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Diao C, Guo P, Yang W, Sun Y, Liao Y, Yan Y, Zhao A, Cai X, Hao J, Hu S, Yu W, Chen M, Wang R, Li W, Zuo Y, Pan J, Hua C, Lu X, Fan W, Zheng Z, Deng W, Luo G, Guo W. SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression. Mol Oncol 2021; 15:1180-1202. [PMID: 33305480 PMCID: PMC8024721 DOI: 10.1002/1878-0261.12878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 10/06/2020] [Accepted: 12/09/2020] [Indexed: 12/24/2022] Open
Abstract
Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism-based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull-down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem-like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human-derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co-control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6-SND1-hTERT axis may create a therapeutic vulnerability in CRC.
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Affiliation(s)
- Chaoliang Diao
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Ping Guo
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Wenjing Yang
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Yao Sun
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Yina Liao
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Yue Yan
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Anshi Zhao
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xin Cai
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Jiaojiao Hao
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Sheng Hu
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Wendan Yu
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Manyu Chen
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Ruozhu Wang
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Wenyang Li
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Yan Zuo
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Jinjin Pan
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Chunyu Hua
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Xiaona Lu
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
| | - Wenhua Fan
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Zongheng Zheng
- The Third Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Wuguo Deng
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Guangyu Luo
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center of Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Wei Guo
- Institute of Cancer Stem Cells and the First Affiliated HospitalDalian Medical UniversityChina
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Wang G, Hiramoto K, Ma N, Yoshikawa N, Ohnishi S, Murata M, Kawanishi S. Glycyrrhizin Attenuates Carcinogenesis by Inhibiting the Inflammatory Response in a Murine Model of Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22052609. [PMID: 33807620 PMCID: PMC7961658 DOI: 10.3390/ijms22052609] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022] Open
Abstract
Glycyrrhizin (GL), an important active ingredient of licorice root, which weakens the proinflammatory effects of high-mobility group box 1 (HMGB1) by blocking HMGB1 signaling. In this study, we investigated whether GL could suppress inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer. ICR mice were divided into four groups (n = 5, each)—control group, GL group, colon cancer (CC) group, and GL-treated CC (CC + GL) group, and sacrificed after 20 weeks. Plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using an enzyme-linked immunosorbent assay. The colonic tissue samples were immunohistochemically stained with DNA damage markers (8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxy-guanosine), inflammatory markers (COX-2 and HMGB1), and stem cell markers (YAP1 and SOX9). The average number of colonic tumors and the levels of IL-6 and TNF-α in the CC + GL group were significantly lower than those in the CC group. The levels of all inflammatory and cancer markers were significantly reduced in the CC + GL group. These results suggest that GL inhibits the inflammatory response by binding HMGB1, thereby inhibiting DNA damage and cancer stem cell proliferation and dedifferentiation. In conclusion, GL significantly attenuates the pathogenesis of AOM/DSS-induced colorectal cancer by inhibiting HMGB1-TLR4-NF-κB signaling.
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Affiliation(s)
- Guifeng Wang
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan;
- Sakuranomori Shiroko Home, Social Service Elderly Facilities, Suzuka University of Medical Science, Suzuka, Mie 513-0816, Japan
| | - Keiichi Hiramoto
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan; (K.H.); (S.O.)
| | - Ning Ma
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan;
- Institute of Traditional Chinese Medicine, Suzuka University of Medical Science, Suzuka, Mie 510-0226, Japan
| | - Nobuji Yoshikawa
- Matsusaka R&D Center, Cokey Co., Ltd., Matsusaka, Mie 515-0041, Japan;
| | - Shiho Ohnishi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan; (K.H.); (S.O.)
| | - Mariko Murata
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan;
- Correspondence: (M.M.); (S.K.); Tel.: +81-59-231-5011 (M.M.); +81-59-340-0550 (S.K.)
| | - Shosuke Kawanishi
- Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan
- Correspondence: (M.M.); (S.K.); Tel.: +81-59-231-5011 (M.M.); +81-59-340-0550 (S.K.)
