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Gary M Williams, Marilyn Aardema, John Acquavella, Sir Colin Berry, David Brusick, Michele M Burns, Joao Lauro Viana de Camargo, David Garabrant, Helmut A Greim, Larry D Kier, David J Kirkland, Gary Marsh, Keith R Solomon, Tom Sorahan, Ashley Roberts, Douglas L Weed
The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies...
September 2016: Critical Reviews in Toxicology
Ariel D Quiroga, María P Ceballos, Juan P Parody, Carla G Comanzo, Florencia Lorenzetti, Gerardo B Pisani, María T Ronco, María de L Alvarez, María C Carrilloa
It is accepted that cancer development is associated with metabolic changes. Previously, we established a model of hepatic preneoplasia in which adult rats were subjected to a 2-phase model of hepatocarcinogenesis (initiated-promoted, IP) for 6weeks until they develop altered hepatic foci (AHF). Here, we found that a whole metabolic shift occurs in order to favor cancer development. IP animals presented with increased plasma lipids due to increased VLDL secretion as well as increased liver lipid accretion due to stimulated transacetylase activity rather than lipogenesis, compared to control rats...
August 12, 2016: Biochimica et Biophysica Acta
Jenna R Karras, Morgan S Schrock, Bahadir Batar, Jie Zhang, Krista La Perle, Teresa Druck, Kay Huebner
The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single-base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome "caretaker" whose loss initiates genome instability in preneoplastic lesions...
August 11, 2016: Cancer Science
Gerardo Bruno Pisani, José Luis Valenti, Alejandra Beatriz Quintana
BACKGROUND: Liver preneoplasia development in rats can be mimicked by an initiation-promotion model that induces the appearance of altered hepatocyte foc (FAH). AIMS: We compare two initiation-promotion models to evaluate the presence of FAH or additional hepatic pathologies in which other organs were affected up to five month post treatment. MATERIAL AND METHODS: FAH were induced in male adult Wistar rats with two doses of dietylnitrosamine (DEN, 150 mg/kg bw) followed by 4 doses per week (3 weeks) of 2-acetylaminofluorene (2-AAF, 20 mg/kg bw) or with one dose of DEN (200 mg/kg bw) followed by 2 doses per week (3 weeks) of 2-AAF...
August 2016: Revista Española de Enfermedades Digestivas
Bridget Nelson, Nicole Cray, Yongfeng Ai, Yinan Fang, Peng Liu, Elizabeth M Whitley, Diane Birt
Dietary fiber has been reported to prevent preneoplastic colon lesions. The aim of this study was to determine the effect of resistant starches, novel dietary fibers, on the development of colonic preneoplasia and Wnt signaling in azoxymethane (AOM)-treated rats and mice fed resistant starches at 55% of the diet after AOM treatment. Another objective was to determine the effect of resistant starches on the development of preneoplasia in rats treated with antibiotics (Ab), administered between AOM treatment and resistant starch feeding...
August 2016: Nutrition and Cancer
Matthys Cornelis Van Aardt, Greta Dreyer, Leon Cornelius Snyman, Karin Louise Richter, Piet Becker, Sebolelo Mpho Mojaki
BACKGROUND: In Africa, data on the relationship between oncogenic human papillomavirus (HPV) types, immune status and cervical preinvasive lesions are lacking. METHODS:  We investigated low-risk (lrHPV) and high-risk (hrHPV) HPV types in a cohort of women with cervical intraepithelial neoplasia (CIN) II/III confirmed on histological examination, in an urban setting with a high prevalence of HIV infection. RESULTS:  Of 270 women with confirmed CIN II/III, 45 were HIV-negative and 225 HIV-positive...
June 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
Lukas Tamayo-Orrego, Shannon M Swikert, Frédéric Charron
The mechanisms leading to brain tumor formation are poorly understood. Using Ptch1(+/-) mice as a medulloblastoma model, sequential mutations were found to shape tumor evolution. Initially, medulloblastoma preneoplastic lesions display loss of heterozygosity of the Ptch1 wild-type allele, an event associated with cell senescence in preneoplasia. Subsequently, p53 mutations lead to senescence evasion and progression from preneoplasia to medulloblastoma. These findings are consistent with a model where high levels of Hedgehog signaling caused by the loss of the tumor suppressor Ptch1 lead to oncogene-induced senescence and drive p53 mutations...
