactivation des gènes suppresseurs de tumeurs

    “A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions”

    • Xue, Wen;Kitzing, Thomas;Roessler, Stephanie;Zuber, Johannes;Krasnitz, Alexander;Schultz, Nikolaus;Revill, Kate;Weissmueller, Susann;Rappaport, Amy R.;Simon, Janelle;Zhang, Jack;Luo, Weijun;Hicks, James;Zender, Lars;Wang, Xin Wei;Powers, Scott;Wigler, Michael;Lowe, Scott W.

    The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a “two-hit” mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large ...


Mots clés : Foie; Biologie (Aberrations chromosomiques)

A partir d'une analyse du nombre de copies de gènes dans 125 échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire et du séquençage des exons sur 24 de ces échantillons, cette étude française identifie des gènes et des voies de signalisation associés au développement de ce cancer

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    A partir d'une analyse du nombre de copies de gènes dans 125 échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire et du séquençage des exons sur 24 de ces échantillons, cette étude française identifie des gènes et des voies de signalisation associés au développement de ce cancer

    “Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma”

    • Guichard, Cecile;Amaddeo, Giuliana;Imbeaud, Sandrine;Ladeiro, Yannick;Pelletier, Laura;Maad, Ichrafe Ben;Calderaro, Julien;Bioulac-Sage, Paulette;Letexier, Melanie;Degos, Francoise;Clement, Bruno;Balabaud, Charles;Chevet, Eric;Laurent, Alexis;Couchy, Gabrielle;Letouze, Eric;Calvo, Fabien;Zucman-Rossi, Jessica

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/ β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides ...


Mots clés : Foie; Biologie (Aberrations chromosomiques)

Cette étude évaue la pertinence d'un modèle "continu" pour rendre compte de la façon dont des mutations somatiques induisent le développement d'une tumeur

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    Cette étude évaue la pertinence d'un modèle "continu" pour rendre compte de la façon dont des mutations somatiques induisent le développement d'une tumeur

    “The continuum model of selection in human tumours: general paradigm or niche product?”

    • Leedham, Simon;Tomlinson, Ian

    Berger et al recently proposed a "continuum" model of how somatic mutations cause tumours to grow, thus supplementing the established binary models such as oncogene activation and "two hits" at tumour suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the "fail-safe" model envisaged an optimum level of gene derangement for tumour growth, but that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten-mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: in part, it re-states the existing "just right" of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell ...


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

Oncogènes et suppresseurs de tumeurs

Menée à l'aide d'un modèle murin et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel la protéine nucléaire Nupr1 favorise la tumorigenèse

  • Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
    The Journal of Clinical Investigation, sous presse, 2012 (article en libre accès)
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    Menée à l'aide d'un modèle murin et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel la protéine nucléaire Nupr1 favorise la tumorigenèse

    “Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis”

    • Hamidi, Tewfik;Algül, Hana;Cano, Carla Eliana;Sandi, Maria José;Molejon, Maria Inés;Riemann, Marc;Calvo, Ezequiel Luis;Lomberk, Gwen;Dagorn, Jean-Charles;Weih, Falk;Urrutia, Raul;Schmid, Roland Michael;Iovanna, Juan Lucio

    Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic KrasG12D, we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from KrasG12D-expressing pancreas. Moreover, pancreas-specific deletion of Relb in ...


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

Menée sur des modèles murins, cette étude suggère que le gène Ncoa2/Src-2 joue un rôle de suppresseur de tumeurs dans les cancers du foie

  • A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée sur des modèles murins, cette étude suggère que le gène Ncoa2/Src-2 joue un rôle de suppresseur de tumeurs dans les cancers du foie

    “A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer”

    • O’Donnell, Kathryn A.;Keng, Vincent W.;York, Brian;Reineke, Erin L.;Seo, Daekwan;Fan, Danhua;Silverstein, Kevin A. T.;Schrum, Christina T.;Xie, Wei Rose;Mularoni, Loris;Wheelan, Sarah J.;Torbenson, Michael S.;O’Malley, Bert W.;Largaespada, David A.;Boeke, Jef D.

