The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP

Gifu-shi, Japan

The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP

Gifu-shi, Japan
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Miyamoto S.,Kyoto University | Yasui Y.,Kanazawa Medical University | Yasui Y.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP | Ohigashi H.,Kyoto University | And 3 more authors.
Chemico-Biological Interactions | Year: 2010

Obesity is known to be a risk factor for colon carcinogenesis. Although there are several reports on the chemopreventive abilities of dietary flavonoids in chemically induced colon carcinogenesis, those have not been addressed in an obesity-associated carcinogenesis model. In the present study, the effects of 3 flavonoids (chrysin, quercetin and nobiletin) on modulation of the occurrence of putative preneoplastic lesions, aberrant crypt foci (ACF), and β-catenin-accumulated crypts (BCACs) in the development of colon cancer were determined in male db/db mice with obesity and diabetic phenotypes. Male db/db mice were given 3 weekly intraperitoneal injections of azoxymethane (AOM) to induce the ACF and BCAC. Each flavonoid (100 ppm), given in the diet throughout the experimental period, significantly reduced the numbers of ACF by 68-91% and BCAC by 64-71%, as well as proliferation activity in the lesions. Clinical chemistry results revealed that the serum levels of leptin and insulin in mice treated with AOM were greater than those in the untreated group. Interestingly, the most pronounced suppression of development of preneoplastic lesions and their proliferation were observed in the quercetin-fed group, in which the serum leptin level was lowered. Furthermore, quercetin-feeding decreased leptin mRNA expression and secretion in differentiated 3T3-L1 mouse adipocytes. These results suggest that the present dietary flavonoids are able to suppress the early phase of colon carcinogenesis in obese mice, partly through inhibition of proliferation activity caused by serum growth factors. Furthermore, they indicate that certain flavonoids may be useful for prevention of colon carcinogenesis in obese humans. © 2009 Elsevier Ireland Ltd. All rights reserved.


Tanaka T.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP | Hosokawa M.,Hokkaido University | Yasui Y.,Rakuno Gakuen University | Ishigamori R.,National Cancer Research Institute | Miyashita K.,Hokkaido University
International Journal of Molecular Sciences | Year: 2011

Conjugated fatty acids (CFA) have received increased interest because of their beneficial effects on human health, including preventing cancer development. Conjugated linoleic acids (CLA) are such CFA, and have been reviewed extensively for their multiple biological activities. In contrast to other types of CFAs including CLA that are found at low concentrations (less than 1%) in natural products, conjugated linolenic acids (CLN) are the only CFAs that occur in higher quantities in natural products. Some plant seeds contain a considerably high concentration of CLN (30 to 70 wt% lipid). Our research group has screened CLN from different plant seed oils to determine their cancer chemopreventive ability. This review describes the physiological functions of CLN isomers that occur in certain plant seeds. CLN are able to induce apoptosis through decrease of Bcl-2 protein in certain human cancer cell lines, increase expression of peroxisome proliferator-activated receptor (PPAR)-γ, and up-regulate gene expression of p53. Findings in our preclinical animal studies have indicated that feeding with CLN resulted in inhibition of colorectal tumorigenesis through modulation of apoptosis and expression of PPARγ and p53. In this review, we summarize chemopreventive efficacy of CLN against cancer development, especially colorectal cancer. © 2011 by the authors; licensee MDPI, Basel, Switzerland.


Kuno T.,Gifu University | Hatano Y.,Gifu University | Tomita H.,Gifu University | Hara A.,Gifu University | And 7 more authors.
Carcinogenesis | Year: 2013

Magnesium (Mg) deficiency increases genomic instability and Mg intake has been reported to be inversely associated with a risk of colorectal cancer (CRC). This study was designed to determine whether organo-Mg in drinking water suppresses inflammation-associated colon carcinogenesis in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (AOM, 10mg/kg body weight) and followed by a 1week exposure to dextran sulfate sodium (DSS, 1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the drinking water containing 7, 35 or 175 p.p.m. organo-Mg for 13 weeks. The chemopreventive efficacy of organo-Mg was determined 16 weeks after the AOM exposure. Administration with organo-Mg at all doses caused a significant inhibition of CRC development (P< 0.01 and P< 0.001). Especially, the highest dose of organo-Mg significantly suppressed the occurrence of all the colonic pathological lesions (mucosal ulcer, dysplasia, adenoma and adenocarcinoma). Organo-Mg also significantly reduced the number of mitoses/anaphase bridging, as well as proliferation of CRC. Additionally, at week 4, organo-Mg lowered the messenger RNA expression of certain proinflammatory cytokines, such as interleukin-1β, interleukin-6, interferon-γ and inducible nitric oxide synthase in the lesion-free colorectal mucosa at week 4 but increased the Nrf-2 messenger RNA expression. Our findings that organo-Mg inhibits inflammation-related mouse colon carcinogenesis by modulating the proliferative activities and chromosomal instability of CRC and suppressing colonic inflammation may suggest potential use of organo-Mg for clinical chemoprevention trials of CRC in the inflamed colon. © The Author 2012. Published by Oxford University Press. All rights reserved.