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Chartier LC, Howarth GS, Trinder D, Mashtoub S. Emu oil and grape seed extract reduce tumour burden and disease parameters in murine colitis-associated colorectal cancer. Carcinogenesis 2021; 42:202-209. [PMID: 32940671 DOI: 10.1093/carcin/bgaa099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/03/2020] [Accepted: 09/16/2020] [Indexed: 01/07/2023] Open
Abstract
Ulcerative colitis is an incurable condition whereby patients are at an increased risk of developing colorectal cancer (CRC). We aimed to investigate the combination of Emu oil (EO) and grape seed extract (GSE) in an azoxymethane (AOM)/dextran sulphate sodium (DSS) model of colitis-associated CRC (CA-CRC). C57BL/6 mice (n = 10/group) were injected i.p. with saline or AOM (7.4 mg/kg) and underwent three DSS/water cycles. Mice were orally-gavaged thrice weekly with water (80 μl), EO (80 μl), GSE (80 μl; 400 mg/kg) or combined EO/GSE (160 μl). Mice were euthanized on day 63. AOM/DSS induced significant bodyweight loss (max -21%) and increased disease activity index (DAI) (max +83%) throughout the trial (P < 0.05). EO (max -53%), GSE (max -51%) and EO/GSE (max -71%) reduced DAI scores in AOM/DSS mice in all DSS cycles (P < 0.05). EO/GSE-treatment in AOM/DSS mice resulted in further DAI reduction compared with EO (max -62%) and GSE (max -71%) alone (P < 0.05). AOM/DSS mice presented with severe colonoscopically-assessed colitis at all time-points, which was reduced by EO, GSE and EO/GSE (P < 0.05). EO, GSE and EO/GSE reduced the number of colonic tumours compared with AOM/DSS controls (P < 0.05). Myeloperoxidase (acute inflammation) and fluorescein isothiocyanate-dextran levels (intestinal permeability) were increased in AOM/DSS controls (P < 0.05). EO (-58%) and EO/GSE (-77%) reduced fluorescein isothiocyanate-dextran compared with AOM/DSS controls (P < 0.05), with no effect on myeloperoxidase. Histologically-assessed severity scores were increased in the distal colon of AOM/DSS mice compared with saline (P < 0.05), with no effect observed following treatment. The combination of EO and GSE improved clinical indicators and reduced colonic tumours in AOM/DSS treated mice, suggesting potential in CA-CRC management.
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Affiliation(s)
- Lauren C Chartier
- Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, South Australia, Australia
| | - Gordon S Howarth
- Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, South Australia, Australia
- School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy campus, Roseworthy, South Australia, Australia
| | - Debbie Trinder
- Medical School, The University of Western Australia, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
- Harry Perkins Institute of Medical Research, Murdoch, Western Australia, Australia
| | - Suzanne Mashtoub
- Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Department of Gastroenterology, Women's and Children's Hospital, North Adelaide, South Australia, Australia
- Medical School, The University of Western Australia, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
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Chartier LC, Howarth GS, Mashtoub S. Chemotherapy-induced mucositis development in a murine model of colitis-associated colorectal cancer. Scand J Gastroenterol 2020; 55:47-54. [PMID: 31825688 DOI: 10.1080/00365521.2019.1699601] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/11/2019] [Accepted: 11/26/2019] [Indexed: 02/04/2023]
Abstract
Objectives: Ulcerative colitis is an incurable inflammatory bowel disease that increases the risk of colorectal cancer (CRC). 5-Fluorouracil (5-FU) is the predominant chemotherapy for CRC patients; however, undesirable side-effects, including mucositis, are common. This study utilised 5-FU-treatment in a model of colitis-associated CRC to develop a pre-clinical setting of intestinal mucositis coincident with manifestation of CRC.Materials/methods: On day 0, female C57BL/6 mice (n = 10/group); (1) saline control, (2) AOM/DSS control, or (3) AOM/DSS + 5-FU were injected with saline or AOM (i.p; 7.4 mg/kg). Groups 2 and 3 underwent cycles of seven days 2%w/v DSS followed by 14 days plain water. After three cycles, 5-FU was administered weekly (i.p; 75 mg/kg) to group 3 for five weeks. Clinical indicators were measured daily and colonoscopy performed at four time-points. Mice were euthanized at 13 weeks (day 91). Intestinal sections were collected for histological and biochemical analyses. p < .05 was considered significant.Results: AOM/DSS resulted in bodyweight loss, increased disease activity index, colitis-severity and tumour number compared to saline controls (p < .05). 5-FU-treatment in AOM/DSS mice decreased bodyweight and disease activity index at selected time-points compared to AOM/DSS controls (p < .05). 5-FU did not impact colitis-severity or overall tumour burden; although, resulted in fewer small tumours compared to AOM/DSS controls (<2mm; p < .05). AOM/DSS increased histological severity scores in intestinal sections (p < .05), however, 5-FU-treatment did not further increase histologically-assessed disease severity (p > .05).Conclusion: Weekly 5-FU administration at a dose of 75 mg/kg was insufficient to reduce overall tumour burden or induce intestinal mucositis in the AOM/DSS mouse model.