    The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy.


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

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire, cette étude suggère que la protéine SCYL1BP1 joue un rôle de suppresseur de tumeurs

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    Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire, cette étude suggère que la protéine SCYL1BP1 joue un rôle de suppresseur de tumeurs

    “SCYL1 binding protein 1 promotes the ubiquitin-dependent degradation of Pirh2 and has tumor suppressive function in the development of hepatocellular carcinoma”

    • Hu, Liang;Liu, Ming;Chen, Leilei;Chan, Tim Hon Man;Wang, Jian;Huo, Ke-Ke;Zheng, Bo-Jian;Xie, Dan;Guan, Xin-Yuan

    Pirh2 is a Ring-H2 domain containing E3 ubiquitin ligase which target several important tumor suppressor genes for proteasomal degradation. Overexpression of Pirh2 is frequently detected in many clinical tumor tissues including hepatocellular carcinoma (HCC). However, the molecular mechanism of Pirh2 activation in tumorigenesis still remains poorly understood. In the present study, we find a Pirh2 binding protein SCYL1 binding protein 1 (SCYL1BP1) can promote the ubiquitin-dependent degradation of Pirh2. SCYL1BP1 co-localized with Pirh2 in the cytoplasm and prevented its localization to the nucleus. Ectopic expression of SCYL1BP1 increased the expression of p53 and further in hibited the G1/S transition of HCC cell lines. Conversely, knock down of SCYL1BP1 restored the expression Pirh2 and inhibited p53 at protein level. Functional assays found that reintroduction of SCYL1BP1 into HCC cell lines significantly inhibited cell proliferation, foci formation, colony formation in soft agar ...


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

Menée à l'aide d'un modèle murin et de 261 échantillons tumoraux prélevés sur des patients atteints de cancer, cette étude évalue le rôle d'une surexpression du gène TRIM27 dans le développement d'un cancer

  • Role of the Tripartite Motif Protein 27 in Cancer Development
    Journal of the National Cancer Institute, sous presse, 2012 (résumé)
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    Menée à l'aide d'un modèle murin et de 261 échantillons tumoraux prélevés sur des patients atteints de cancer, cette étude évalue le rôle d'une surexpression du gène TRIM27 dans le développement d'un cancer

    “Role of the Tripartite Motif Protein 27 in Cancer Development”

    • Zoumpoulidou, Georgia;Broceño, Cristina;Li, He;Bird, Demelza;Thomas, George;Mittnacht, Sibylle

    Background The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Here, we investigated the role of TRIM27 expression in cancer development.Methods We assessed TRIM27 expression in human cancer using cancer profiling arrays containing paired tumor and normal cRNA (n = 261) as well as in murine skin cancer induced by 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). We generated mice with disrupted expression of murine TRIM27 (Trim27−/−) and assessed their susceptibility to DMBA/TPA-induced skin tumor development compared with isogenic littermates (n = 26 mice per group). We assessed the effect of Trim27 loss on senescence propensity in mouse embryonic ...


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

Cet article passe en revue le rôle des facteurs de transcription "pionniers" dans le développement des cancers hormono-dépendants

  • Pioneer factors in hormone-dependent cancers
    Nature Reviews Cancer, sous presse, 2012 (résumé)
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    Cet article passe en revue le rôle des facteurs de transcription "pionniers" dans le développement des cancers hormono-dépendants

    “Pioneer factors in hormone-dependent cancers”

    • Jozwik, Kamila M.;Carroll, Jason S.

    Pioneer factors are a special class of transcription factor that can associate with compacted chromatin to facilitate the binding of additional transcription factors. The function of pioneer factors was originally described during development; more recently, they have been implicated in hormone-dependent cancers, such as oestrogen receptor-positive breast cancer and androgen receptor-positive prostate cancer. We discuss the importance of pioneer factors in these specific cancers, the discovery of new putative pioneer factors and the interplay between these proteins in mediating nuclear receptor function in cancer.


