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1. Reuniting philosophy and science to advance cancer research

Author

Pradeu, Thomas, Daignan‐Fornier, Bertrand, Ewald, Andrew, Germain, Pierre‐Luc, Okasha, Samir, Plutynski, Anya, Benzekry, Sébastien, Bertolaso, Marta, Bissell, Mina, Brown, Joel S, Chin‐Yee, Benjamin, Chin‐Yee, Ian, Clevers, Hans, Cognet, Laurent, Darrason, Marie, Farge, Emmanuel, Feunteun, Jean, Galon, Jérôme, Giroux, Elodie, Green, Sara, Gross, Fridolin, Jaulin, Fanny, Knight, Rob, Laconi, Ezio, Larmonier, Nicolas, Maley, Carlo, Mantovani, Alberto, Moreau, Violaine, Nassoy, Pierre, Rondeau, Elena, Santamaria, David, Sawai, Catherine M, Seluanov, Andrei, Sepich‐Poore, Gregory D, Sisirak, Vanja, Solary, Eric, Yvonnet, Sarah, and Laplane, Lucie

Subjects
Biological Sciences, Cancer, Philosophy, Research, Interdisciplinary Studies, Neoplasms, driver mutation, clonal evolution, multicellularity, tumorigenesis, tumour microenvironment, oncoimmunology, cancer stem cells, philosophy of cancer, Evolutionary Biology, Biological sciences
Abstract

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

Published
2023

3. Dietary Rhythms and MASLD-Related Hepatocellular Carcinoma.

Author

Malakmahmoudi, Nadia, Pisu, Roberta, Laconi, Ezio, and Marongiu, Fabio

Subjects
METABOLIC disorders, NON-alcoholic fatty liver disease, FOOD consumption, DIETARY patterns, INTERMITTENT fasting, CHRONIC diseases, FOOD habits, AGING, HEPATOCELLULAR carcinoma, DISEASE complications
Abstract

Simple Summary: Diet is a fundamental determinant of health and longevity. This relationship is complex. Historically, among the most investigated variables have been quality and quantity of food. However, over the past 2 decades increasing attention has been devoted to dietary rhythms, including time of food consumption during the day and length of fasting intervals. In this respect, contrasting evidence has recently emerged in the literature regarding the effect of adequate intervals of fasting on the evolution of diet-related chronic liver diseases, including hepatocellular carcinoma. In this review, we briefly refer to this evidence and propose a hypothesis that may help reconcile apparently conflicting observations. Dietary rhythms have emerged as a relevant variable in the equation relating nutrition and health. Both experimental and epidemiological studies point to potential beneficial effects of adequate fasting intervals between meals on the evolution of chronic diseases associated with aging. Metabolic dysfunction-associated steatotic liver disease (MASLD) is eminently related to diet and unsurprisingly, diet-based approaches are a mainstay in countering its long-term clinical evolution, including the emergence of hepatocellular carcinoma (HCC). We briefly discuss current evidence linking fasting intervals, MASLD, and HCC and propose a working hypothesis to reconcile some of the apparently conflicting results. This hypothesis relates the beneficial effects of time-restricted eating schedules to the quantity and quality of food, and it is easily amenable to testing. [ABSTRACT FROM AUTHOR]

Published
2024
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6. The effect of environmental chemicals on the tumor microenvironment

Author

Casey, Stephanie C, Vaccari, Monica, Al-Mulla, Fahd, Al-Temaimi, Rabeah, Amedei, Amedeo, Barcellos-Hoff, Mary Helen, Brown, Dustin G, Chapellier, Marion, Christopher, Joseph, Curran, Colleen S, Forte, Stefano, Hamid, Roslida A, Heneberg, Petr, Koch, Daniel C, Krishnakumar, PK, Laconi, Ezio, Maguer-Satta, Veronique, Marongiu, Fabio, Memeo, Lorenzo, Mondello, Chiara, Raju, Jayadev, Roman, Jesse, Roy, Rabindra, Ryan, Elizabeth P, Ryeom, Sandra, Salem, Hosni K, Scovassi, A Ivana, Singh, Neetu, Soucek, Laura, Vermeulen, Louis, Whitfield, Jonathan R, Woodrick, Jordan, Colacci, Annamaria, Bisson, William H, and Felsher, Dean W

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Stem Cell Research, Cancer, Prevention, 2.2 Factors relating to the physical environment, Aetiology, 2.1 Biological and endogenous factors, Animals, Carcinogenesis, Environmental Exposure, Hazardous Substances, Humans, Neoplasms, Tumor Microenvironment, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

Published
2015

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

Author

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, Louis, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, Maria Fiammetta, Chapellier, Marion, Williams, Marc A, and Wade, Mark

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, 2.2 Factors relating to the physical environment, Animals, Carcinogenesis, Carcinogens, Environmental, Environmental Exposure, Hazardous Substances, Humans, Neoplasms, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

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.

