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10 results on '"MESH: Carcinogenesis"'

1. Prioritization of mycotoxins based on mutagenicity and carcinogenicity evaluation using combined in silico QSAR methods

Author

Pierre Lemée, Valérie Fessard, Denis Habauzit, Laboratoire de Fougères - ANSES, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), This research was supported by the Interreg Agritox project EAPA-998-2018 and ANSES., and European Project: EAPA-998-2018

Subjects
Génotoxicité, Health, Toxicology and Mutagenesis, metabolite, MESH: Mutagenicity Tests, Toxicology, MESH: Carcinogens, MESH: Computer Simulation, métabolite, MESH: Mutagens, carcinogenicity, mutagénicité, prédiction, Toxicity prediction, database, base de données, Mycotoxin, MESH: Quantitative Structure-Activity Relationship, QSAR, mutagenicity, toxicologie, cancérogénicité, General Medicine, MESH: Carcinogenesis, Pollution, NAMs, NAM, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Genotoxicity, Mycotoxine
Abstract

International audience; Mycotoxins and their metabolites are a family of compounds that contains a great diversity of both structure and biological properties. Information on their toxicity is spread within several databases and in scientific literature. Due to the number of molecules and their structure diversity, the cost and time required for hazard evaluation of each compound is unrealistic. In that purpose, new approach methodologies (NAMs) can be applied to evaluate such large set of molecules. Among them, quantitative structure-activity relationship (QSAR) in silico models could be useful to predict the mutagenic and carcinogenic properties of mycotoxins. First, a complete list of 904 mycotoxins and metabolites was built. Then, some known mycotoxins were used to determine the best QSAR tools for mutagenicity and carcinogenicity predictions. The best tool was further applied to the whole list of 904 mycotoxins. At the end, 95 mycotoxins were identified as both mutagen and carcinogen and should be prioritized for further evaluation.

Published
2023

2. Lipid metabolism and Calcium signaling in epithelial ovarian cancer

Author

Aurélie Chantôme, Marie Potier-Cartereau, Sana Kouba, Caroline Goupille, Christophe Vandier, Lobna Ouldamer, Céline Garcia, Delphine Fontaine, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de gynécologie-obstétrique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Gynécologie-Obstétrique [CHRU Tours], and CCSD, Accord Elsevier

Subjects
0301 basic medicine, endocrine system diseases, Physiology, Carcinogenesis, Disease, medicine.disease_cause, Pathogenesis, chemistry.chemical_compound, 0302 clinical medicine, Lysophosphatidic acid, Medicine, MESH: Animals, Calcium signaling, MESH: Lipid Metabolism, Ovarian Neoplasms, Arachidonic Acid, MESH: Risk, MESH: Carcinogenesis, female genital diseases and pregnancy complications, 3. Good health, MESH: Ovarian Neoplasms, MESH: Epithelial Cells, Female, Risk, MESH: Receptor Cross-Talk, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Calcium Signaling, MESH: Lysophospholipids, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Animals, Humans, Calcium Signaling, Molecular Biology, MESH: Humans, business.industry, Lipid metabolism, Epithelial Cells, Cell Biology, Lipid signaling, Receptor Cross-Talk, Lipid Metabolism, MESH: Arachidonic Acid, 030104 developmental biology, chemistry, Cancer cell, Cancer research, Lysophospholipids, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Epithelial Ovarian cancer (EOC) is the deadliest gynecologic malignancy and represents the fifth leading cause of all cancer-related deaths in women. The majority of patients are diagnosed at an advanced stage of the disease that has spread beyond the ovaries to the peritoneum or to distant organs (stage FIGO III-IV) with a 5-year overall survival of about 29%. Consequently, it is necessary to understand the pathogenesis of this disease. Among the factors that contribute to cancer development, lipids and ion channels have been described to be associated to cancerous diseases particularly in breast, colorectal and prostate cancers. Here, we reviewed the literature data to determine how lipids or lipid metabolites may influence EOC risk or progression. We also highlighted the role and the expression of the calcium (Ca2+) and calcium-activated potassium (KCa) channels in EOC and how lipids might regulate them. Although lipids and some subclasses of nutritional lipids may be associated to EOC risk, lipid metabolism of LPA (lysophosphatidic acid) and AA (arachidonic acid) emerges as an important signaling network in EOC. Clinical data showed that they are found at high concentrations in EOC patients and in vitro and in vivo studies referred to them as triggers of the Ca2+entry in the cancer cells inducing their proliferation, migration or drug resistance. The cross-talk between lipid mediators and Ca2+ and/or KCa channels needs to be elucidated in EOC in order to facilitate the understanding of its outcomes and potentially suggest novel therapeutic strategies including treatment and prevention.