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

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine nucléaire TRADD joue un rôle suppresseur de tumeur

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    Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine nucléaire TRADD joue un rôle suppresseur de tumeur

    “TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation”

    • Christine Chio, Iok In;Sasaki, Masato;Ghazarian, Danny;Moreno, Juan;Done, Susan;Ueda, Takeshi;Inoue, Satoshi;Chang, Yu-Ling;Chen, Nien Jung;Mak, Tak Wah

    Tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) protein is a central adaptor in the TNFR1 signalling complex that mediates both cell death and inflammatory signals. Here, we report that Tradd deficiency in mice accelerated tumour formation in a chemical-induced carcinogenesis model independently of TNFR1 signalling. In vitro, primary cells lacking TRADD were less susceptible to HRas-induced senescence and showed a reduced level of accumulation of the p19Arf tumour suppressor protein. Our data indicate that TRADD shuttles dynamically from the cytoplasm into the nucleus to modulate the interaction between p19Arf and its E3 ubiquitin ligase ULF, thereby promoting p19Arf protein stability and tumour suppression. These results reveal a previously unknown tumour-suppressive role for nuclear TRADD, augmenting its long-established cytoplasmic functions in inflammatory and immune signalling cascades. Our findings also make an important contribution to the rapidly ...


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

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la sirtuine SIRT7 dans la régulation de la chromatine, les programmes de transformation cellulaire et la formation d'une tumeur

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    Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la sirtuine SIRT7 dans la régulation de la chromatine, les programmes de transformation cellulaire et la formation d'une tumeur

    “SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation”

    • Barber, Matthew F.;Michishita-Kioi, Eriko;Xi, Yuanxin;Tasselli, Luisa;Kioi, Mitomu;Moqtaderi, Zarmik;Tennen, Ruth I.;Paredes, Silvana;Young, Nicolas L.;Chen, Kaifu;Struhl, Kevin;Garcia, Benjamin A.;Gozani, Or;Li, Wei;Chua, Katrin F.

    Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by ...


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

Progression et métastases

Menée à l'aide de xénogreffes et d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude suggère que la protéine FRMD4A joue un rôle clé dans le processus métastatique

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    Menée à l'aide de xénogreffes et d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude suggère que la protéine FRMD4A joue un rôle clé dans le processus métastatique

    “FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis”

    • Goldie, Stephen J.;Mulder, Klaas W.;Tan, David Wei-Min;Lyons, Scott K.;Sims, Andrew H.;Watt, Fiona M.

    New therapeutic strategies are needed to improve treatment for head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here we report that FRMD4A upregulation occurs in primary human HNSCC where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A ...


Mots clés : Voies aérodigestives supérieures; Biologie (Progression et métastases)

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints de neuroblastome, cette étude met en évidence un mécanisme par lequel le micro-ARN 9, en régulant l'expression de la métalloprotéase matricielle MMP-14, inhibe les processus invasif et métastatique

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    Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints de neuroblastome, cette étude met en évidence un mécanisme par lequel le micro-ARN 9, en régulant l'expression de la métalloprotéase matricielle MMP-14, inhibe les processus invasif et métastatique

    “microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis and angiogenesis of neuroblastoma cells”

    • Zhang, Huanyu;Qi, Meng;Li, Shiwang;Qi, Teng;Mei, Hong;Huang, Kai;Zheng, Liduan;Tong, Qiangsong

    Matrix metalloproteinase 14 (MMP-14) is the only membrane anchored MMP that plays a critical role in tumor metastasis and angiogenesis. However, the mechanisms underlying MMP-14 expression in tumors still remain largely unknown. In this study, MMP-14 immunostaining was identified in 29/42 neuroblastoma (NB) tissues, which was correlated with clinicopathological features and shorter patients' survival. In subtotal twenty NB cases, microRNA 9 (miR-9) was down-regulated and inversely correlated with MMP-14 expression. Bioinformatics analysis revealed a putative miR-9 binding site in the 3′-untranslated region (3′-UTR) of MMP-14 mRNA. Over-expression or knockdown of miR-9 responsively altered both the mRNA and protein levels of MMP-14 and its downstream gene, vascular endothelial growth factor (VEGF), in cultured NB cell lines SH-SY5Y and SK-N-SH. In a MMP-14 3′-UTR luciferase reporter system, miR-9 down-regulated the luciferase activity, and these effects were abolished by ...


