Faculty Profiles - SONE, Hirohito

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice. Reviewed International journal

Noriko Suzuki-Kemuriyama, Takashi Matsuzaka, Motoko Kuba, Hiroshi Ohno, Song-Iee Han, Yoshinori Takeuchi, Masaaki Isaka, Kazuto Kobayashi, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Katsuhiro Miyajima, Dai Nakae, Naoya Yahagi, Yoshimi Nakagawa, Hirohito Sone, Nobuhiro Yamada, Hitoshi Shimano

PloS one 11 ( 6 ) e0157580 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

DOI： 10.1371/journal.pone.0157580

Fulminant Type 1 Diabetes Mellitus Associated with Coxsackie Virus Type A2 Infection: A Case Report and Literature Review Reviewed

Nobumasa Ohara, Masanori Kaneko, Takeaki Nishibori, Kazuhiro Sato, Tatsuo Furukawa, Tadashi Koike, Hirohito Sone, Kenzo Kaneko, Kyuzi Kamoi

INTERNAL MEDICINE 55 ( 6 ) 643 - 646 2016

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

A 65-year-old Japanese man presented to our hospital in June 2013 with a 6-day history of fever and fatigue, a 24-h history of thirst, and polyuria. His temperature was 37.8 degrees C and he was alert. However, laboratory tests revealed severe hyperglycemia, undetectable C-peptide levels, and diabetic ketoacidosis. Serum antibody testing confirmed a Coxsackie virus A2 infection. A variety of viral infections are reported to be involved in the development of fulminant type 1 diabetes mellitus (FT1D). Our patient is the first reported case of FT1D associated with Coxsackie virus A2 infection and supports the etiological role of common viral infections in FT1D.

DOI： 10.2169/internalmedicine.55.5292

Fibromyalgia in a Patient with Cushing's Disease Accompanied by Central Hypothyroidism Reviewed

Nobumasa Ohara, Shinichi Katada, Takaho Yamada, Naomi Mezaki, Hiroshi Suzuki, Akiko Suzuki, Osamu Hanyu, Yuichiro Yoneoka, Izumi Kawachi, Takayoshi Shimohata, Akiyoshi Kakita, Masatoyo Nishizawa, Hirohito Sone

INTERNAL MEDICINE 55 ( 21 ) 3185 - 3190 2016

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

A 39-year-old woman with a 3-year history of a rounded face developed widespread myalgia. Detailed examinations revealed no disorders that could explain the pain other than concomitant Cushing's disease and central hypothyroidism. Both the hypercortisolemia and hypothyroidism completely resolved after the patient underwent surgery to treat Cushing's disease, but she continued to experience unresolved myalgia and met the diagnostic criteria for fibromyalgia. Few studies have so far investigated patients with fibromyalgia associated with Cushing's syndrome. In our case, the hypothyroidism caused by Cushing's disease probably played an important role in triggering and exacerbating fibromyalgia. This highlights the need to examine the endocrine function in patients with muscle pain.

DOI： 10.2169/internalmedicine.55.5926

A case of hypoglycemia attributable to atypical antipsychotic drugs Reviewed

Hajime Ishiguro, Osamu Hanyu, Satoshi Houya, Kazuaki Morohashi, Ganji Kuroiwa, Osamu Kuwabara, Tsukasa Nakamaru, Katsuya Fuse, Kouji Sato, Hirohito Sone

Diabetology International 6 ( 4 ) 341 - 346 2015.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer-Verlag Tokyo

We report a 55-year-old Japanese man who presented with symptomatic hypoglycemia attributable to atypical antipsychotic drugs (APD). He had been taking olanzapine, quetiapine, and paliperidone. One morning, his consciousness level dropped without inducement and his blood glucose was low. His symptoms improved after intravenous glucose infusion. These episodes reoccurred a few times, but ceased after APD were stopped. Physical examination did not find any organic disease that might cause hypoglycemia. Hyperglycemia, dyslipidemia, and body weight gain are well-documented side-effects of APD, but hypoglycemia is rare. There are a variety of hypotheses on how APD cause hypoglycemia: (1) Weight gain and dyslipidemia caused by APD might increase insulin resistance, meaning that excess insulin is secreted, causing hypoglycemia. (2) The quantity of basal insulin secreted by pancreatic beta cells might be enhanced by APD, which might cause hypoglycemia. (3) APD might work as an antagonist of muscarinic receptors such that insulin secretion might continue even after the glucose level has returned to normal, which might cause hypoglycemia. However, the mechanism is not fully understood and more research is needed.