Published
2019

3. Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

Author

Didier Jean, Marie-Claude Jaurand, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-Oncologie [Paris] (Université Paris Descartes - Sorbonne Paris Cité), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire de Technologie - Saint-Denis (IUT Saint-Denis), Université Sorbonne Paris Nord, and Jean, Didier

Subjects
0301 basic medicine, Mesothelioma, Lung Neoplasms, Review, Gene mutation, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Epithelium, lcsh:Chemistry, Animals, Genetically Modified, Mice, 0302 clinical medicine, CDKN2A, MESH: Animals, lcsh:QH301-705.5, Lung, Spectroscopy, Mutation, General Medicine, MESH: Carcinogenesis, 3. Good health, Computer Science Applications, MESH: Neoplasms, Experimental, 030220 oncology & carcinogenesis, malignant mesothelioma, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], carcinogenesis, MESH: Mutation, MESH: Rats, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Catalysis, Inorganic Chemistry, MESH: Animals, Genetically Modified, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, mesothelium, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, Neoplastic transformation, MESH: Lung, Physical and Theoretical Chemistry, Molecular Biology, Gene, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, gene mutations, MESH: Humans, MESH: Mesothelioma, Organic Chemistry, Mesothelioma, Malignant, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Neoplasms, Experimental, medicine.disease, Rats, MESH: Lung Neoplasms, MESH: Epithelium, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cancer research, mineral fibres, tumor suppressor genes, Carcinogenesis, signalling pathways
Abstract

International audience; Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by Cdkn2a and Trp53 seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation.

Published
2018

4. Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of the oncogenic protein AEG-1 and activation of AMP-activated protein kinase (AMPK)

Author

Hossam M. Draz, Alexander A. Goldberg, J. Thomas Sanderson, Stephen Safe, Vladimir I. Titorenko, Emma S. Tomlinson Guns, National Research Centre - NRC (EGYPT), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), McGill University = Université McGill [Montréal, Canada], Concordia University [Montreal], University of British Columbia (UBC), Texas A&M University [College Station], and This work was funded by an operating grant from the Canadian Institutes of Health Research (CIHR grant no. MOP-115019) to JTS, EG and SS. HD received a scholarship from the Fonds de Recherche du Québec - Santé (FRQS). All authors declare to have no conflicts of interest.

Subjects
Male, 0301 basic medicine, AMPK, MESH: Signal Transduction, Indoles, Halogenation, genetic structures, Carcinogenesis, [SDV]Life Sciences [q-bio], Apoptosis, AMP-Activated Protein Kinases, 0302 clinical medicine, AMP-activated protein kinase, MESH: RNA, Small Interfering, MESH: AMP-Activated Protein Kinases, RNA, Small Interfering, MESH: Indoles, Prostate cancer, biology, Chemistry, LNCaP, RNA-Binding Proteins, MESH: Carcinogenesis, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, AEG-1, Signal Transduction, Atg1, MESH: Cell Line, Tumor, Diindolylmethane, 03 medical and health sciences, Cell Line, Tumor, Autophagy, Humans, MESH: Autophagy, C42B, Protein kinase A, MESH: Halogenation, MESH: Humans, MESH: Apoptosis, Membrane Proteins, Prostatic Neoplasms, Cell Biology, MESH: Male, 030104 developmental biology, MESH: Prostatic Neoplasms, Cancer cell, biology.protein, sense organs, Cell Adhesion Molecules
Abstract

International audience; 3,3'-Diindolylmethane (DIM) and its synthetic halogenated derivatives 4,4'-Br2- and 7,7'-Cl2DIM (ring-DIMs) have recently been shown to induce protective autophagy in human prostate cancer cells. The mechanisms by which DIM and ring-DIMs induce autophagy have not been elucidated. As DIM is a mitochondrial ATP-synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of intracellular AMP/ATP ratios and activation of AMP-activated protein kinase (AMPK) signaling in prostate cancer cells. We found that DIM and ring-DIMs induced autophagy was accompanied by increased autophagic vacuole formation and conversion of LC3BI to LC3BII in LNCaP and C42B human prostate cancer cells. DIM and ring-DIMs also induced AMPK, ULK-1 (unc-51-like autophagy activating kinase 1; Atg1) and acetyl-CoA carboxylase (ACC) phosphorylation in a time-dependent manner. DIM and the ring-DIMs time-dependently induced the oncogenic protein astrocyte-elevated gene 1 (AEG-1) in LNCaP and C42B cells. Downregulation of AEG-1 or AMPK inhibited DIM- and ring-DIM-induced autophagy. Pretreatment with ULK1 inhibitor MRT 67307 or siRNAs targeting either AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with overtly cytotoxic concentrations of DIM or ring-DIMs and inhibited the onset of apoptosis in response to these compounds. In summary, we have identified a novel mechanism for DIM- and ring-DIM-induced protective autophagy, via induction of AEG-1 and subsequent activation of AMPK. Our findings could facilitate the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants.