Published
2015

12. Reuniting philosophy and science to advance cancer research

Author

CMM, Cancer, Hubrecht Institute with UMC, Pradeu, Thomas, Daignan-Fornier, Bertrand, Ewald, Andrew, Germain, Pierre Luc, Okasha, Samir, Plutynski, Anya, Benzekry, Sébastien, Bertolaso, Marta, Bissell, Mina, Brown, Joel S., Chin-Yee, Benjamin, Chin-Yee, Ian, Clevers, Hans, Cognet, Laurent, Darrason, Marie, Farge, Emmanuel, Feunteun, Jean, Galon, Jérôme, Giroux, Elodie, Green, Sara, Gross, Fridolin, Jaulin, Fanny, Knight, Rob, Laconi, Ezio, Larmonier, Nicolas, Maley, Carlo, Mantovani, Alberto, Moreau, Violaine, Nassoy, Pierre, Rondeau, Elena, Santamaria, David, Sawai, Catherine M., Seluanov, Andrei, Sepich-Poore, Gregory D., Sisirak, Vanja, Solary, Eric, Yvonnet, Sarah, Laplane, Lucie, CMM, Cancer, Hubrecht Institute with UMC, Pradeu, Thomas, Daignan-Fornier, Bertrand, Ewald, Andrew, Germain, Pierre Luc, Okasha, Samir, Plutynski, Anya, Benzekry, Sébastien, Bertolaso, Marta, Bissell, Mina, Brown, Joel S., Chin-Yee, Benjamin, Chin-Yee, Ian, Clevers, Hans, Cognet, Laurent, Darrason, Marie, Farge, Emmanuel, Feunteun, Jean, Galon, Jérôme, Giroux, Elodie, Green, Sara, Gross, Fridolin, Jaulin, Fanny, Knight, Rob, Laconi, Ezio, Larmonier, Nicolas, Maley, Carlo, Mantovani, Alberto, Moreau, Violaine, Nassoy, Pierre, Rondeau, Elena, Santamaria, David, Sawai, Catherine M., Seluanov, Andrei, Sepich-Poore, Gregory D., Sisirak, Vanja, Solary, Eric, Yvonnet, Sarah, and Laplane, Lucie

Published
2023

13. Reuniting philosophy and science to advance cancer research

Author

Centre National de la Recherche Scientifique (France), Ligue Nationale contre le Cancer (France), Pradeu, Thomas, Daignan-Fornier, Bertrand, Ewald, Andrew, Germain, Pierre-Luc, Okasha, Samir, Plutynski, Anya, Benzekry, Sébastien, Bertolaso, Marta, Bissell, Mina, Brown, Joel S., Chin-Yee, Benjamin, Chin-Yee, Ian, Clevers, Hans, Cognet, Laurent, Darrason, Marie, Farge, Emmanuel, Feunteun, Jean, Galon, Jérôme, Giroux, Elodie, Green, Sara, Gross, Fridolin, Jaulin, Fanny, Knight, Rob, Laconi, Ezio, Larmonier, Nicolás, Maley, Carlo, Mantovani, Alberto, Moreau, Violaine, Nassoy, Pierre, Rondeau, Elena, Santamaria, David, Sawai, Catherine M., Seluanov, Andrei, Sepich-Poore, Gregory D., Sisirak, Vanja, Solary, Eric, Yvonnet, Sarah, Laplane, Lucie, Centre National de la Recherche Scientifique (France), Ligue Nationale contre le Cancer (France), Pradeu, Thomas, Daignan-Fornier, Bertrand, Ewald, Andrew, Germain, Pierre-Luc, Okasha, Samir, Plutynski, Anya, Benzekry, Sébastien, Bertolaso, Marta, Bissell, Mina, Brown, Joel S., Chin-Yee, Benjamin, Chin-Yee, Ian, Clevers, Hans, Cognet, Laurent, Darrason, Marie, Farge, Emmanuel, Feunteun, Jean, Galon, Jérôme, Giroux, Elodie, Green, Sara, Gross, Fridolin, Jaulin, Fanny, Knight, Rob, Laconi, Ezio, Larmonier, Nicolás, Maley, Carlo, Mantovani, Alberto, Moreau, Violaine, Nassoy, Pierre, Rondeau, Elena, Santamaria, David, Sawai, Catherine M., Seluanov, Andrei, Sepich-Poore, Gregory D., Sisirak, Vanja, Solary, Eric, Yvonnet, Sarah, and Laplane, Lucie

Abstract

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.