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Affiliation(s)
- Lauren C Chartier
- Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
- Gastroenterology Department, Women's and Children's Hospital, North Adelaide, Australia
| | - Gordon S Howarth
- Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
- Gastroenterology Department, Women's and Children's Hospital, North Adelaide, Australia
- School of Animal & Veterinary Sciences, The University of Adelaide, Roseworthy, Australia
| | - Suzanne Mashtoub
- Discipline of Physiology, Adelaide Medical School, The University of Adelaide, Adelaide, Australia
- Gastroenterology Department, Women's and Children's Hospital, North Adelaide, Australia
- School of Medicine, The University of Western Australia, Murdoch, Australia
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Convallatoxin protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB signaling through activation of PPARγ. Pharmacol Res 2019; 147:104355. [DOI: 10.1016/j.phrs.2019.104355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 07/08/2019] [Accepted: 07/15/2019] [Indexed: 01/14/2023]
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Abstract
Interleukin-32 (IL-32) was originally identified in natural killer (NK) cells activated by IL-2 in 1992. Thus, it was named NK cell transcript 4 (NK4) because of its unknown function at that time. The function of IL-32 has been elucidated over the last decade. IL-32 is primarily considered to be a booster of inflammatory reactions because it is induced by pro-inflammatory cytokines and stimulates the production of those cytokines and vice versa. Therefore, many studies have been devoted to studying the roles of IL-32 in inflammation-associated cancers, including gastric, colon cancer, and hepatocellular carcinoma. At the same time, roles of IL-32 have also been discovered in other cancers. Collectively, IL-32 fosters the tumor progression by nuclear factor-κB (NF-κB)-mediated cytokines and metalloproteinase production, as well as stimulation of differentiation into immunosuppressive cell types in some cancer types. However, it is also able to induce tumor cell apoptosis and enhance NK and cytotoxic T cell sensitivity in other cancer types. In this review, we will address the function of each IL-32 isoform in different cancer types studied to date, and suggest further strategies to comprehensively elucidate the roles of IL-32 in a context-dependent manner.
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Affiliation(s)
- Sora Han
- Research Institute for Women's Health, Sookmyung Women's University, Seoul 04310, Korea
| | - Young Yang
- Department of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea
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Araki A, Jin L, Nara H, Takeda Y, Nemoto N, Gazi MY, Asao H. IL-21 Enhances the Development of Colitis-Associated Colon Cancer: Possible Involvement of Activation-Induced Cytidine Deaminase Expression. THE JOURNAL OF IMMUNOLOGY 2019; 202:3326-3333. [DOI: 10.4049/jimmunol.1800550] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 03/26/2019] [Indexed: 02/06/2023]
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Kang JH, Choi S, Jang JE, Ramalingam P, Ko YT, Kim SY, Oh SH. Wasabia japonica is a potential functional food to prevent colitis via inhibiting the NF-κB signaling pathway. Food Funct 2017; 8:2865-2874. [PMID: 28726958 DOI: 10.1039/c7fo00576h] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are prevalent and debilitating health problems worldwide. Many types of drugs are used to treat IBDs, but they exhibit adverse effects such as vomiting, nausea, abdominal pain, diarrhea, etc. In order to overcome the limitations of current therapeutic drugs, scientists have searched for functional foods from natural resources. In this study, we investigated the anti-colitic effects of Wasabia japonica extract in a DSS-induced colitis model. Wasabi japonica is a plant of the Brassicaceae family that has recently been reported to exhibit properties of detoxification, anti-inflammation, and induction of apoptosis in cancer cells. In this study, we generated wasabi ethanol extract (WK) and assessed its anti-colitic effect. In addition, in order to improve delivery of the extract to the colon, WK was coated with 5% Eudragit S100 (WKE), after which the anti-colitic effects of WKE were assessed. In conclusion, WK prevented development of colitis through inhibition of the NF-kB signaling pathway and recovery of epithelial tight junctions. In addition, the anti-colitic effect of WK was enhanced by improving its delivery to the colon by coating the WK with Eudragit S100. Therefore, we suggest that wasabi can be used as a new functional food to prevent IBDs due to its anti-colitic effect.