DOI： 10.1007/s13340-015-0203-5

Fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large B-cell lymphoma that developed after lung transplantation Reviewed

K. Kawamoto, Y. Shibasaki, S. Sato, H. Nemoto, J. Takizawa, M. Narita, M. Tsuchida, H. Sone, M. Masuko

Transplant Infectious Disease 17 ( 6 ) 872 - 875 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Inc.

Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.

DOI： 10.1111/tid.12458

Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model Reviewed

Motoko Kuba, Takashi Matsuzaka, Rie Matsumori, Ryo Saito, Naoko Kaga, Hikari Taka, Kei Ikehata, Naduki Okada, Takuya Kikuchi, Hiroshi Ohno, Song-Iee Han, Yoshinori Takeuchi, Kazuto Kobayashi, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Hirohito Sone, Naoya Yahagi, Yoji Arakawa, Tsutomu Fujimura, Yoshimi Nakagawa, Nobuhiro Yamada, Hitoshi Shimano

SCIENTIFIC REPORTS 5 17604 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr(-/-)) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr(-/-) mice.

DOI： 10.1038/srep17604

[Clinical and pathophysiological features of Japanese patients with type 2 diabetes mellitus and their risk factors for diabetic complication]. Reviewed

Sone H

Nihon rinsho. Japanese journal of clinical medicine 73 ( 12 ) 1979 - 1987 2015.12

Clinical Significance of MYC, BCL2 and BCL6 Rearrangement and Protein Expression in GCB and Non-GCB Type Diffuse Large B-Cell Lymphoma Invited Reviewed

Keisuke Kawamoto, Jun Takizawa, Hiroaki Miyoshi, Noriaki Yoshida, Yasuhiko Shibasaki, Masayoshi Masuko, Hirohito Sone, Naoya Nakamura, Koichi Ohshima

BLOOD 126 ( 23 ) 2015.12

Risk factors associated with abnormal cognition in Japanese outpatients with diabetes, hypertension or dyslipidemia Reviewed

Hiroki Yokoyama, Mayumi Ogawa, Jun Honjo, Shinichiro Okizaki, Daishiro Yamada, Ryushi Shudo, Hitoshi Shimizu, Hirohito Sone, Masakazu Haneda

DIABETOLOGY INTERNATIONAL 6 ( 4 ) 268 - 274 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Aims According to the recent increase in life expectancy in patients with diabetes, the incidence of dementia with diabetes is increasing drastically in Japan. However, the number of studies on the prevalence of abnormal cognition and the associated risk factors in a large number of outpatients with diabetes in a primary care setting is very limited.Methods The Mini-Mental State Examination (MMSE) test was performed in 1,449 outpatients aged >= 50 years with diabetes, hypertension or dyslipidemia (126 without and 1,323 with diabetes). Prevalence of abnormal cognition defined as an MMSE score <24 and the associated risk factors were explored.Results Prevalence of abnormal cognition was 5.8 % in total, and was 8.3 % in outpatients aged >= 65 years with diabetes. Logistic regression analysis after adjustment for age, sex, BMI and smoking indicated that abnormal cognition was associated with lower serum albumin and higher uric acid levels in all subjects. In subjects with diabetes, in addition to the associations with serum albumin and uric acid levels, lower renal function, retinopathy, use of insulin and a-glucosidase inhibitor, and non-use of pioglitazone and metformin were significantly associated with abnormal cognition independent of the effect of duration of diabetes, hypertension, dyslipidemia, and history of coronary heart disease and stroke.Conclusions Because of the higher prevalence of abnormal cognition in aged outpatients with diabetes found in primary care practice and significant associations with serum albumin, uric acid, renal function, retinopathy and antidiabetic drugs, there is a need for early diagnosis and strategies against dementia.

DOI： 10.1007/s13340-014-0194-7

Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy Reviewed

Yoshinori Osaki, Yoshimi Nakagawa, Shoko Miyahara, Hitoshi Iwasaki, Akiko Ishii, Takashi Matsuzaka, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Ken Ohashi, Shun Ishibashi, Nobuhiro Yamada, Hitoshi Shimano

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 466 ( 3 ) 536 - 540 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonic acid (MVA); this is the rate-limiting enzyme of the mevalonate pathway that synthesizes cholesterol. Statins, HMGCR inhibitors, are widely used as cholesterol-reducing drugs. However, statin-induced myopathy is the most adverse side effect of statins. To eludicate the mechanisms underlying statin the myotoxicity and HMGCR function in the skeletal muscle, we developed the skeletal muscle-specific HMGCR knockout mice. Knockout mice exhibited postnatal myopathy with elevated serum creatine kinase levels and necrosis. Myopathy in knockout mice was completely rescued by the oral administration of MVA. These results suggest that skeletal muscle toxicity caused by statins is dependent on the deficiencies of HMGCR enzyme activity and downstream metabolites of the mevalonate pathway in skeletal muscles rather than the liver or other organs. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.09.065

