Cet article passe en revue les travaux récents sur les causes de l'hétérogénéité observée à l'intérieur des tumeurs

Intra-tumour heterogeneity: a looking glass for cancer?

Marusyk, Andriy ; Almendro, Vanessa ; Polyak, Kornelia

Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent [...]

Menée sur 31 échantillons tumoraux prélevés sur 31 patients atteints d'un cancer du poumon non à petites cellules, cette étude de séquençage des exons identifie des mutations somatiques de différents gènes, notamment le gène CSMD3 dont la perte induit une prolifération accrue de cellules épithéliales des voies aériennes supérieures

Identification of Somatic Mutations in Non-Small Cell Lung Carcinomas Using Whole-Exome Sequencing

Liu, Pengyuan ; Morrison, Carl ; Wang, Liang ; Xiong, Donghai ; Vedell, Peter ; Cui, Peng ; Hua, Xing ; Ding, Feng ; Lu, Yan ; James, Michael ; Ebben, John ; Xu, Haiming ; Adjei, Alex A. ; Head, Karen ; Andrae, Jaime W. ; Tschannen, Michael R. ; Jacob, Howard ; Pan, Jing ; Zhang, Qi ; Van den Bergh, Francoise ; Xiao, Haijie ; Lo, Ken C. ; Patel, Jigar ; Richmond, Todd ; Watt, Mary-Anne ; Albert, Thomas ; Selzer, Rebecca ; Anderson, Marshall ; Wang, Jiang ; Wang, Yian ; Starnes, Sandra ; Yang, Ping ; You, Ming

Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most of lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole exome sequencing in 31 NSCLC and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas (ADC) and squamous cell [...]

Menée initialement sur 997 échantillons tumoraux prélévés sur des patientes atteintes d'un cancer du sein, puis validée sur 995 échantillons complémentaires, cette étude met en évidence des anomalies de nombres de copies de gènes en association avec le pronostic de la maladie

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

Curtis, Christina ; Shah, Sohrab P. ; Chin, Suet-Feung ; Turashvili, Gulisa ; Rueda, Oscar M. ; Dunning, Mark J. ; Speed, Doug ; Lynch, Andy G. ; Samarajiwa, Shamith ; Yuan, Yinyin ; Graf, Stefan ; Ha, Gavin ; Haffari, Gholamreza ; Bashashati, Ali ; Russell, Roslin ; McKinney, Steven ; Langerod, Anita ; Green, Andrew ; Provenzano, Elena ; Wishart, Gordon ; Pinder, Sarah ; Watson, Peter ; Markowetz, Florian ; Murphy, Leigh ; Ellis, Ian ; Purushotham, Arnie ; Borresen-Dale, Anne-Lise ; Brenton, James D. ; Tavare, Simon ; Caldas, Carlos ; Aparicio, Samuel

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were [...]

Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel un stress chronique, en agissant sur l'expression de p53, favorise une tumorigenèse

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

Feng, Zhaohui ; Liu, Lianxin ; Zhang, Cen ; Zheng, Tongsen ; Wang, Jiabei ; Lin, Meihua ; Zhao, Yuhan ; Wang, Xiaowen ; Levine, Arnold J. ; Hu, Wenwei

Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53+/− mice. The tumor suppressor protein p53 plays a central role in tumor [...]

Cet article passe en revue les travaux récents menés dans un cadre évolutionniste pour analyser le rôle des infections dans l'oncogenèse

Infection, mutation, and cancer evolution

Ewald, Paul ; Swain Ewald, Holly

An understanding of oncogenesis can be fostered by an integration of mechanistic studies with evolutionary considerations, which help explain why these mechanisms occur. This integration emphasizes infections and mutations as joint essential causes for many cancers. It suggests that infections may play a broader causal role in oncogenesis than has been generally appreciated. An evolutionary perspective also suggests that oncogenic viruses will tend to be transmitted by routes that provide [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par l'expression du récepteur des produits de glycation avancée (RAGE) dans les premières étapes d'une cancérogenèse du pancréas

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia

Kang, Rui ; Loux, Tara ; Tang, Daolin ; Schapiro, Nicole E. ; Vernon, Philip ; Livesey, Kristen M. ; Krasinskas, Alyssa ; Lotze, Michael T. ; Zeh, Herbert J.

Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)–mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in [...]

Menée à l'aide d'un modèle murin et sur des échantillons tumoraux prélevés sur des patients atteints d'une leucémie myéloïde chronique, cette étude met en évidence un mécanisme de régulation des cellules souches leucémiques dans le micro-environnement

Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia

Zhang, Bin ; Ho, Yin Wei ; Huang, Qin ; Maeda, Takahiro ; Lin, Allen ; Lee, Sung-uk ; Hair, Alan ; Holyoake, Tessa L ; Huettner, Claudia ; Bhatia, Ravi

We characterized leukemia stem cells (LSC) in chronic phase chronic myelogenous leukemia (CML) using a transgenic mouse model. LSC were restricted to cells with long-term hematopoietic stem cell (LTHSC) phenotype. CML LTHSC demonstrated reduced homing and retention in the bone marrow (BM), related to decreased CXCL12 expression in CML BM, resulting from increased G-CSF production by leukemia cells. Altered cytokine expression in CML BM was associated with selective impairment of normal LTHSC [...]

Menée sur des lignées cellulaires, à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur des patients atteints de mélanome, cette étude met en évidence le rôle joué par la protéine PHIP dans le processus métastatique

Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis

De Semir, David ; Nosrati, Mehdi ; Bezrookove, Vladimir ; Dar, Altaf A. ; Federman, Scot ; Bienvenu, Geraldine ; Venna, Suraj ; Rangel, Javier ; Climent, Joan ; Meyer Tamgüney, Tanja M. ; Thummala, Suresh ; Tong, Schuyler ; Leong, Stanley P. L. ; Haqq, Chris ; Billings, Paul ; Miller, James R. ; Sagebiel, Richard W. ; Debs, Robert ; Kashani-Sabet, Mohammed

Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en activant le récepteur alpha des œstrogènes dans le stroma, l'estradiol favorise la croissance d'un cancer du sein ER-

Stromal ER-alpha promotes tumor growth by normalizing an increased angiogenesis

Pequeux, Christel ; Raymond-Letron, Isabelle ; Blacher, Silvia ; Boudou, Frédéric ; Adlanmerini, Marine ; Fouque, Marie-José ; Rochaix, Philippe ; Noel, Agnes ; Foidart, Jean-Michel ; Krust, Andrée ; Chambon, Pierre ; Brouchet, Laurent ; Arnal, Jean-François ; LENFANT, Françoise B.

Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the pro-tumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-negative tumors. Using different mouse models of ER-negative cancer cells grafted [...]

Cet article compare deux modèles de consentement proposés aux patients pour le don d'échantillons biologiques à des fins de recherche

Consent for Research With Biological Samples: One-Time General Consent Versus a Gift Model

Wendler, David

Technological advances have dramatically increased the scientific value of the hundreds of millions of human tissue and blood samples that are currently stored in laboratories and the tens of millions of new samples that are obtained each year (1, 2). These advances have led to continuing debate over what consent process should be used to obtain and store human biological samples for future research (3). Some commentators argue that, as with other types of research with humans, donors should [...]