Mots clés : Système nerveux central; Biologie (Progression et métastases)

Menée sur un modèle murin de cancer mammaire, cette étude met en évidence un mécanisme vasculaire par lequel la perte du gène HIF-1α dans les fibroblastes associés aux tumeurs accélère la croissance tumorale

  • Loss of fibroblast HIF-1α accelerates tumorigenesis
    Cancer Research, sous presse, 2012 (résumé)
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    Menée sur un modèle murin de cancer mammaire, cette étude met en évidence un mécanisme vasculaire par lequel la perte du gène HIF-1α dans les fibroblastes associés aux tumeurs accélère la croissance tumorale

    “Loss of fibroblast HIF-1α accelerates tumorigenesis”

    • Kim, Jung-whan;Evans, Colin;Weidemann, Alexander;Takeda, Norihiko;Lee, Yun Sok;Stockmann, Christian;Branco-Price, Cristina;Brandberg, Filip;Leone, Gustavo;Ostrowski, Michael C;Johnson, Randall S.

    Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization.


Mots clés : Sein; Biologie (Progression et métastases)

Menée in vitro et in vivo, cette étude montre que les cellules de cancer de la prostate avec un faible niveau d'expression du PSA ont des caractéristiques de cellules souches cancéreuses et qu'elles contribuent probablement à la résistance aux traitements anti-androgéniques

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    Menée in vitro et in vivo, cette étude montre que les cellules de cancer de la prostate avec un faible niveau d'expression du PSA ont des caractéristiques de cellules souches cancéreuses et qu'elles contribuent probablement à la résistance aux traitements anti-androgéniques

    “The PSA /lo Prostate Cancer Cell Population Harbors Self-Renewing Long-Term Tumor-Propagating Cells that Resist Castration”

    • Qin, Jichao;Liu, Xin;Laffin, Brian;Chen, Xin;Choy, Grace;Jeter, Collene R.;Calhoun-Davis, Tammy;Li, Hangwen;Palapattu, Ganesh S;Pang, Shen;Lin, Kevin;Huang, Jiaoti;Ivanov, Ivan;Li, Wei;Suraneni, Mahipal V;Tang, Dean G

    Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA+) and low (PSA /lo) levels of the differentiation marker PSA. PSA /lo PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division to generate PSA+ cells. Importantly, PSA /lo PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and they harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH+CD44+±2²1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, undergo ...


  • PSA Lo and Behold: Prostate Cancer Stem Cells
    Cell stem cell, Vol. 10 (5), pp. 482-483, 2012 (commentaire)
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    Menée in vitro et in vivo, cette étude montre que les cellules de cancer de la prostate avec un faible niveau d'expression du PSA ont des caractéristiques de cellules souches cancéreuses et qu'elles contribuent probablement à la résistance aux traitements anti-androgéniques

    “PSA Lo and Behold: Prostate Cancer Stem Cells”

    • Wicha, Max S.

    Human prostate cancers contain multiple cell populations marked by varying levels of the differentiation marker prostate-specific antigen (PSA). In this issue of Cell Stem Cell, Qin et al. (2012) show that PSA /lo cells are enriched for cells with tumor-initiating characteristics and may participate in resistance to androgen-ablative therapies.


Mots clés : Prostate; Biologie (Progression et métastases)

Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux, cette étude met en évidence un mécanisme par lequel le micro-ARN 708, en régulant l'expression de CD44 dans les cellules souches cancéreuses, joue un rôle dans le développement et la progression d'un cancer de la prostate

  • miRNA-708 control of CD44+ prostate cancer initiating cells
    Cancer Research, sous presse, 2012 (résumé)
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    Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux, cette étude met en évidence un mécanisme par lequel le micro-ARN 708, en régulant l'expression de CD44 dans les cellules souches cancéreuses, joue un rôle dans le développement et la progression d'un cancer de la prostate

    “miRNA-708 control of CD44+ prostate cancer initiating cells”