Published
2023

22. The evolving concept of tumor microenvironments

Author

Laconi, Ezio

Subjects
Tumor staging -- Research, Cancer invasiveness -- Research, Cancer invasiveness -- Environmental aspects, Cancer cells -- Environmental aspects, Cancer cells -- Research, Biological sciences
Abstract

The distinction between the microenvironment that altered/preneoplastic/neoplastic cells find in the tissue where they reside and the peculiar microenvironment inside the focal lesion that these cells contribute to create is described. The two microenvironments have acted in sequence and have played complementary roles in the development of overt neoplasia, which have important implications for the management of preneoplastic/neoplastic lesions at various stages of cancer development.

Published
2007

25. Hepatic differentiation of amniotic epithelial cells

Author

Marongiu, Fabio, Gramignoli, Roberto, Dorko, Kenneth, Miki, Toshio, Ranade, Aarati R., Paola Serra, Maria, Doratiotto, Silvia, Sini, Marcella, Sharma, Shringi, Mitamura, Keitaro, Sellaro, Tiffany L., Tahan, Veysel, Skvorak, Kristen J., Ellis, Ewa C. S., Badylak, Stephen F., Davila, Julio C., Hines, Ronald, Laconi, Ezio, and Strom, Stephen C.

Published
2011
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28. Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver

Author

Gensous, Noémie, primary, Ravaioli, Francesco, additional, Pirazzini, Chiara, additional, Gramignoli, Roberto, additional, Ellis, Ewa, additional, Storci, Gianluca, additional, Capri, Miriam, additional, Strom, Stephen, additional, Laconi, Ezio, additional, Franceschi, Claudio, additional, Garagnani, Paolo, additional, Marongiu, Fabio, additional, and Bacalini, Maria Giulia, additional

Published
2020
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43. Regenerative Medicine

Author

Marongiu, Fabio, primary, Serra, Maria Paola, additional, Fanti, Maura, additional, Cadoni, Erika, additional, Serra, Monica, additional, and Laconi, Ezio, additional

Published
2017
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48. Assessing the Carcinogenic Potential of Low Dose Exposures to Chemical Mixtures in the Environment: Replicative immortality