May 26, 2016: Cell Cycle
Atsushi Umemura, Feng He, Koji Taniguchi, Hayato Nakagawa, Shinichiro Yamachika, Joan Font-Burgada, Zhenyu Zhong, Shankar Subramaniam, Sindhu Raghunandan, Angeles Duran, Juan F Linares, Miguel Reina-Campos, Shiori Umemura, Mark A Valasek, Ekihiro Seki, Kanji Yamaguchi, Kazuhiko Koike, Yoshito Itoh, Maria T Diaz-Meco, Jorge Moscat, Michael Karin
p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death...
June 13, 2016: Cancer Cell
Jean-Philippe Foy, Antonin Tortereau, Carlos Caulin, Vincent Le Texier, Emilie Lavergne, Emilie Thomas, Sylvie Chabaud, David Perol, Joël Lachuer, Wenhua Lang, Waun Ki Hong, Patrick Goudot, Scott M Lippman, Chloé Bertolus, Pierre Saintigny
A better understanding of the dynamics of molecular changes occurring during the early stages of oral tumorigenesis may help refine prevention and treatment strategies. We generated genome-wide expression profiles of microdissected normal mucosa, hyperplasia, dysplasia and tumors derived from the 4-NQO mouse model of oral tumorigenesis. Genes differentially expressed between tumor and normal mucosa defined the "tumor gene set" (TGS), including 4 non-overlapping gene subsets that characterize the dynamics of gene expression changes through different stages of disease progression...
March 24, 2016: Oncotarget
Lukas Tamayo-Orrego, Chia-Lun Wu, Nicolas Bouchard, Ahmed Khedher, Shannon M Swikert, Marc Remke, Patryk Skowron, Michael D Taylor, Frédéric Charron
How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1(+/-) mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH...
March 29, 2016: Cell Reports
Yiannis Drosos, Geoffrey Neale, Jianming Ye, Leena Paul, Emin Kuliyev, Anirban Maitra, Anna L Means, M Kay Washington, Jerold Rehg, David B Finkelstein, Beatriz Sosa-Pineda
The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas...
March 2016: Neoplasia: An International Journal for Oncology Research
Sylvie Lantuejoul, Isabelle Rouquette, Elisabeth Brambilla, William D Travis
The 2015 WHO classification of tumors of the lung, pleura, thymus and heart has just been published with numerous important changes from the 2004 WHO classification. The most significant changes involve (1) use of immunohistochemistry throughout the classification, (2) integration of molecular testing for personalized strategies for advanced lung cancer patients, (3) a new classification for small biopsies and cytology, (4) a new classification of lung adenocarcinoma as proposed by the 2011 IASLC/ATS/ERS, (5) restriction of the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation...
January 2016: Annales de Pathologie
Benjamin D Simons
Using deep sequencing technology, methods based on the sporadic acquisition of somatic DNA mutations in human tissues have been used to trace the clonal evolution of progenitor cells in diseased states. However, the potential of these approaches to explore cell fate behavior of normal tissues and the initiation of preneoplasia remain underexploited. Focusing on the results of a recent deep sequencing study of eyelid epidermis, we show that the quantitative analysis of mutant clone size provides a general method to resolve the pattern of normal stem cell fate and to detect and characterize the mutational signature of rare field transformations in human tissues, with implications for the early detection of preneoplasia...
January 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Neeta Bagul, Anjali Ganjre, S N Goryawala, Rahul Kathariya, Shrikant Dusane
Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts (MFs). MFs are spindle-shaped cells with stress fibres and well-developed fibronexus, and they display α-smooth muscle actin immunohistochemically and smooth-muscle myofilaments ultrastructurally. MFs play a crucial role in physiological and pathological processes. Derived from various sources, they play pivotal roles not only by synthesizing and producing extracellular matrix components, such as other connective tissue cells, but also are involved in force production...