    • Saini, Sharanjot;Majid, Shahana;Shahryari, Varahram;Arora, Sumit;Yamamura, Soichiro;Chang, Inik;Zaman, Mohd. Saif;Deng, Guoren;Tanaka, Yuichiro;Dahiya, Rajvir

    Tumor recurrence in prostate cancer (PCa) has been attributed to the presence of CD44 expressing tumor-initiating cells (TIC). In this study, we report that miR-708 is a key negative regulator of this CD44+ subpopulation of PCa cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44+ cells from PCa xenografts. Reconstitution of miR-708 in PCa cell lines or CD44+ PCa cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human PCa. Conversely, miR-708 silencing in a purified CD44- population of PCa cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression and recurrence in PCa ...


Mots clés : Prostate; Biologie (Progression et métastases)

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel la surexpression de la protéine HMGB1 favorise la prolifération des cellules de mésothéliome malin

  • Détails
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    Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel la surexpression de la protéine HMGB1 favorise la prolifération des cellules de mésothéliome malin

    “Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma”

    • Jube, Sandro;Rivera, Zeyana;Bianchi, Marco E;Powers, Amy;Wang, Ena;Pagano, Ian S;Pass, Harvey I;Gaudino, Giovanni;Carbone, Michele;Yang, Haining

    Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that is believed to be caused by chronic exposure to asbestos and erionite. Prognosis for this cancer is generally poor due to late-stage diagnosis and resistance to current conventional therapies. The damage-associated molecular pattern (DAMP) protein HMGB1 has been implicated previously in transformation of mesothelial cells. Here we show that HMGB1 establishes an autocrine circuit in MM cells that influences their proliferation and survival. MM cells strongly expressed HMGB1 and secreted it at high levels in vitro. Accordingly, HMGB1 levels in MM patient sera were higher than that found in healthy individuals. The motility, survival and anchorage-independent growth of HMGB1-secreting MM cells was inhibited in vitro by treatment with monoclonal antibodies directed against HMGB1 or against the receptor for advanced glycation end products (RAGE), a putative HMGB1 receptor. HMGB1 inhibition in vivo reduced the ...


Mots clés : Appareil respiratoire (autre); Biologie (Progression et métastases)

Cette étude suggère qu'une enzyme du métabolisme de la choline, EDI3, joue un rôle dans le processus métastatique des cancers de l'ovaire et de l'endomètre

  • Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis
    Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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    Cette étude suggère qu'une enzyme du métabolisme de la choline, EDI3, joue un rôle dans le processus métastatique des cancers de l'ovaire et de l'endomètre

    “Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis”

    • Stewart, Joanna D.;Marchan, Rosemarie;Lesjak, Michaela S.;Lambert, Joerg;Hergenroeder, Roland;Ellis, James K.;Lau, Chung-Ho;Keun, Hector C.;Schmitz, Gerd;Schiller, Juergen;Eibisch, Mandy;Hedberg, Christian;Waldmann, Herbert;Lausch, Ekkehart;Tanner, Berno;Sehouli, Jalid;Sagemueller, Jens;Staude, Hagen;Steiner, Eric;Hengstler, Jan G.

    Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and ...


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

Ressources et infrastructures (Biologie)

Cet article passe en revue les perspectives offertes par les techniques de séquençage du génome à l'aide de nanopores

  • Search for Pore-fection
    Science, Vol. 336 (6081), pp. 534-537, 2012 (résumé)
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    Cet article passe en revue les perspectives offertes par les techniques de séquençage du génome à l'aide de nanopores

    “Search for Pore-fection”

    • Pennisi, Elizabeth

    Oxford Nanopore Technologies is set to achieve the first commercialization of a long-awaited and oft-doubted technology called nanopore sequencing. The technology, based on protein pores so tiny that 25,000 of them can fit on the cross section of a human hair, could be the next big thing in genome sequencing and analysis. Although they've gotten much cheaper and smaller in recent years, machines that read DNA and RNA still usually cost hundreds of thousands of dollars, take up entire lab benches, and require much upfront and postsequencing processing to generate a genome. Nanopore sequencing could change all that. But some scientists say many technical hurdles remain to be overcome before nanopore devices produce actual sequence data.


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

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