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Affiliation(s)
- Ju-Hee Kang
- Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
| | - Seungho Choi
- College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Jeong-Eun Jang
- Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
| | - Prakash Ramalingam
- Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
| | - Young Tag Ko
- Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
| | - Sun Yeou Kim
- Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
| | - Seung Hyun Oh
- Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, Republic of Korea.
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Chen JX, Wang H, Liu A, Zhang L, Reuhl K, Yang CS. From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells. Toxicol Sci 2016; 155:224-233. [PMID: 27664423 DOI: 10.1093/toxsci/kfw190] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In the past decades, experimental rodent models developed to study the pathogenesis of human colorectal cancer (CRC) generally employed synthetic chemical carcinogens or genetic manipulation. Our lab, in order to establish a more physiologically relevant CRC model, recently developed a colon carcinogenesis model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS)-induced colitis in the cytochrome P450 1A-humanized (hCYP1A) mice. The resulting colon tumors shared many histologic and molecular features of human colon cancer. In this study, we characterized the early stages of PhIP/DSS-induced colon carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the colon mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas. Molecular analysis of the early time-points (ie, days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/β-catenin mutations and β-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent normal tissues. In addition, we investigated the role of Lgr5+ colon stem cells in the PhIP/DSS-induced colon carcinogenesis and found the presence of Lgr5-enhance green fluorescent protein-expressing cells amidst some ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5+ stem cells in this dietary carcinogen-induced, inflammation-promoted colon carcinogenesis model. Overall, the findings suggest that PhIP/DSS-induced colon carcinogenesis is likely initiated by dominant active Ctnnb1/β-catenin mutation in residual epithelial cells, which when promoted by colitis, developed into high-grade dysplasia and adenocarcinoma.
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Affiliation(s)
- Jayson X Chen
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Hong Wang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Anna Liu
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Lanjing Zhang
- Department of Pathology, University Medical Center of Princeton, Plainsboro, New Jersey
| | - Kenneth Reuhl
- Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Chung S Yang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey;
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Peterlik D, Flor PJ, Uschold-Schmidt N. The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders. Curr Neuropharmacol 2016; 14:514-39. [PMID: 27296643 PMCID: PMC4983752 DOI: 10.2174/1570159x13666150515234920] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 04/04/2015] [Accepted: 05/12/2015] [Indexed: 12/28/2022] Open
Abstract
Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders.
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Affiliation(s)
| | - Peter J Flor
- Faculty of Biology and Preclinical Medicine, University of Regensburg, D-93053 Regensburg, Germany.
| | - Nicole Uschold-Schmidt
- Faculty of Biology and Preclinical Medicine, University of Regensburg, D-93053 Regensburg, Germany.
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11
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Li N, Yousefi M, Nakauka-Ddamba A, Li F, Vandivier L, Parada K, Woo DH, Wang S, Naqvi AS, Rao S, Tobias J, Cedeno RJ, Minuesa G, Y K, Barlowe TS, Valvezan A, Shankar S, Deering RP, Klein PS, Jensen ST, Kharas MG, Gregory BD, Yu Z, Lengner CJ. The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins. Cell Rep 2015; 13:2440-2455. [PMID: 26673327 DOI: 10.1016/j.celrep.2015.11.022] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 09/08/2015] [Accepted: 11/04/2015] [Indexed: 12/19/2022] Open
Abstract
Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.
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Affiliation(s)
- Ning Li
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maryam Yousefi
- Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Angela Nakauka-Ddamba
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Fan Li
- Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lee Vandivier
- Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kimberly Parada
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Dong-Hun Woo
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shan Wang
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ammar S Naqvi
- Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shilpa Rao
- PENN Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - John Tobias
- PENN Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ryan J Cedeno
- Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Gerard Minuesa
- Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Katz Y
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Trevor S Barlowe
- Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Alexander Valvezan
- Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sheila Shankar
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Peter S Klein
- Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shane T Jensen
- Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael G Kharas
- Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Brian D Gregory
- Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Zhengquan Yu
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China.