Published
2017

5. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Author

Dustin G. Brown, Tove Hultman, Judith Weisz, H. Kim Lyerly, Paola A. Marignani, Ann-Karin Olsen, Rabindra Roy, Kim Moorwood, Masoud H. Manjili, Monica Vaccari, Jesse Roman, Hasiah Ab Hamid, Kalan R. Prudhomme, Periyadan K. Krishnakumar, Chenfang Dong, Tiziana Guarnieri, Leandro S. D'Abronzo, Gloria M. Calaf, Amelia K Charles, Emanuela Corsini, Yunus A. Luqmani, Graeme Williams, Louis Vermeulen, Pankaj Vadgama, Sarah N Bay, Véronique Maguer-Satta, Sabine A. S. Langie, Christian C. Naus, Le Jian, Gladys N. Nangami, Lorenzo Memeo, Stephanie C. Casey, Thomas Sanderson, Takemi Otsuki, Nichola Cruickshanks, William H. Bisson, Sudjit Luanpitpong, Jonathan Whitfield, Ahmed Lasfar, Yon Rojanasakul, A. Ivana Scovassi, Shelley A. Harris, Ferdinando Chiaradonna, Richard Ponce-Cusi, Gregory T. Wolf, Valérian Dormoy, Roslida Abd Hamid, Hyun Ho Park, Matilde E. Lleonart, William K. Decker, Maria Romano, Leroy Lowe, Fabio Marongiu, Jan Vondráček, Chiara Mondello, Luc Leyns, Josiah Ochieng, Pratima Nangia-Makker, Edward A. Ratovitski, Zhiwei Hu, Jayadev Raju, Hemad Yasaei, Rafaela Andrade-Vieira, Jordan Woodrick, Hideko Sone, Harini Krishnan, W. Kimryn Rathmell, Andrew Collins, Luoping Zhang, Barry J. Barclay, Amaya Azqueta, Laura Soucek, Marc A. Williams, David O. Carpenter, Roberta Palorini, Rita Nahta, Juan Fernando Martinez-Leal, Firouz Darroudi, Rita Dornetshuber-Fleiss, James E. Klaunig, Elizabeth P. Ryan, Qiang Shawn Cheng, Arthur Berg, Andrew Ward, Gudrun Koppen, Tao Chen, Petr Heneberg, Michael Gilbertson, Amedeo Amedei, Sakina E. Eltom, Ezio Laconi, Joseph Christopher, Hiroshi Kondoh, Neetu Singh, Danielle J Carlin, Marion Chapellier, Michalis V. Karamouzis, Rekha Mehta, Tae-Jin Lee, Annamaria Colacci, Venkata S. Sabbisetti, Mark Wade, Micheline Kirsch-Volders, Patricia Ostrosky-Wegman, Isabelle R. Miousse, Patricia A. Thompson, Philippa D. Darbre, Frederik J. van Schooten, Sofia Pavanello, Igor Koturbash, Binhua P. Zhou, Ranjeet Kumar Sinha, Anna C. Salzberg, Mahara Valverde, Fahd Al-Mulla, Julia Kravchenko, Nicole Kleinstreuer, Carolyn J. Baglole, Menghang Xia, Samira A. Brooks, Amancio Carnero, Gunnar Brunborg, Sandra S. Wise, Daniel C. Koch, John Pierce Wise, Rabeah Al-Temaimi, Laetitia Gonzalez, Lisa J. McCawley, R. Brooks Robey, Gary S. Goldberg, Thierry Massfelder, Linda S M Gulliver, Olugbemiga Ogunkua, Emilio Rojas, Eun-Yi Moon, Lin Li, Silvana Papagerakis, Nik van Larebeke, Adela Lopez de Cerain Salsamendi, Staffan Eriksson, Simona Romano, Dean W. Felsher, Paramita M. Ghosh, Karine A. Cohen-Solal, Paul Dent, Jun Sun, Carmen Blanco-Aparicio, Riccardo Di Fiore, Chia-Wen Hsu, Mahin Khatami, Kannan Badri Narayanan, Francis Martin, Colleen S. Curran, Dale W. Laird, William H. Goodson, Abdul Manaf Ali, Valerie Odero-Marah, Michael J. Gonzalez, Renza Vento, Liang Tzung Lin, Clement G. Yedjou, Hosni Salem, Hsue-Yin Hsu, Zhenbang Chen, Nuzhat Ahmed, Gerard Wagemaker, Sandra Ryeom, Stefano Forte, Debasish Roy, Nancy B. Kuemmerle, Robert C. Castellino, Po Sing Leung, Wilhelm Engström, National Institute of Environmental Health Sciences (US), Research Council of Norway, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Junta de Andalucía, Ministerio de Educación y Ciencia (España), Ministero dell'Istruzione, dell'Università e della Ricerca, University of Oslo, Regione Emilia Romagna, National Institutes of Health (US), Consejo Nacional de Ciencia y Tecnología (México), Associazione Italiana per la Ricerca sul Cancro, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Ministry of Education, Culture, Sports, Science and Technology (Japan), Japan Science and Technology Agency, Ministry of Science and Technology (Taiwan), Arkansas Biosciences Institute, Czech Science Foundation, Fundación Fero, Swim Across America, American Cancer Society, Research Foundation - Flanders, Austrian Science Fund, Institut National de la Santé et de la Recherche Médicale (France), Natural Sciences and Engineering Research Council of Canada, Farmacologie en Toxicologie, RS: NUTRIM - R4 - Gene-environment interaction, Goodson, William H, Lowe, Leroy, Carpenter, David O, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K, Collins, Andrew R, Ward, Andrew, Salzberg, Anna C, Colacci, Annamaria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J, Zhou, Binhua P, Blanco Aparicio, Carmen, Baglole, Carolyn J, Dong, Chenfang, Mondello, Chiara, Hsu, Chia Wen, Naus, Christian C, Yedjou, Clement, Curran, Colleen S, Laird, Dale W, Koch, Daniel C, Carlin, Danielle J, Felsher, Dean W, Roy, Debasish, Brown, Dustin G, Ratovitski, Edward, Ryan, Elizabeth P, Corsini, Emanuela, Rojas, Emilio, Moon, Eun Yi, Laconi, Ezio, Marongiu, Fabio, Al Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L, Van Schooten, Frederik J, Goldberg, Gary S, Wagemaker, Gerard, Nangami, Gladys N, Calaf, Gloria M, Williams, Graeme, Wolf, Gregory T, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K, Hsu, Hsue Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, Isabelle R, Scovassi, A. Ivana, Klaunig, James E, Vondráček, Jan, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, Jonathan R, Woodrick, Jordan, Christopher, Joseph A, Ochieng, Josiah, Martinez Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R, Narayanan, Kannan Badri, Cohen Solal, Karine A, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D'Abronzo, Leandro S, Lin, Liang Tzung, Li, Lin, Gulliver, Linda, Mccawley, Lisa J, Memeo, Lorenzo, Vermeulen, Loui, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, MARIA FIAMMETTA, Chapellier, Marion, Williams, Marc A, Wade, Mark, Manjili, Masoud H, Lleonart, Matilde E, Xia, Menghang, Gonzalez, Michael J, Karamouzis, Michalis V, Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B, Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K, Vadgama, Pankaj, Marignani, Paola A, Ghosh, Paramita M, Ostrosky Wegman, Patricia, Thompson, Patricia A, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Sing Leung, Po, Nangia Makker, Pratima, Cheng, Qiang Shawn, Robey, R. Brook, Al Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C, Palorini, Roberta, Abd Hamid, Roslida, Langie, Sabine A. S, Eltom, Sakina E, Brooks, Samira A, Ryeom, Sandra, Wise, Sandra S, Bay, Sarah N, Harris, Shelley A, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C, Luanpitpong, Sudjit, Lee, Tae Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thoma, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Marah, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K, Bisson, William H, Rojanasakul, Yon, Luqmani, Yunu, Chen, Zhenbang, Hu, Zhiwei, Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondráček, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L., Lin, L., Li, L., Gulliver, L., Mccawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M., Chapellier, M., Williams, M., Wade, M., Manjili, M., Lleonart, M., Xia, M., Gonzalez, M., Karamouzis, M., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P., Vadgama, P., Marignani, P., Ghosh, P., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P., Nangia-Makker, P., Cheng, Q., Brooks Robey, R., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R., Palorini, R., Hamid, R., Langie, S., Eltom, S., Brooks, S., Ryeom, S., Wise, S., Bay, S., Harris, S., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Kimryn Rathmell, W., Engström, W., Decker, W., Bisson, W., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z., Goodson, W.H., Carpenter, D.O., Ali, A.M., de Cerain Salsamendi, A.L., Charles, A.K., Collins, A.R., Salzberg, A.C., Olsen, A.-K., Barclay, B.J., Zhou, B.P., Baglole, C.J., Hsu, C.-W., Naus, C.C., Curran, C.S., Laird, D.W., Koch, D.C., Carlin, D.J., Felsher, D.W., Brown, D.G., Ryan, E.P., Moon, E.-Y., Martin, F.L., Van Schooten, F.J., Goldberg, G.S., Calaf, G.M., Wolf, G.T., Hamid, H.A., Salem, H.K., Hsu, H.-Y., Park, H.H., Miousse, I.R., Klaunig, J.E., Vondracek, J., Wise, J.P., Whitfield, J.R., Christopher, J.A., Martinez-Leal, J.F., Prudhomme, K.R., Narayanan, K.B., Cohen-Solal, K.A., D'Abronzo, L.S., Lin, L.-T., Mccawley, L.J., Romano, M.F., Williams, M.A., Manjili, M.H., Gonzalez, M.J., Karamouzis, M.V., Kuemmerle, N.B., Krishnakumar, P.K., Marignani, P.A., Ghosh, P.M., Leung, P.S., Cheng, Q.S., Sinha, R.K., Castellino, R.C., Hamid, R.A., Langie, S.A.S., Brooks, S.A., Wise, S.S., Bay, S.N., Harris, S.A., Casey, S.C., Lee, T.-J., Engstrom, W., Decker, W.K., Bisson, W.H., sans affiliation, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276), Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript, William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation, Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia, Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey, Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012), Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support, Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012), Andrew R.Collins was supported by the University of Oslo, Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy, Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S), Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370), Christian C.Naus holds a Canada Research Chair, Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581), Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151, Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964), Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS), Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea, Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06), Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro, IG 15364), Francis L.Martin acknowledges funding from Rosemere Cancer Foundation, he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years, Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation, Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA), Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium, Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697), Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST, Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002), Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449), Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S), Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health, Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain, Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology, Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback, Jun Sun is supported by a Swim Across America Cancer Research Award, Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE), Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07), Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain, Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19), Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand, Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164), Mahara Valverde would like to thank CONACyT support 153781, Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India, Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C), P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association, Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774), Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y, Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021, Qiang Cheng was supported in part by grant NSF IIS-1218712, R. Brooks Robey is supported by the United States Department of Veterans Affairs, Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447), Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007, Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013), Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung, Roberta Palorini is supported by a SysBioNet fellowship, Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165, Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013, Sakina Eltom is supported by NIH grant SC1CA153326, Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship, Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation, Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg, Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR, MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC, 313313) and the California Breast Cancer Research Program (CBCRP, 17UB-8703), Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy, W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society, William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas, William H.Bisson was supported with funding from the NIH P30 ES000210, Yon Rojanasakul was supported with NIH grant R01-ES022968, Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593), Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program., Sans affiliation, Courcelles, Michel, Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z