Terakura D.,Gifu University | Shimizu M.,Gifu University | Iwasa J.,Gifu University | Baba A.,Gifu University | And 9 more authors.
Carcinogenesis | Year: 2012

Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ, p21CIP1 and p27KIP1 messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1β, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals. © The Author 2012. Published by Oxford University Press. All rights reserved.


Shimizu M.,Gifu University | Kubota M.,Gifu University | Tanaka T.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP | Moriwaki H.,Gifu University
International Journal of Molecular Sciences | Year: 2012

Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals. © 2012 by the authors; licensee MDPI, Basel, Switzerland.


Tanaka T.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP | Tanaka T.,Gifu University
Journal of Experimental and Clinical Medicine(Taiwan) | Year: 2013

Cancer chemoprevention, which is defined as the use of natural or synthetic chemical agents to reverse or suppress carcinogenic processes, is an important strategy to reduce the risk of cancer. Many laboratory studies have suggested beneficial effects of various dietary compounds (phytochemicals) in reducing the risk of cancer. Apoptosis (programmed cell death) plays a critical role in normal physiological functions, but there is a dysregulation of apoptosis in cancer as well as in other chronic diseases, such as neurodegenerative disorders. Many natural cancer chemopreventive compounds are known to induce apoptosis. At the molecular level, dietary chemopreventive compounds can modulate a number of key elements of cell signal transduction pathways involved in the apoptotic process. This review stresses the importance of apoptosis induction by natural dietary agents for cancer chemoprevention. © 2013, Taipei Medical University. Published by Elsevier Taiwan LLC.


Yasui Y.,Kanazawa Medical University | Tanaka T.,Kanazawa Medical University | Tanaka T.,The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP
American Journal of Community Psychology | Year: 2011

Accumulating epidemiological, clinical, and experimental evidence demonstrates that chronic inflammation plays a critical role in multistep oncogenesis. While long-term users of selective cycloxygenase (COX)-2 inhibitors (- coxibs) and non-steroidal anti-inflammatory drugs (NSAIDs) exert a reduced risk of development of certain types of cancer, including colorectal cancer (CRC), the adverse gastrointestinal and cardiovascular side effects associated with these drugs have limited their daily use for cancer chemoprevention. The role of various proinflammatory mediators during carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis has been recently highlighted. A variety of chemopreventive phytochemicals and phytonutrients are able to alter or correct undesired cellular functions caused by abnormal pro-inflammatory signal transmissions that are mediated by NF-kappaB, etc. Modulation of cellular signaling involved in chronic inflammatory responses, induced by anti-inflammatory agents, hence provides a rational and practical strategy in molecular target-based cancer chemoprevention. This short review will focus on the role of chronic inflammation in colorectal oncogenesis and introduce dietary cancer chemopreventive agents with anti-inflammatory activity. © 2010 Bentham Science Publishers Ltd.


PubMed | The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2010

Colorectal cancer (CRC) is the third most common epithelial malignancy in the world. Since CRC develops slowly from removable precancerous lesions, detection of the lesion at an early stage by regular health examinations can reduce the incidence and mortality of this malignancy. Colonoscopy significantly improves the detection rate of CRC, but the examination is expensive and inconvenient. Therefore, we need novel biomarkers that are non-invasive to enable us to detect CRC quite early. A number of validation studies have been conducted to evaluate genetic, epigenetic or protein markers for identification in the stool and/or serum. Currently, the fecal occult blood test is the most widely used method of screening for CRC. However, advances in genomics and proteomics will lead to the discovery of novel non-invasive biomarkers.


PubMed | The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP
Type: | Journal: International journal of inflammation | Year: 2012

Chronic inflammation is a well-recognized risk factor for development of human cancer in several tissues, including large bowel. Inflammatory bowel disease, including ulcerative colitis and Crohns disease, is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer development. Several molecular events involved in chronic inflammatory process may contribute to multistep carcinogenesis of human colorectal cancer in the inflamed colon. They include overproduction of reactive oxygen and nitrogen species, overproduction and upregulation of productions and enzymes of arachidonic acid biosynthesis pathway and cytokines, and intestinal immune system dysfunction. In this paper, I will describe several methods to induce colorectal neoplasm in the inflamed colon. First, I will introduce a protocol of a novel inflammation-associated colon carcinogenesis in mice. In addition, powerful tumor-promotion/progression activity of dextran sodium sulfate in the large bowel of Apc(Min/+) mice will be described. Finally, chemoprevention of inflammation-associated colon carcinogenesis will be mentioned.


PubMed | The Tohkai Cytopathology Institute Cancer Research and Prevention TCI CaRP
Type: | Journal: Journal of oncology | Year: 2011

Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer.

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