| | - Christopher J Lengner
- Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Langgartner D, Füchsl AM, Uschold-Schmidt N, Slattery DA, Reber SO. Chronic subordinate colony housing paradigm: a mouse model to characterize the consequences of insufficient glucocorticoid signaling. Front Psychiatry 2015; 6:18. [PMID: 25755645 PMCID: PMC4337237 DOI: 10.3389/fpsyt.2015.00018] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/29/2015] [Indexed: 12/30/2022] Open
Abstract
Chronic, in particular chronic psychosocial, stress is a burden of modern societies and known to be a risk factor for numerous somatic and affective disorders (in detail referenced below). However, based on the limited existence of appropriate, and clinically relevant, animal models for studying the effects of chronic stress, the detailed behavioral, physiological, neuronal, and immunological mechanisms linking stress and such disorders are insufficiently understood. To date, most chronic stress studies in animals employ intermittent exposure to the same (homotypic) or to different (heterotypic) stressors of varying duration and intensity. Such models are only of limited value, since they do not adequately reflect the chronic and continuous situation that humans typically experience. Furthermore, application of different physical or psychological stimuli renders comparisons to the mainly psychosocial stressors faced by humans, as well as between the different stress studies almost impossible. In contrast, rodent models of chronic psychosocial stress represent situations more akin to those faced by humans and consequently seem to hold more clinical relevance. Our laboratory has developed a model in which mice are exposed to social stress for 19 continuous days, namely the chronic subordinate colony housing (CSC) paradigm, to help bridge this gap. The main aim of the current review article is to provide a detailed summary of the behavioral, physiological, neuronal, and immunological consequences of the CSC paradigm, and wherever possible relate the findings to other stress models and to the human situation.
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Affiliation(s)
- Dominik Langgartner
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
| | - Andrea M. Füchsl
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
| | - Nicole Uschold-Schmidt
- Laboratory of Molecular and Cellular Neurobiology, Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany
| | - David A. Slattery
- Department of Behavioural and Molecular Neurobiology, University of Regensburg, Regensburg, Germany
| | - Stefan O. Reber
- Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany
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Sliva D, Loganathan J, Jiang J, Jedinak A, Lamb JG, Terry C, Baldridge LA, Adamec J, Sandusky GE, Dudhgaonkar S. Mushroom Ganoderma lucidum prevents colitis-associated carcinogenesis in mice. PLoS One 2012; 7:e47873. [PMID: 23118901 PMCID: PMC3484149 DOI: 10.1371/journal.pone.0047873] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 09/24/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Epidemiological studies suggest that mushroom intake is inversely correlated with gastric, gastrointestinal and breast cancers. We have recently demonstrated anticancer and anti-inflammatory activity of triterpene extract isolated from mushroom Ganoderma lucidum (GLT). The aim of the present study was to evaluate whether GLT prevents colitis-associated carcinogenesis in mice. METHODS/PRINCIPAL FINDINGS Colon carcinogenesis was induced by the food-borne carcinogen (2-Amino-1-methyl-6-phenylimidazol[4,5-b]pyridine [PhIP]) and inflammation (dextran sodium sulfate [DSS]) in mice. Mice were treated with 0, 100, 300 and 500 mg GLT/kg of body weight 3 times per week for 4 months. Cell proliferation, expression of cyclin D1 and COX-2 and macrophage infiltration was assessed by immunohistochemistry. The effect of GLT on XRE/AhR, PXR and rPXR was evaluated by the reporter gene assays. Expression of metabolizing enzymes CYP1A2, CYP3A1 and CYP3A4 in colon tissue was determined by immunohistochemistry. GLT treatment significantly suppressed focal hyperplasia, aberrant crypt foci (ACF) formation and tumor formation in mice exposed to PhIP/DSS. The anti-proliferative effects of GLT were further confirmed by the decreased staining with Ki-67 in colon tissues. PhIP/DSS-induced colon inflammation was demonstrated by the significant shortening of the large intestine and macrophage infiltrations, whereas GLT treatment prevented the shortening of colon lengths, and reduced infiltration of macrophages in colon tissue. GLT treatment also significantly down-regulated PhIP/DSS-dependent expression of cyclin D1, COX-2, CYP1A2 and CYP3A4 in colon tissue. CONCLUSIONS Our data suggest that GLT could be considered as an alternative dietary approach for the prevention of colitis-associated cancer.
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Affiliation(s)
- Daniel Sliva
- Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America.