Subjects
Cancer Research, Carcinogenesis, [SDV]Life Sciences [q-bio], METHOXYCHLOR-INDUCED ALTERATIONS, Review, Pharmacology, MESH: Carcinogens, Environmental, Carcinogenic synergies, Chemical mixtures, Neoplasms, MESH: Animals, MESH: Neoplasms, Carcinogenesi, Risk assessment, Cancer, ACTIVATED PROTEIN-KINASES, Medicine (all), Low dose, 1. No poverty, Cumulative effects, BREAST-CANCER CELLS, General Medicine, Environmental exposure, MESH: Carcinogenesis, BIO/10 - BIOCHIMICA, EPITHELIAL-MESENCHYMAL TRANSITION, 3. Good health, [SDV] Life Sciences [q-bio], Environmental Carcinogenesis, ESTROGEN-RECEPTOR-ALPHA, Human, MESH: Environmental Exposure, ENDOCRINE-DISRUPTING CHEMICALS, TARGETING TISSUE FACTOR, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Prototypical chemical disruptors, Exposure, [SDV.CAN] Life Sciences [q-bio]/Cancer, Environmental health, medicine, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Carcinogen, Environmental carcinogenesis, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Animal, POLYBROMINATED DIPHENYL ETHERS, Environmental Exposure, medicine.disease, MESH: Hazardous Substances, Carcinogens, Environmental, MIGRATION INHIBITORY FACTOR, VASCULAR ENDOTHELIAL-CELLS, Hazardous Substance, Neoplasm
Abstract

Goodson, William H. et al., © The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964); Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program.

