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Accueil Nota Bene Cancer V2 Numéro 129 du 27 Mars 2012 Biologie

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Nota Bene Cancer Numéro 129 du 27 Mars 2012 RSS

Biologie

Aberrations chromosomiques

Menée in vitro et in vivo, cette étude met en évidence un mécanisme de nature épigénétique impliquant une protéine, résultat de la fusion des gènes SS18 et SSX, dans l'étiologie d'un sarcome synovial

  • Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics
    Cancer cell, Vol. 21 (3), pp. 333-347, 2012 (article en libre accès)
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    Menée in vitro et in vivo, cette étude met en évidence un mécanisme de nature épigénétique impliquant une protéine, résultat de la fusion des gènes SS18 et SSX, dans l'étiologie d'un sarcome synovial

    “Deconstruction of the SS18-SSX Fusion Oncoprotein Complex: Insights into Disease Etiology and Therapeutics”

    • Su, Le;Sampaio, Arthur V;Jones, Kevin B;Pacheco, Marina;Goytain, Angela;Lin, Shujun;Poulin, Neal;Yi, Lin;Rossi, Fabio M;Kast, Juergen;Capecchi, Mario R;Underhill, T.  Michael;Nielsen, Torsten O

    Synovial sarcoma is a translocation-associated sarcoma where the underlying chromosomal event generates SS18-SSX fusion transcripts. In vitro and in vivo studies have shown that the SS18-SSX fusion oncoprotein is both necessary and sufficient to support tumorigenesis; however, its mechanism of action remains poorly defined. We have purified a core SS18-SSX complex and discovered that SS18-SSX serves as a bridge between activating transcription factor 2 (ATF2) and transducin-like enhancer of split 1 (TLE1), resulting in repression of ATF2 target genes. Disruption of these components by siRNA knockdown or treatment with HDAC inhibitors rescues target gene expression, leading to growth suppression and apoptosis. Together, these studies define a fundamental role for aberrant ATF2 transcriptional dysregulation in the etiology of synovial sarcoma. º SS18-SSX interacts with ATF2 and TLE1 in human synovial sarcoma cells º ATF2 recruits the SS18-SSX complex to specific gene promoters º ...


  • Targeting Epigenetic Misregulation in Synovial Sarcoma
    Cancer cell, Vol. 21 (3), pp. 323-324, 2012 (commentaire en libre accès)
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    Menée in vitro et in vivo, cette étude met en évidence un mécanisme de nature épigénétique impliquant une protéine, résultat de la fusion des gènes SS18 et SSX, dans l'étiologie d'un sarcome synovial

    “Targeting Epigenetic Misregulation in Synovial Sarcoma”

    • Waterfall, Joshua J ; Meltzer, Paul S

    Like many sarcomas, synovial sarcoma is driven by a characteristic oncogenic transcription factor fusion, SS18-SSX. In this issue of Cancer Cell, Su et al. elucidate the protein partners necessary for target gene misregulation and demonstrate a direct effect of histone deacetylase inhibitors on the SS18-SSX complex composition, expression misregulation, and apoptosis.


Mots clés : Sarcome; Biologie (Aberrations chromosomiques)

Menée sur 53 patients atteints d'une néoplasie myéloproliférative qui s'est transformée en leucémie, cette étude de séquençage identifie des mutations du gène SRSF2 associées à la transformation

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    Menée sur 53 patients atteints d'une néoplasie myéloproliférative qui s'est transformée en leucémie, cette étude de séquençage identifie des mutations du gène SRSF2 associées à la transformation

    “Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms reveals recurrent SRSF2 mutations which are associated with adverse outcome”

    • Zhang, Su-Jiang;Rampal, Raajit;Manshouri, Taghi;Patel, Jay;Mensah, Nana;Kayserian, Andrew;Hricik, Todd;Heguy, Adriana;Hedvat, Cyrus;Gönen, Mithat;Kantarjian, Hagop;Levine, Ross L.;Abdel-Wahab, Omar;Verstovsek, Srdan

    Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (p=0.05). Importantly, SRSF2 mutations ...


Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Menée sur des échantillons de tumeurs gastriques et de tissus non cancéreux prélevés sur des patients asiatiques, cette étude de séquençage des ARNs messagers et des micro-ARNs suggère que la protéine AMPK-α, qui intervient dans la régulation du métabolisme, pourrait servir de cible thérapeutique dans cette population

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    Menée sur des échantillons de tumeurs gastriques et de tissus non cancéreux prélevés sur des patients asiatiques, cette étude de séquençage des ARNs messagers et des micro-ARNs suggère que la protéine AMPK-α, qui intervient dans la régulation du métabolisme, pourrait servir de cible thérapeutique dans cette population

    “AMPKα modulation in cancer progression: multilayer integrative transcriptome analysis in Asian gastric cancer”

    • Kim, Yon Hui S;Liang, Han;Liu, Xiuping;Lee, Ju-Seog;Cho, Jae Yong;Cheong, Jae-Ho;Kim, Hoguen;Li, Min;Downey, Thomas;Dyer, Matthew D;Sun, Yongming;Sun, Jingtao;Beasley, Ellen M;Chung, Hyun Cheol;Noh, Sung Hoon;Weinstein, John N;Liu, Chang-Gong;Powis, Garth

    Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and microRNAs). A multi-layer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations and key differentially expressed microRNAs. Through this approach, we identified the central metabolic regulator AMPK-α as a potential functional target in Asian gastric cancer. Further, we experimentally demonstrated the translational relevance of this gene as a ...


Mots clés : Estomac; Biologie (Aberrations chromosomiques)

Cet article passe en revue les travaux récents sur la formation de cellules cancéreuses polyploïdes en association avec le phénomène de cannibalisme cellulaire

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    Cet article passe en revue les travaux récents sur la formation de cellules cancéreuses polyploïdes en association avec le phénomène de cannibalisme cellulaire

    “Mechanisms of Ploidy Increase in Human Cancers: A New Role for Cell Cannibalism”

    • Krajcovic, Matej;Overholtzer, Michael

    Aneuploidy is a hallmark of human cancers originating from abnormal mitoses. Many aneuploid cancer cells also have greater-than-diploid DNA content, suggesting that polyploidy is a common precursor to aneuploidy during tumor progression. Polyploid cells can originate from cell fusion, endoreplication, and cytokinesis failure. Recently we found that cell cannibalism by entosis, a form of cell engulfment involving live cells, also leads to polyploidy, as internalized cells disrupt cytokinesis of their engulfing cell hosts. By this mechanism, cannibalistic cell behavior could promote tumor progression by leading to aneuploidy. Here, we discuss cell cannibalism in cancer and other mechanisms that result in the formation of polyploid cancer cells. Cancer Res; 72(7); 1–6. ©2012 AACR.


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

Oncogènes et suppresseurs de tumeurs

Menée sur un modèle animal (poisson zèbre) de neuroblastome, cette étude met en évidence le rôle d'une activation du gène ALK, associée à une amplification de MYCN, dans la pathogenèse de ce cancer

  • Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis
    Cancer cell, Vol. 21 (3), pp. 362-373, 2012 (article en libre accès)
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    Menée sur un modèle animal (poisson zèbre) de neuroblastome, cette étude met en évidence le rôle d'une activation du gène ALK, associée à une amplification de MYCN, dans la pathogenèse de ce cancer

    “Activated ALK Collaborates with MYCN in Neuroblastoma Pathogenesis”

    • Zhu, Shizhen;Lee, Jeong-Soo;Guo, Feng;Shin, Jimann;Perez-Atayde, Antonio R;Kutok, Jeffery L;Rodig, Scott J;Neuberg, Donna S;Helman, Daniel;Feng, Hui;Stewart, Rodney A;Wang, Wenchao;George, Rani E;Kanki, John P;Look, A.  Thomas