December 10, 2015: World Journal of Clinical Oncology
Madhav V Dhodapkar, Rachael Sexton, Rituparna Das, Kavita M Dhodapkar, Lin Zhang, Ranjini Sundaram, Sonal Soni, John J Crowley, Robert Z Orlowski, Bart Barlogie
Blockade of immune checkpoints (ICPs) has led to impressive responses in cancer patients. However, the impact of preexisting immunity and ICPs on the risk of malignant transformation in human preneoplasia has not been prospectively studied. We prospectively analyzed antigen-specific B/T-cell immunity, immune composition of the tumor microenvironment, and the expression of a panel of ICPs on tumor and tumor-infiltrating immune cells in 305 patients with asymptomatic monoclonal gammopathy enrolled in S0120 under the auspices of SWOG...
November 26, 2015: Blood
George S Karagiannis, Hara Afaloniati, Elisavet Karamanavi, Theofilos Poutahidis, Katerina Angelopoulou
The suppression of the bone morphogenetic protein (BMP) signaling pathway has been recently shown to promote adenoma-to-carcinoma transition in sporadic colon cancer. However, its role in the evolution of early preneoplastic changes to neoplasia remains elusive. In the present study, we aimed to investigate the gene expression levels of multiple extracellular BMP family constituents, including BMP ligands/receptors and inhibitors, during the early stages of inflammation-associated colon carcinogenesis. For that, we used the recently developed urokinase-type plasminogen activator (uPA)-deficient mouse model of colonic polypoidogenesis, in which adenomatous polyps arise several months after the induction of dextran sodium sulfate (DSS) colitis...
February 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Eva M Serrao, Mikko I Kettunen, Tiago B Rodrigues, Piotr Dzien, Alan J Wright, Aarthi Gopinathan, Ferdia A Gallagher, David Y Lewis, Kristopher K Frese, Jaime Almeida, William J Howat, David A Tuveson, Kevin M Brindle
OBJECTIVES: Pancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging. DESIGN: The concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour...
March 2016: Gut
Cristian Taccioli, Michela Garofalo, Hongping Chen, Yubao Jiang, Guidantonio Malagoli Tagliazucchi, Gianpiero Di Leva, Hansjuerg Alder, Paolo Fadda, Justin Middleton, Karl J Smalley, Tommaso Selmi, Srivatsava Naidu, John L Farber, Carlo M Croce, Louise Y Fong
BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks...
November 2015: Journal of the National Cancer Institute
Marina C Vera, Gerardo B Pisani, María E Biancardi, Hebe Bottai, María de Luján Alvarez, Alejandra B Quintana
BACKGROUND: One established model to induce hepatic preneoplasia (HP) (DEN 150) uses diethylnitrosamine (DEN) as initiator agent and 2-acetylaminofluorene (2-AAF) as a promoter drug. In addition, both chemicals cause liver cholestasis and fibrosis. AIM: We compared DEN 150 model with another adapted by us, DEN 200 to simplify the first one and to evaluate the effectiveness of both treatments to induce HP in rats. MATERIAL AND METHODS: Male Wistar rats were divided in 3 groups: controls; DEN 150 (rats received 2 doses of DEN, 150 mg/kg body weight, 2 weeks apart, and then 2-AAF, 20 mg/kg body weight, 4 doses per week during 3 weeks); and DEN 200 (rats received a single dose of DEN 200 mg/kg body weight, and 2 weeks apart 2-AAF, 20 mg/kg body weight, 2 doses per week during 3 weeks)...
March 2015: Annals of Hepatology
T Tu, W S Mason, A D Clouston, N A Shackel, G W McCaughan, M M Yeh, E R Schiff, A R Ruszkiewicz, J W Chen, H A J Harley, U H Stroeher, A R Jilbert
Hepatocyte clone size was measured in liver samples of 21 patients in various stages of chronic hepatitis B virus (HBV) infection and from 21 to 76 years of age. Hepatocyte clones containing unique virus-cell DNA junctions formed by the integration of HBV DNA were detected using inverse nested PCR. The maximum hepatocyte clone size tended to increase with age, although there was considerable patient-to-patient variation in each age group. There was an upward trend in maximum clone size with increasing fibrosis, inflammatory activity and with seroconversion from HBV e-antigen (HBeAg)-positive to HBeAg-negative, but these differences did not reach statistical significance...
September 2015: Journal of Viral Hepatitis
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