Published
2015

6. New roles for Dicer in the nucleolus and its relevance to cancer

Author

Benjamin Roche, Robert A. Martienssen, Benoit Arcangioli, Cold Spring Harbor Laboratory (CSHL), Dynamique du Génome - Dynamics of the genome, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was funded by NIH grant R01 GM076396-08, the Howard Hughes Medical Institute and Gordon and Betty Moore Foundation Plant Biology Investigator Program (to R.M.), and the Agence Nationale de la Recherche grant ANR-13-BSV8-0018 (to B.A.). The authors acknowledge support from the Chaire Blaise Pascal (Fondation de I'École Normale Supérieure, France)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ribonuclease III, 0301 basic medicine, Carcinogenesis, Nucleolus, Ribosome biogenesis, rDNA, Biology, DNA, Ribosomal, 03 medical and health sciences, MESH: Ribonuclease III, Transcription (biology), Neoplasms, RNA polymerase I, Animals, Humans, Gene silencing, PTEN, cancer, Genes, Tumor Suppressor, MESH: Animals, MESH: Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, nucleolus, Molecular Biology, Genetics, dicer, MESH: DNA, Ribosomal, MESH: Humans, epigenetics, Extra View, Cell Biology, MESH: Carcinogenesis, MESH: Genes, Tumor Suppressor, biology.organism_classification, 030104 developmental biology, Schizosaccharomyces pombe, biology.protein, MESH: Cell Nucleolus, Cell Nucleolus, Developmental Biology, Dicer
Abstract

International audience; The nucleolus is a distinct compartment of the nucleus responsible for ribosome biogenesis. Mis-regulation of nucleolar functions and of the cellular translation machinery has been associated with disease, in particular with many types of cancer. Indeed, many tumor suppressors (p53, Rb, PTEN, PICT1, BRCA1) and proto-oncogenes (MYC, NPM) play a direct role in the nucleolus, and interact with the RNA polymerase I transcription machinery and the nucleolar stress response. We have identified Dicer and the RNA interference pathway as having an essential role in the nucleolus of quiescent Schizosaccharomyces pombe cells, distinct from pericentromeric silencing, by controlling RNA polymerase I release. We propose that this novel function is evolutionarily conserved and may contribute to the tumorigenic pre-disposition of DICER1 mutations in mammals.

Published
2017

7. Microbiota, Inflammation and Colorectal Cancer

Author

Lucas, Cecily, BARNICH, Nicolas, Nguyen, Hang Thi Thu, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Ministere de la Recherche et de la Technologie, Inserm UMR1071, INRA (USC), European Union FP7 People Marie Curie International Incoming Fellowship, 'Nouveau chercheur' grant from Region Auvergne, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Université Clermont Auvergne (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), and Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)

Subjects
MESH: Inflammation, intestinal microbiota, endotoxin, colorectal cancer, inflammation, genotoxins, host-pathogen interaction, Carcinogenesis, [SDV]Life Sciences [q-bio], MESH: Cell Cycle, microbiote digestif, Review, Adaptive Immunity, endotoxine, MESH: Gastrointestinal Microbiome, lcsh:Chemistry, MESH: Risk Factors, Risk Factors, MESH: Mutagens, Humans, lcsh:QH301-705.5, MESH: Humans, Bacteria, MESH: Host-Pathogen Interactions, Cell Cycle, interaction hôte pathogène, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Carcinogenesis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immunity, Innate, Gastrointestinal Microbiome, MESH: Bacteria, Cell Transformation, Neoplastic, lcsh:Biology (General), lcsh:QD1-999, MESH: Cell Transformation, Neoplastic, Food, cancer colorectal, Host-Pathogen Interactions, MESH: Immunity, Innate, Colorectal Neoplasms, colorectal neoplasm, MESH: Adaptive Immunity, MESH: Food, MESH: Colorectal Neoplasms, host pathogen systems, Mutagens
Abstract

International audience; Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the intestinal microbiota composition in colorectal cancer patients compared to control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. This review will summarize the current knowledge about the potential links between the intestinal microbiota and colorectal cancer, with a focus on the pro-carcinogenic properties of bacterial microbiota such as induction of inflammation, the biosynthesis of genotoxins that interfere with cell cycle regulation and the production of toxic metabolites. Finally, we will describe the potential therapeutic strategies based on intestinal microbiota manipulation for colorectal cancer treatment.

Published
2017

8. PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development

Author

Drelon, Coralie, Berthon, Annabel, Sahut-Barnola, Isabelle, Mathieu, Mickael, Dumontet, Typhanie, Rodriguez, Stéphanie, Batisse-Lignier, Marie, Tabbal, Houda, Tauveron, Igor, Martinez, Anne-Marie, Pointud, Jean-Christophe, Gomez-Sanchez, Celso, Vainio, Seppo, Shan, Jingdong, Val, Sonia, Val, Andreas, Stratakis, Constantine, Martinez, Antoine, VAL, Pierre, Lefrançois-Martinez, Marie, Sacco, Sonia, Schedl, Andreas, Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Interactions génétiques et cellulaires au cours de la différenciation, Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, University of Mississippi Medical Center (UMMC), Laboratory of Developmental Biology, Department of Medical Biochemistry and Molecular Biology, University of Oulu and Biocenter Oulu, Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD ), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Universitaire Lorrain d'Histoire (CRULH), Université de Lorraine (UL), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Génétique du développement normal et pathologique, and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Carcinogenesis, Cellular differentiation, MESH: beta Catenin, Adrenal Gland Neoplasms, General Physics and Astronomy, MESH: Zona Fasciculata, Mice, chemistry.chemical_compound, WNT4, MESH: Animals, Phosphorylation, Wnt Signaling Pathway, beta Catenin, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Aldosterone, biology, Adrenal cortex, Wnt signaling pathway, MESH: Wnt Signaling Pathway, Cell Differentiation, MESH: Carcinogenesis, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Cell biology, medicine.anatomical_structure, Female, Zona Glomerulosa, MESH: Cell Differentiation, endocrine system, medicine.medical_specialty, Beta-catenin, MESH: Cell Line, Tumor, MESH: Zona Glomerulosa, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Cyclic AMP-Dependent Protein Kinases, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Zona fasciculata, Cell Line, Tumor, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, MESH: Mice, MESH: Humans, MESH: Phosphorylation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Cyclic AMP-Dependent Protein Kinases, MESH: Adrenal Gland Neoplasms, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Endocrinology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, chemistry, Zona glomerulosa, biology.protein, Zona Fasciculata, MESH: Female
Abstract

Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates β-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling., The adrenal cortex undergoes functional zonation to generate an outer zona glomerulosa (ZG) and inner zona fasciculata (ZF), but how this is regulated at a molecular level is unclear. Here, the authors show that ZG differentiation is stimulated by WNT signalling and that PKA blocks WNT signalling to allow ZF differentiation and also prevents WNT-induced cancer development.

Published
2016

9. Association of HLA-G+3142 C > G polymorphism and breast cancer in Tunisian population

Author

Hanene Chelbi, Ahmed Baligh Laaribi, Refaat Sebai, Amel Mezlini, Hamza Ben Yahia, Amna Ben Hassine, Olfa Dziri, Nour Zidi, Wafa Babay, Nadia Boujelebene, Hela Rifi, Inès Zidi, Université de Tunis El Manar (UTM), Departement Medecine Oncologique [Tunis], Institut Salah Azaiz [Tunis] (ISA), Departement Anatomopathologie [ISA, Tunis], Laboratoire de Parasitologie Médicale, Biotechnologies et Biomolécules (LR11IPT06), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis (FST)

Subjects
Carcinogenesis, MICRORNAS, [SDV]Life Sciences [q-bio], VARIANTS, SUSCEPTIBILITY, medicine.disease_cause, 0302 clinical medicine, Breast cancer, Gene Frequency, HLA-G, Genotype, ANTIGEN-G EXPRESSION, MESH: Breast Neoplasms/pathology, Sequence Deletion, MESH: Genetic Association Studies, MESH: Genotype, Genetics, MESH: Aged, MESH: Middle Aged, MESH: Risk, PLASMA, Age Factors, MESH: Genetic Predisposition to Disease, MESH: Neoplasm Staging, Middle Aged, MESH: Carcinogenesis, +G%22">+3142 C > G, 3. Good health, MESH: Breast Neoplasms/genetics, SHLA-G MOLECULES, 030220 oncology & carcinogenesis, +3142 C&gt, SECRETION, Female, MESH: Tunisia, Adult, Risk, Tunisia, HLA-G GENE, CARCINOMA, Immunology, Breast Neoplasms, Human leukocyte antigen, Biology, REGION, 03 medical and health sciences, MESH: Polymorphism, Genetic, medicine, Carcinoma, MESH: Gene Frequency, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, MESH: HLA-G Antigens/genetics, Allele frequency, Genetic Association Studies, Aged, Neoplasm Staging, HLA-G Antigens, MESH: Age Factors, 14-bp Insertion/deletion, Polymorphism, Genetic, MESH: Humans, MESH: Sequence Deletion/genetics, MESH: Adult, medicine.disease, Molecular biology, MESH: Female, 030215 immunology
Abstract

International audience; HLA-G is highly expressed in cancer. Also, it is associated to its progression. Here, we explored the relationship between two HLA-G polymorphisms with breast cancer (BC) and tried to make a correlation with sHLA-G levels. We genotyped 104 patients with BC and 83 controls (CTRL) for HLA-G 14-bp insertion/deletion (Ins/Del) and HLA-G +3142 C > G polymorphisms. The mutations were identified with PCR and PCR-RFLP. The sHLA-G dosage was performed on plasma samples by a specific ELISA. A significant association with BC was found concerning the G allele in the +3142 C > G polymorphism (p = 0.0004). The G/G genotype is the protective genotype (1 % in BC patients vs. 13.1 % in CTRL, OR 0.065, 95 % CI 0.008-0.523). No statistically significant differences were observed for the 14-bp Ins/Del polymorphism between BC patients and controls frequencies. The protection by G/G genotype of +3142 C > G polymorphism is maintained in young patients (< 50 years, p = 0.0006) and in early-diagnosed BC patients (< 50 years, p = 0.0033). In addition, an association was found between the haplotypes inferred by both HLA-G polymorphisms and BC susceptibility. Indeed, the (DelG) haplotype is found as the protective haplotype against BC (OR 0.269, 95 % CI 0.081-0.895, p = 0.023). The ELISA dosage of sHLA-G revealed increased levels in BC compared to CTRL (p < 0.0001). We demonstrated also that sHLA-G is closely associated with advanced stages of BC without significance. sHLA-G is increased in TNM IV and SBR III subgroups. It is also enhanced in patients with a tumor size over 20 mm and in triple-negative patients. Taken together, our findings demonstrate, for the first time, the association of HLA-G +3142 C > G polymorphism with BC susceptibility in Tunisian population. Our results revealed also a potential implication of sHLA-G in advanced stages of BC.