    Amplification of the MYCN oncogene in childhood neuroblastoma is often accompanied by mutational activation of ALK (anaplastic lymphoma kinase), suggesting their pathogenic cooperation. We generated a transgenic zebrafish model of neuroblastoma in which MYCN-induced tumors arise from a subpopulation of neuroblasts that migrate into the adrenal medulla analog following organogenesis. Coexpression of activated ALK with MYCN in this model triples the disease penetrance and markedly accelerates tumor onset. MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. Coexpression of activated ALK with MYCN provides prosurvival signals that block this apoptotic response and allow continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma. º Zebrafish neuroblastomas ...


  • ALK and MYCN: When Two Oncogenes Are Better than One
    Cancer cell, Vol. 21 (3), pp. 325-326, 2012 (commentaire en libre accès)
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    Menée sur un modèle animal (poisson zèbre) de neuroblastome, cette étude met en évidence le rôle d'une activation du gène ALK, associée à une amplification de MYCN, dans la pathogenèse de ce cancer

    “ALK and MYCN: When Two Oncogenes Are Better than One”

    • Liu, Zhihui ; Thiele, Carol J

    Mutations of ALK are frequently observed in MYCN-amplified neuroblastomas and correlate with poor clinical outcome, but how these oncogenes cooperate in neuroblastoma development remains unclear. In this issue of Cancer Cell, Zhu et al. describe a mechanism by which ALK and MYCN synergistically induce neuroblastoma in the zebrafish model system.


Mots clés : Système nerveux central; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par l'expression du gène PFKFB4, un régulateur de l'activité glycolytique, dans le cancer métastatique de la prostate

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    Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par l'expression du gène PFKFB4, un régulateur de l'activité glycolytique, dans le cancer métastatique de la prostate

    “Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival”

    • Ros, Susana;Santos, Claudio R.;Moco, Sofia;Baenke, Franziska;Kelly, Gavin;Howell, Michael;Zamboni, Nicola;Schulze, Almut

    Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial cell line. This approach revealed significant complexity in the metabolic requirements of prostate cancer cells and identified several genes selectively required for their survival. Among these genes was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), an isoform of phosphofructokinase 2 (PFK2). We show that PFKFB4 is required to balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells. Depletion of PFKFB4 inhibited tumor growth in a xenograft model, indicating that it is required under physiologic nutrient levels. PFKFB4 mRNA expression was also found to be greater in metastatic prostate cancer compared with ...


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

Menée in vitro, cette étude met en évidence le rôle de suppresseur de tumeurs joué par CD45, une protéine à activité tyrosine-phosphatase codée par le gène PTPRC, dans la leucémie aiguë lymphoblastique T

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    Menée in vitro, cette étude met en évidence le rôle de suppresseur de tumeurs joué par CD45, une protéine à activité tyrosine-phosphatase codée par le gène PTPRC, dans la leucémie aiguë lymphoblastique T

    “Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia”

    • Porcu, Michaël;Kleppe, Maria;Gianfelici, Valentina;Geerdens, Ellen;De Keersmaecker, Kim;Tartaglia, Marco;Foà, Robin;Soulier, Jean;Cauwelier, Barbara;Uyttebroeck, Anne;Macintyre, Elizabeth;Vandenberghe, Peter;Asnafi, Vahid;Cools, Jan

    The protein tyrosine phosphatase CD45, encoded by the PTPRC gene, is well known as a regulator of B- and T-cell receptor signaling. In addition, CD45 negatively regulates JAK family kinases downstream of cytokine receptors. Here, we report the presence of CD45 inactivating mutations in T-cell acute lymphoblastic leukemia (T-ALL). Loss-of-function mutations of CD45 were detected in combination with activating mutations in IL7R, JAK1 or LCK, and downregulation of CD45 expression caused increased signaling downstream of these oncoproteins. Furthermore, we demonstrate that downregulation of CD45 expression sensitizes T-cells to cytokine stimulation, as observed by increased JAK/STAT signaling, whereas overexpression of CD45 decreases cytokine-induced signaling. Taken together, our data identify a tumor suppressor role for CD45 in T-ALL.