Prevalence of resistant hypertension and associated factors in Japanese subjects with type 2 diabetes

H. Yokoyama, S. Araki, S. Watanabe, J. Honjo, S. Okizaki, D. Yamada, R. Shudo, H. Shimizu, H. Sone, M. Haneda

DIABETES RESEARCH AND CLINICAL PRACTICE 110 ( 1 ) 18 - 25 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: The prevalence of treatment resistant hypertension (RH) depends on methods used for blood pressure (BP) measurements, goals of BP, and therapeutic efforts in terms of medication and adherence. We focused on diabetic subjects and explored the prevalence of RH in primary care practice.
Methods: In 1737 subjects with type 2 diabetes who continued regular visits, office BP was evaluated by multiple measurements over one year. RH was defined as using more than four antihypertensive drugs or failure to achieve the goal with three antihypertensive drugs from different classes. The RH prevalence was investigated with BP goals <130/80 and 140/90 mmHg.
Results: The percentage of subjects who achieved BP goals <130/80 and 140/90 were 70.5% and 93.8% with adherence to medication >= 95%, and the corresponding prevalence rates of RH in treated subjects were 28.4% and 21.8%, respectively. Factors independently associated with RH were age (odds ratio 1.02 [95% CI 1.01-1.04]), body mass index (1.10 [1.06-1.13]), variability in systolic BP (1.06 [1.02-1.09]), triglycerides (2.86 [1.34-6.11]), macroalbuminuria (3.33 [2.03-5.48]), estimated glomerular filtration rate (0.98 [0.97-0.99]), retinopathy (1.91 [1.39-2.61]), and family history of hypertension (1.85 [1.23-2.21]). Worsening albuminuria and glomerular filtration rate enhanced the prevalence of RH in a graded manner.
Conclusion: Careful estimation of office BP values over one year with a high achievement of BP goals and adequate adherence revealed that the prevalence of RH in type 2 diabetes is high. RH was characterized by accumulation of cardiovascular genetic and environmental risks. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2015.08.007

Impact of population aging on trends in diabetes prevalence: A meta-regression analysis of 160,000 Japanese adults Reviewed

Hadrien Charvat, Atsushi Goto, Maki Goto, Machiko Inoue, Yoriko Heianza, Yasuji Arase, Hirohito Sone, Tomoko Nakagami, Xin Song, Qing Qiao, Jaakko Tuomilehto, Shoichiro Tsugane, Mitsuhiko Noda, Manami Inoue

JOURNAL OF DIABETES INVESTIGATION 6 ( 5 ) 533 - 542 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Aims/IntroductionTo provide age- and sex-specific trends, age-standardized trends, and projections of diabetes prevalence through the year 2030 in the Japanese adult population.
Materials and MethodsIn the present meta-regression analysis, we included 161,087 adults from six studies and nine national health surveys carried out between 1988 and 2011 in Japan. We assessed the prevalence of diabetes using a recorded history of diabetes or, for the population of individuals without known diabetes, either a glycated hemoglobin level of 6.5% (48mmol/mol) or the 1999 World Health Organization criteria (i.e., a fasting plasma glucose level of 126mg/dL and/or 2-h glucose level of 200mg/dL in the 75-g oral glucose tolerance test).
ResultsFor both sexes, prevalence appeared to remain unchanged over the years in all age categories except for men aged 70years or older, in whom a significant increase in prevalence with time was observed. Age-standardized diabetes prevalence estimates based on the Japanese population of the corresponding year showed marked increasing trends: diabetes prevalence was 6.1% among women (95% confidence interval [CI] 5.5-6.7), 9.9% (95% CI 9.2-10.6) among men, and 7.9% (95% CI 7.5-8.4) among the total population in 2010, and was expected to rise by 2030 to 6.7% (95% CI 5.2-9.2), 13.1% (95% CI 10.9-16.7) and 9.8% (95% CI 8.5-12.0), respectively. In contrast, the age-standardized diabetes prevalence using a fixed population appeared to remain unchanged.
ConclusionsThis large-scale meta-regression analysis shows that a substantial increase in diabetes prevalence is expected in Japan during the next few decades, mainly as a result of the aging of the adult population.