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Wakeman D, Schneider JE, Liu J, Wandu WS, Erwin CR, Guo J, Stappenbeck TS, Warner BW. Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis. Surgery 2012; 152:286-93. [PMID: 22828150 DOI: 10.1016/j.surg.2012.05.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 05/10/2012] [Indexed: 12/19/2022]
Abstract
BACKGROUND p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. Previous studies have found that p38-MAPK activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38-MAPK would lead to increased tumorigenesis in the colon. METHODS p38-MAPK was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter [villin-Cre ERT2(+), MAPK14(f/f)]. An azoxymethane and dextran sodium sulfate protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. RESULTS The number of mice that developed tumors was not statistically different when comparing wild-type mice (7/14) to inducible, intestine epithelial-deleted p38-MAPK (9/11) mice after azoxymethane/dextran sodium sulfate treatment (P = .21). However, the epithelial-deleted p38-MAPK mice developed significantly more tumors (3.7 vs 1.1; P = .008) and nearly 4 times the total tumor burden as wild-type mice (17.4 vs 4.8 mm(2); P = .03). Wild-type and epithelial-deleted p38-MAPK groups demonstrated a similar degree of colon inflammation. CONCLUSION Deletion of p38-MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Because the severity of colitis was not augmented in mice with p38-MAPK deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38-MAPK activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease.
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Affiliation(s)
- Derek Wakeman
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
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15
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The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models. J Gastroenterol 2012; 47:97-106. [PMID: 22218775 DOI: 10.1007/s00535-011-0523-6] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2011] [Accepted: 12/05/2011] [Indexed: 02/04/2023]
Abstract
Accumulating evidence has indicated that inflammatory responses are important for cancer development. Epidemiological studies have shown that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colon cancer development. Subsequently, mouse genetic studies have shown that cyclooxygenase (COX)-2, one of the target molecules of NSAIDs, and its downstream product, prostaglandin E(2) (PGE(2)), play an important role in gastrointestinal tumorigenesis. Bacterial infection stimulates the Toll-like receptor (TLR)/MyD88 pathway in tumor tissues, which leads to the induction of COX-2 in stromal cells, including macrophages. Induction of the COX-2/PGE(2) pathway in tumor stroma is important for the development and maintenance of an inflammatory microenvironment in gastrointestinal tumors. In such a microenvironment, tumor-associated macrophages express proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, and these cytokines, respectively, activate the nuclear factor (NF)-κB and Stat3 transcription factors in epithelial cells, as well as in stromal cells. Recent mouse studies have uncovered the role of such an inflammatory network in the promotion of gastrointestinal tumor development. Genetically engineered and chemically induced mouse tumor models which mimic sporadic or inflammation-associated tumorigenesis were used in these studies. In this review article, we focus on mouse genetic studies using these tumor models, which have contributed to the elucidation of the molecular mechanisms associated with the inflammatory network in gastrointestinal tumors, and we also discuss the role of each pathway in cancer development. The involvement of immune cells such as macrophages, mast cells, and regulatory T cells in tumor promotion is also discussed.
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Abstract
This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model) will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma). These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.
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Affiliation(s)
- Takuji Tanaka
- Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan.
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De Robertis M, Massi E, Poeta ML, Carotti S, Morini S, Cecchetelli L, Signori E, Fazio VM. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. J Carcinog 2011; 10:9. [PMID: 21483655 PMCID: PMC3072657 DOI: 10.4103/1477-3163.78279] [Citation(s) in RCA: 413] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 02/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci–adenoma–carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS–treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.
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Affiliation(s)
- Mariangela De Robertis
- Laboratory of Molecular Medicine and Biotechnology, CIR, Campus Bio-Medico University of Rome, Via Álvaro del Portillo 21 - 00128 Rome, Italy
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18
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Terapias anti-TNF y neoplasias. ACTA ACUST UNITED AC 2010; 6:102-5. [DOI: 10.1016/j.reuma.2009.01.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Revised: 01/15/2009] [Accepted: 01/15/2009] [Indexed: 12/17/2022]
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Increased visceral fat mass and insulin signaling in colitis-related colon carcinogenesis model mice. Chem Biol Interact 2009; 183:271-5. [PMID: 19931517 DOI: 10.1016/j.cbi.2009.11.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Revised: 11/11/2009] [Accepted: 11/16/2009] [Indexed: 12/28/2022]
Abstract
Leptin, a pleiotropic hormone regulating food intake and metabolism, plays an important role in the regulation of inflammation and immunity. We previously demonstrated that serum leptin levels are profoundly increased in mice which received azoxymethane (AOM) and dextran sulfate sodium (DSS) as tumor-initiator and -promoter, respectively, in a colon carcinogenesis model. In this study, we attempted to address underlying mechanism whereby leptin is up-regulated in this rodent model. Five-week-old male ICR mice were given a single intraperitoneal injection of AOM (week 0), followed by 1% DSS in drinking water for 7 days. Thereafter, the weights of visceral fats and the serum concentration of leptin were determined at week 20. Of interest, the relative epididymal fat pad and mesenteric fat weights, together with serum leptin levels in the AOM and/or DSS-treated mice were markedly increased compared to that in untreated mice. In addition, leptin protein production in epididymal fat pad with AOM/DSS-treated mice was 4.7-fold higher than that of control. Further, insulin signaling molecules, such as protein kinase B (Akt), S6, mitogen-activate protein kinase/extracellular signaling-regulated kinase 1/2, and extracellular signaling-regulated kinase 1/2, were concomitantly activated in epididymal fat of AOM/DSS-treated mice. This treatment also increased the serum insulin and IGF-1 levels. Taken together, our results suggest that higher levels of serum insulin and IGF-1 promote the insulin signaling in epididymal fat and thereby increasing serum leptin, which may play an crucial role in, not only obesity-related, but also -independent colon carcinogenesis.