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

Cet article passe en revue les travaux récents sur le métabolisme des cellules cancéreuses et suggère que les anomalies métaboliques constituent une caractéristique essentielle du cancer

  • Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
    Cancer cell, Vol. 21 (3), pp. 297-308, 2012 (article en libre accès)
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    Cet article passe en revue les travaux récents sur le métabolisme des cellules cancéreuses et suggère que les anomalies métaboliques constituent une caractéristique essentielle du cancer

    “Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate”

    • Ward, Patrick S;Thompson, Craig B

    Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer.


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

Progression et métastases

Menée in vitro sur des lignées cellulaires de cancer de la prostate, cette étude identifie un mécanisme par lequel la surexpression du gène Myb favorise la transition épithélio-mésenchymateuse et la résistance à la castration

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    Menée in vitro sur des lignées cellulaires de cancer de la prostate, cette étude identifie un mécanisme par lequel la surexpression du gène Myb favorise la transition épithélio-mésenchymateuse et la résistance à la castration

    “Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance”

    • Srivastava, Sanjeev K.;Bhardwaj, Arun;Singh, Seema;Arora, Sumit;McClellan, Steven;Grizzle, William E.;Reed, Eddie;Singh, Ajay P.

    Myb, a cellular progenitor of v-Myb oncogenes, is amplified in prostate cancer and exhibits greater amplification frequency in hormone-refractory disease. Here, we have investigated the functional significance of Myb in prostate cancer. Our studies demonstrate Myb expression in all prostate cancer cell lines (LNCaP, C4-2, PC3 and DU145) examined, whereas it is negligibly expressed in normal/benign prostate epithelial cells (RWPE1 and RWPE2). Notably, Myb is significantly upregulated, both at transcript (> 60- fold) and protein (>15- fold) levels, in castration-resistant (C4-2) cells as compared to androgen-dependent (LNCaP) prostate cancer cells of the same genotypic lineage. Using loss- and gain- of function approaches, we demonstrate that Myb promotes and sustains cell cycle progression and survival under androgen-supplemented and –deprived conditions, respectively, through induction of cyclins (A1, D1, and E1), Bcl-xL and Bcl2, and downregulation of p27 and Bax. Interestingly, ...


Mots clés : Prostate; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur les cellules souches cancéreuses et discute de la pertinence de ce modèle dans divers types de cancer

  • Cancer Stem Cells: Impact, Heterogeneity, and Uncertainty
    Cancer cell, Vol. 21 (3), pp. 283-296, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur les cellules souches cancéreuses et discute de la pertinence de ce modèle dans divers types de cancer

    “Cancer Stem Cells: Impact, Heterogeneity, and Uncertainty”

    • Magee, Jeffrey A;Piskounova, Elena;Morrison, Sean J

    The differentiation of tumorigenic cancer stem cells into nontumorigenic cancer cells confers heterogeneity to some cancers beyond that explained by clonal evolution or environmental differences. In such cancers, functional differences between tumorigenic and nontumorigenic cells influence response to therapy and prognosis. However, it remains uncertain whether the model applies to many, or few, cancers due to questions about the robustness of cancer stem cell markers and the extent to which existing assays underestimate the frequency of tumorigenic cells. In cancers with rapid genetic change, reversible changes in cell states, or biological variability among patients, the stem cell model may not be readily testable.


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

Cet article passe en revue le rôle du micro-environnement tumoral et de ses interactions avec les cellules cancéreuses dans la progression d'un cancer

  • Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
    Cancer cell, Vol. 21 (3), pp. 309-322, 2012 (résumé)
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    Cet article passe en revue le rôle du micro-environnement tumoral et de ses interactions avec les cellules cancéreuses dans la progression d'un cancer

    “Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment”

    • Hanahan, Douglas;Coussens, Lisa M

    Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy.


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

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