DOI： 10.1111/jdi.12333

Pioglitazone treatment and cardiovascular event and death in subjects with type 2 diabetes without established cardiovascular disease (JDDM 36)

H. Yokoyama, S. Araki, K. Kawai, K. Hirao, M. Oishi, K. Sugimoto, H. Sone, H. Maegawa, A. Kashiwagi

DIABETES RESEARCH AND CLINICAL PRACTICE 109 ( 3 ) 485 - 492 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Aims: The protective association of pioglitazone with cardiovascular events and death was investigated over 6-years in large-scale type 2 diabetic subjects without established cardiovascular disease in a primary care setting.
Methods: A six-year observational cohort study including 2864 subjects with type 2 diabetes without established cardiovascular disease was performed. The primary endpoint was a composite of first occurrence of cardiovascular disease or death. The effect of pioglitazone use at a baseline year with a Cox proportional hazard model and the time-dependent use in each one-year examination interval with a pooled logistic regression model were analyzed.
Results: Baseline use of pioglitazone (n = 493) did not show a statistically protective effect on the primary endpoint (n = 175), although it tended to reduce the risk (adjusted hazard ratio 0.67 [95% CI: 0.43-1.05]). However, pooled logistic regression analysis indicated a significant protective association of pioglitazone with the primary endpoint (0.58 [0.38 to 0.87] and cardiovascular disease (0.54 [0.33-0.88]), independent of concurrent levels of blood glucose, blood pressure, lipids, albuminuria, and renal function. In particular, this protective association was observed in those with diabetic nephropathy regardless of the daily dose of pioglitazone. Among a total of 898 subjects who took pioglitazone during the period, 43% experienced a discontinuation at least once; however, serious adverse effects were rare.
Conclusions: This observational study indicated a protective association of pioglitazone with cardiovascular disease and death in type 2 diabetic subjects without established vascular disease, particularly those with nephropathy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2015.06.005

HSCT後のγ/δT細胞低値およびTreg細胞高値はいずれも再発の独立リスク因子である(Both low γ/δ T cells and high Treg cells after HSCT is an independent risk factor for relapse)

Shibasaki Yasuhiko, Miyakoshi Syukuko, Suwabe Tatsuya, Katagiri Takayuki, Fuse Kyoko, Kobayashi Hironori, Ushiki Takashi, Moriyama Masato, Takizawa Jun, Narita Miwako, Sone Hirohito, Furukawa Tatsuo, Masuko Masayoshi

臨床血液 56 ( 9 ) 1666 - 1666 2015.9

レシピエントに対する移植前評価としてのHCT-CI/年齢スコアの臨床的意義(The clinical relevance of HCT-CI/age score as pre-transplant assessment for recipients)

Katagiri Takayuki, Shibasaki Yasuhiko, Suwabe Tatsuya, Miyakoshi Shukuko, Fuse Kyoko, Kobayashi Hironori, Ushiki Takashi, Moriyama Masato, Takizawa Jun, Narita Miwako, Sone Hirohito, Masuko Masayoshi

臨床血液 56 ( 9 ) 1665 - 1665 2015.9

DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis

Naoki Kubo, Hidehiro Toh, Kenjiro Shirane, Takayuki Shirakawa, Hisato Kobayashi, Tetsuya Sato, Hidetoshi Sone, Yasuyuki Sato, Shin-Ichi Tomizawa, Yoshinori Tsurusaki, Hiroki Shibata, Hirotomo Saitsu, Yutaka Suzuki, Naomichi Matsumoto, Mikita Suyama, Tomohiro Kono, Kazuyuki Ohbo, Hiroyuki Sasaki

BMC Genomics 16 ( 1 ) 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BioMed Central Ltd.

Background: In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported. Results: To understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia, and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific transcription factors including the SOX family members. Conclusions: Our findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and represent a unique phase of male germ cell development.

DOI： 10.1186/s12864-015-1833-5

Possible Involvement of Lung Cells Harboring an Abnormal Karyotype in the Pathogenesis of Pulmonary Alveolar Proteinosis Associated with Myelodysplastic Syndrome Reviewed

Hirohito Sone

Annals of the American Thoracic Society 12 ( 8 ) 1251 - 1253 2015.8

The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling

Wilhelm Engström, Philippa Darbre, Staffan Eriksson, Linda Gulliver, Tove Hultman, Michalis V. Karamouzis, James E. Klaunig, Rekha Mehta, Kim Moorwood, Thomas Sanderson, Hideko Sone, Pankaj Vadgama, Gerard Wagemaker, Andrew Ward, Neetu Singh, Fahd Al-Mulla, Rabeah Al-Temaimi, Amedeo Amedei, Anna Maria Colacci, Monica Vaccari, Chiara Mondello, A. Ivana Scovassi, Jayadev Raju, Roslida A. Hamid, Lorenzo Memeo, Stefano Forte, Rabindra Roy, Jordan Woodrick, Hosni K. Salem, Elizabeth Ryan, Dustin G. Brown, William H. Bisson

Carcinogenesis 36 S38 - S60 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.

DOI： 10.1093/carcin/bgv030