Published
2016

10. Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity

Author

Arne Zibat, Manfred Jücker, Sebastian Gärtner, Klaus Pantel, Tobias M. Gorges, Tuan Zea Tan, Daniel J Smit, Gökhan Yigit, Simon A. Joosse, Andra Kuske, Qing Zhou, Kai Bartkowiak, Leonie Ott, Kaamini Raithatha, Claudia Koch, Parinaz Mossahebi Mohammadi, Gabriela Salinas-Riester, Kerstin Borgmann, Janine Altmüller, Sabine Riethdorf, Laura Battista, George Sflomos, Michael R. Speicher, Volkmar Müller, Cathrin Brisken, Sonja Thaler, Catherine Alix-Panabières, Jean Paul Thiery, Yvonne Goy, Laure Cayrefourcq, Stefan Werner, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University Medical Center Göttingen (UMG), Institut Suisse de Recherches Expérimentales sur le Cancer Lausanne (EPFL) (ISREC - EPFL), Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Heidelberg, Medical Faculty, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of Cologne, National University of Singapore (NUS), LPP - Laboratoire de Phonétique et Phonologie - UMR 7018 (LPP), Université Sorbonne Nouvelle - Paris 3-Centre National de la Recherche Scientifique (CNRS), Medical University Graz, Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The institute of cancer research [London], and Retiveau, Nolwenn

Subjects
0301 basic medicine, Medicine (General), Carcinogenesis, QH426-470, Regenerative Medicine, Metastasis, stem-cells, Mice, Breast cancer, 0302 clinical medicine, Circulating tumor cell, Functional studies, MESH: Animals, Neoplasm Metastasis, Cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Articles, tumor-cells, MESH: Carcinogenesis, Neoplastic Cells, Circulating, Primary tumor, 3. Good health, Molecular Medicine, Female, MESH: DNA Copy Number Variations, MESH: Biomarkers, Tumor, Technology Platforms, Stem cell, DNA Copy Number Variations, palbociclib, education, epithelial-mesenchymal transition, Breast Neoplasms, challenges, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Neoplastic Cells, Circulating, Palbociclib, survival, Article, 03 medical and health sciences, R5-920, [SDV.CAN] Life Sciences [q-bio]/Cancer, kinase 4/6 inhibitor, expression, Biomarkers, Tumor, Genetics, medicine, Animals, Humans, Epithelial–mesenchymal transition, Liquid biopsy, MESH: Mice, neoplasms, MESH: Humans, business.industry, Circulating tumor cells, mutations, medicine.disease, MESH: Neoplasm Metastasis, 030104 developmental biology, Cancer research, identification, business, MESH: Female, MESH: Breast Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency of CTCs and lack of appropriate models. Here, we describe the characterization of a novel CTC‐derived breast cancer cell line, designated CTC‐ITB‐01, established from a patient with metastatic estrogen receptor‐positive (ER +) breast cancer, resistant to endocrine therapy. CTC‐ITB‐01 remained ER + in culture, and copy number alteration (CNA) profiling showed high concordance between CTC‐ITB‐01 and CTCs originally present in the patient with cancer at the time point of blood draw. RNA‐sequencing data indicate that CTC‐ITB‐01 has a predominantly epithelial expression signature. Primary tumor and metastasis formation in an intraductal PDX mouse model mirrored the clinical progression of ER + breast cancer. Downstream ER signaling was constitutively active in CTC‐ITB‐01 independent of ligand availability, and the CDK4/6 inhibitor Palbociclib strongly inhibited CTC‐ITB‐01 growth. Thus, we established a functional model that opens a new avenue to study CTC biology., Blood‐born dissemination and subsequent outgrowth of tumor cells ‐ a process called metastasis ‐ is the leading cause of cancer‐related death. Cell lines derived from circulating tumor cells (CTCs) in blood of cancer patients provide excellent models to study the largely unknown biology of CTCs.

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