Author

80402890, Goodson, William H., Lowe, Leroy, Carpenter, O. David, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, K. Amelia, Laird, Dale W., Koch, C. Daniel, Carlin, J. Danielle, Felsher, W. Dean, Roy, Debasish, Brown, G. Dustin, Ratovitski, Edward, Ryan, P. Elizabeth, Corsini, Emanuela, Rojas, Emilio, Manjili, H. Masoud, Moon, Eun-Yi, Laconi, Ezio, Marongiu, Fabio, Al-Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L., Van Schooten, J. Frederik, Goldberg, S. Gary, Wagemaker, Gerard, Lleonart, E. Matilde, Nangami, N. Gladys, Calaf, M. Gloria, Williams, P. Graeme, Wolf, T. Gregory, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Xia, Menghang, Sone, Hideko, Kondoh, Hiroshi, Salem, K. Hosni, Hsu, Hsue-Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, R. Isabelle, Scovassi, A.Ivana, Klaunig, E. James, Vondráček, Jan, Gonzalez Guzman, J. Michael, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, R. Jonathan, Woodrick, Jordan, Christopher, A. Joseph, Ochieng, Josiah, Martinez-Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Karamouzis, V. Michalis, Sun, Jun, Prudhomme, R. Kalan, Narayanan, Kannan Badri, Cohen-Solal, A. Karine, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D’Abronzo, S. Leandro, Lin, Liang-Tzung, Kirsch-Volders, Micheline, Li, Lin, Gulliver, Linda, McCawley, J. Lisa, Memeo, Lorenzo, Vermeulen, Louis, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, Maria Fiammetta, Vaccari, Monica, Chapellier, Marion, Williams, A. Marc, Wade, Mark, Kuemmerle, B. Nancy, Singh, Neetu, Cruickshanks, Nichola, Collins, R. Andrew, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K., Vadgama, Pankaj, Marignani, A. Paola, Ghosh, M. Paramita, Ostrosky-Wegman, Patricia, Thompson, A. Patricia, Ward, Andrew, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Leung, Po Sing, Nangia-Makker, Pratima, Cheng, Qiang (Shawn), Robey, R. Brooks, Al-Temaimi, Rabeah, Roy, Rabindra, Andrade-Vieira, Rafaela, Salzberg, C. Anna, Sinha, K. Ranjeet, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce-Cusi, Richard, Dornetshuber-Fleiss, Rita, Nahta, Rita, Castellino, C. Robert, Palorini, Roberta, Hamid, A. Roslida, Colacci, Anna Maria, Langie, A. S. Sabine, Eltom, E. Sakina, Brooks, A. Samira, Ryeom, Sandra, Wise, S. Sandra, Bay, N. Sarah, Harris, A. Shelley, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Olsen, Ann-Karin, Eriksson, Staffan, Forte, Stefano, Casey, C. Stephanie, Luanpitpong, Sudjit, Lee, Tae-Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thomas, Guarnieri, Tiziana, Berg, Arthur, Hultman, Tove, Dormoy, Valérian, Odero-Marah, Valerie, Sabbisetti, Venkata, Maguer-Satta, Veronique, Rathmell, W.Kimryn, Engström, Wilhelm, Decker, K. William, Bisson, H. William, Rojanasakul, Yon, Barclay, J. Barry, Luqmani, Yunus, Chen, Zhenbang, Hu, Zhiwei, Zhou, P. Binhua, Blanco-Aparicio, Carmen, Baglole, J. Carolyn, Dong, Chenfang, Mondello, Chiara, Hsu, Chia-Wen, Naus, C. Christian, Yedjou, Clement, Curran, S. Colleen, 80402890, Goodson, William H., Lowe, Leroy, Carpenter, O. David, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, K. Amelia, Laird, Dale W., Koch, C. Daniel, Carlin, J. Danielle, Felsher, W. Dean, Roy, Debasish, Brown, G. Dustin, Ratovitski, Edward, Ryan, P. Elizabeth, Corsini, Emanuela, Rojas, Emilio, Manjili, H. Masoud, Moon, Eun-Yi, Laconi, Ezio, Marongiu, Fabio, Al-Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L., Van Schooten, J. Frederik, Goldberg, S. Gary, Wagemaker, Gerard, Lleonart, E. Matilde, Nangami, N. Gladys, Calaf, M. Gloria, Williams, P. Graeme, Wolf, T. Gregory, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Xia, Menghang, Sone, Hideko, Kondoh, Hiroshi, Salem, K. Hosni, Hsu, Hsue-Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, R. Isabelle, Scovassi, A.Ivana, Klaunig, E. James, Vondráček, Jan, Gonzalez Guzman, J. Michael, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, R. Jonathan, Woodrick, Jordan, Christopher, A. Joseph, Ochieng, Josiah, Martinez-Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Karamouzis, V. Michalis, Sun, Jun, Prudhomme, R. Kalan, Narayanan, Kannan Badri, Cohen-Solal, A. Karine, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D’Abronzo, S. Leandro, Lin, Liang-Tzung, Kirsch-Volders, Micheline, Li, Lin, Gulliver, Linda, McCawley, J. Lisa, Memeo, Lorenzo, Vermeulen, Louis, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, Maria Fiammetta, Vaccari, Monica, Chapellier, Marion, Williams, A. Marc, Wade, Mark, Kuemmerle, B. Nancy, Singh, Neetu, Cruickshanks, Nichola, Collins, R. Andrew, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K., Vadgama, Pankaj, Marignani, A. Paola, Ghosh, M. Paramita, Ostrosky-Wegman, Patricia, Thompson, A. Patricia, Ward, Andrew, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Leung, Po Sing, Nangia-Makker, Pratima, Cheng, Qiang (Shawn), Robey, R. Brooks, Al-Temaimi, Rabeah, Roy, Rabindra, Andrade-Vieira, Rafaela, Salzberg, C. Anna, Sinha, K. Ranjeet, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce-Cusi, Richard, Dornetshuber-Fleiss, Rita, Nahta, Rita, Castellino, C. Robert, Palorini, Roberta, Hamid, A. Roslida, Colacci, Anna Maria, Langie, A. S. Sabine, Eltom, E. Sakina, Brooks, A. Samira, Ryeom, Sandra, Wise, S. Sandra, Bay, N. Sarah, Harris, A. Shelley, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Olsen, Ann-Karin, Eriksson, Staffan, Forte, Stefano, Casey, C. Stephanie, Luanpitpong, Sudjit, Lee, Tae-Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thomas, Guarnieri, Tiziana, Berg, Arthur, Hultman, Tove, Dormoy, Valérian, Odero-Marah, Valerie, Sabbisetti, Venkata, Maguer-Satta, Veronique, Rathmell, W.Kimryn, Engström, Wilhelm, Decker, K. William, Bisson, H. William, Rojanasakul, Yon, Barclay, J. Barry, Luqmani, Yunus, Chen, Zhenbang, Hu, Zhiwei, Zhou, P. Binhua, Blanco-Aparicio, Carmen, Baglole, J. Carolyn, Dong, Chenfang, Mondello, Chiara, Hsu, Chia-Wen, Naus, C. Christian, Yedjou, Clement, and Curran, S. Colleen

Abstract

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.