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Abstract
The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma-carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer.
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Affiliation(s)
- Daniel W Rosenberg
- Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101, USA.
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Nathanson JW, Yadron NE, Farnan J, Kinnear S, Hart J, Rubin DT. p53 mutations are associated with dysplasia and progression of dysplasia in patients with Crohn's disease. Dig Dis Sci 2008; 53:474-80. [PMID: 17676397 DOI: 10.1007/s10620-007-9886-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2006] [Accepted: 05/21/2007] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mutations in the tumor suppressor gene p53 are associated with neoplasia in ulcerative colitis, but little is understood of their significance in Crohn's disease (CD). PURPOSE To explore p53 expression as a marker of neoplasia in CD patients. METHODS This is a retrospective review of CD patients who underwent p53 IHC staining in our center between 1995 and 2003. The p53 status was correlated to the presence and grade of neoplasia at the time of staining and in subsequent follow-up. RESULTS Fourteen CD patients had p53 assessment: eight were p53 positive and six were p53 negative. Seven of eight p53+ had dysplasia (six LGD, one HGD); one of six p53-had dysplasia (LGD) (P = 0.03). Four p53+ patients with follow-up had persistent dysplasia and two had progression to a higher grade. Three p53- patients with follow-up remained free of dysplasia. CONCLUSIONS This limited study shows that p53 over expression in CD patients is associated with dysplasia that may progress to a higher grade of neoplasia over time.
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Affiliation(s)
- Jeffrey W Nathanson
- Reva and David Logan Gastrointestinal Clinical Research Center at the University of Chicago, Chicago, IL, USA
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Belizon A, Balik E, Kirman I, Remotti H, Ciau N, Jain S, Whelan RL. Insulin-like growth factor binding protein-3 inhibits colitis-induced carcinogenesis. Dis Colon Rectum 2007; 50:1377-83. [PMID: 17668267 DOI: 10.1007/s10350-007-0258-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Chronic inflammation in the setting of inflammatory bowel disease is thought to result in altered epithelial cell growth regulation and ultimately carcinogenesis. This loss in cell growth regulation may be partially caused by a decrease in circulating intact insulin-like growth factor binding protein-3 (IFGB-3) as a result of chronic inflammation. This study evaluates the effect of IFGB-3 on carcinogenesis in the setting of colitis. METHODS A previously described animal model for colitis-induced carcinogenesis was used. Colitis was induced in both wild-type and IFGB-3 transgenic CD1 mice with a one-week oral exposure to dextran sodium sulfate (2 percent in drinking water). All mice received a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic colonic carcinogen, azoxymethane. At Week 20, the animals were killed and their colons were excised. The colons were examined by a pathologist under blinded conditions. Criteria assessed included the severity of colitis, number of aberrant crypt foci per mouse colon, incidence of colonic adenomas, and mean size of colonic adenomas. RESULTS A total of 20 mice (10 in each group) were included in the study. The severity of colitis was not significantly different between the two groups (mean colitis score wild-type = 13.2; IFGB-3 transgenic = 11; P = not significant). The average number of aberrant crypt foci per colon was significantly lower in the IFGB-3 transgenic mice compared with the wild-type mice (1.5 +/- 1.4 vs. 4.5 +/- 2.7, respectively; P < 0.0001). The number of adenomas per colon was significantly lower in IFGB-3 transgenic group (1.2 +/- 1.8) compared with the wild-type mice (3.7 +/- 2.7; P = 0.005). In addition the average size of adenomas was significantly smaller in IFGB-3 transgenic mice (1.4 +/- 1.3 mm) compared with the wild-type mice (2.6 +/- 2 mm; P = 0.013). CONCLUSIONS IFGB-3 significantly reduces the development of colonic tumors and precursor lesions in the setting of induced murine colitis. It is possible that the loss of IFGB-3 as a result of chronic inflammation may be associated with an increased rate of carcinogenesis in the inflammatory bowel disease setting. Although further studies are necessary, in theory, inhibiting the depletion of IFGB-3 or replacement of IFGB-3 may serve as a novel treatment strategy to prevent the development of colitis-induced carcinogenesis.