Published
2015

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

Author

Goodson III, William H., Lowe, Leroy, Carpenter, David O., Gilbertson, Michael, Ali, Abdul Manaf, Salsamendi, Adela Lopez de Cerain, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K., Collins, Andrew R., Ward, Andrew, Salzberg, Anna C., Colacci, Anna Maria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J., Zhou, Binhua P., Aparicio, Carmen Blanco, Baglole, Carolyn J., Dong, Chenfang, Mondello, Chiara, Chia, Wen Hsu, 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, Eun, Yi Moon, Laconi, Ezio, Marongiu, Fabio, Al-Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L., Schooten, Frederik J. Van, Goldberg, Gary S., Wagemaker, Gerard, Nangami, Gladys N., Calaf, Gloria M., Williams, Graeme P., Wolf, Gregory T., Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab. Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K., Hsue, Yin Hsu, Hyun, Ho Park, Koturbash, Igor, Miousse, Isabelle R., Scovassi, A. Ivana, Klaunig, James E., Vondrá ček, Jan, Raju, Jayadev, Roman, Jesse, Wise Sr., 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., Liang, Tzung Lin, Li, Lin, Gulliver, Linda, McCawley, Lisa J., Memeo, Lorenzo, Vermeulen, Louis, 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 Guzma, Michael J., Karamouzis, Michalis V., Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B., Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, Larebeke, Nik van, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K., Vadgama, Pankaj, Marignani, Paola A., Ghosh, Paramita M., Ostrosky Wegman, Patricia, Thompson, Patricia A., Dent, Paul, Darbre, Philippa, Heneberg, Petr, Po, Sing Leung, Nangia Makker, Pratima, Cheng, Qiang, Robey, R. Brooks, 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 @ Abdul Razak, 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, Tae, Jin Lee, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thomas, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Mara, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K., Bisson, William H., Rojanasakul, Yon, Luqmani, Yunus, Chen, Zhenbang, Hu, Zhiwei, Goodson III, William H., Lowe, Leroy, Carpenter, David O., Gilbertson, Michael, Ali, Abdul Manaf, Salsamendi, Adela Lopez de Cerain, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K., Collins, Andrew R., Ward, Andrew, Salzberg, Anna C., Colacci, Anna Maria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J., Zhou, Binhua P., Aparicio, Carmen Blanco, Baglole, Carolyn J., Dong, Chenfang, Mondello, Chiara, Chia, Wen Hsu, 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, Eun, Yi Moon, Laconi, Ezio, Marongiu, Fabio, Al-Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L., Schooten, Frederik J. Van, Goldberg, Gary S., Wagemaker, Gerard, Nangami, Gladys N., Calaf, Gloria M., Williams, Graeme P., Wolf, Gregory T., Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab. Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K., Hsue, Yin Hsu, Hyun, Ho Park, Koturbash, Igor, Miousse, Isabelle R., Scovassi, A. Ivana, Klaunig, James E., Vondrá ček, Jan, Raju, Jayadev, Roman, Jesse, Wise Sr., 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., Liang, Tzung Lin, Li, Lin, Gulliver, Linda, McCawley, Lisa J., Memeo, Lorenzo, Vermeulen, Louis, 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 Guzma, Michael J., Karamouzis, Michalis V., Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B., Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, Larebeke, Nik van, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K., Vadgama, Pankaj, Marignani, Paola A., Ghosh, Paramita M., Ostrosky Wegman, Patricia, Thompson, Patricia A., Dent, Paul, Darbre, Philippa, Heneberg, Petr, Po, Sing Leung, Nangia Makker, Pratima, Cheng, Qiang, Robey, R. Brooks, 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 @ Abdul Razak, 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, Tae, Jin Lee, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thomas, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Mara, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K., Bisson, William H., Rojanasakul, Yon, Luqmani, Yunus, Chen, Zhenbang, and Hu, Zhiwei

Abstract

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.

Published
2015

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