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Affiliation(s)
- A Belizon
- Department of Surgery, Division of Colon and Rectal Surgery, Columbia University Medical Center, New York, NY 10032, USA
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von Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn's disease. Dis Colon Rectum 2007; 50:839-55. [PMID: 17308939 DOI: 10.1007/s10350-006-0848-z] [Citation(s) in RCA: 193] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The risk of cancer in patients with Crohn's disease is not well defined. Using meta-analytical techniques, the present study was designed to quantify the risk of intestinal, extraintestinal, and hemopoietic malignancies in such patients. METHODS A literature search identified 34 studies of 60,122 patients with Crohn's disease. The incidence and relative risk of cancer were calculated for patients with Crohn's disease and compared with the baseline population of patients without Crohn's disease. Overall pooled estimates, with 95 percent confidence intervals, were obtained, using a random-effects model. RESULTS The relative risk of small bowel, colorectal, extraintestinal cancer, and lymphoma compared with the baseline population was 28.4 (95 percent confidence interval, 14.46-55.66), 2.4 (95 percent confidence interval, 1.56-4.36), 1.27 (95 percent confidence interval, 1.1-1.47), and 1.42 (95 percent confidence interval, 1.16-1.73), respectively. On subgroup analysis, patients with Crohn's disease had an increased risk of colon cancer (relative risk, 2.59; 95 percent confidence interval, 1.54-4.36) but not of rectal cancer (relative risk, 1.46; 95 percent confidence interval, 0.8-2.55). There was significant association between the anatomic location of the diseased bowel and the risk of cancer in that segment. The risk of small bowel cancer and colorectal cancer was found to be higher in North America and the United Kingdom than in Scandinavian countries with no evidence of temporal changes in the cancer incidence. CONCLUSIONS The present meta-analysis demonstrated an increased risk of small bowel, colon, extraintestinal cancers, and lymphoma in patients with Crohn's disease. Patients with extensive colonic disease that has been present from a young age should be candidates for endoscopic surveillance; however, further data are required to evaluate the risk of neoplasia over time.
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Affiliation(s)
- Alexander C von Roon
- Department of Biosurgery and Surgical Technology, Imperial College, St. Mary's Hospital, London, W2 1NY, UK
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Kästner F, Paulus W, Deckert M, Schlegel P, Evers S, Husstedt IW. [Primary CNS lymphoma in azathioprine therapy for autoimmune diseases: review of the literature and case report]. DER NERVENARZT 2007; 78:451-6. [PMID: 17375274 DOI: 10.1007/s00115-007-2255-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
We present a 31-year-old female patient with primary non-Hodgkin's lymphoma of the CNS after immunosuppressive therapy. Colitis ulcerosa had been diagnosed 2 years previously. Prophylactic therapy with azathioprine over 9 months was stopped after the development of listeria meningitis which was treated successfully with antibiotics. At this time native CCT was normal. Three months later the patient developed an epileptic seizure and multiple cerebral lesions were detected in CCT and MRI. Although antibiotic therapy was started, the cerebral lesions showed no regression. Stereotactic biopsy revealed immunochemical and histologic high-grade malignant B cell lymphoma. The risk of primary CNS lymphoma under azathioprine treatment for an autoimmune disease with a possible congenital immunodeficiency is presented and the literature is reviewed.
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Affiliation(s)
- F Kästner
- Klinik und Poliklinik für Neurologie, Universitätsklinikum, Albert-Schweitzer-Strasse 33, 48129 Münster.
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Taniguchi K, Kakinuma S, Tokairin Y, Arai M, Kohno H, Wakabayashi K, Imaoka T, Ito E, Koike M, Uetake H, Nishimura M, Yamauchi K, Sugihara KI, Shimada Y. Mild inflammation accelerates colon carcinogenesis in Mlh1-deficient mice. Oncology 2007; 71:124-30. [PMID: 17347588 DOI: 10.1159/000100522] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2006] [Accepted: 11/19/2006] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. METHOD Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1(-/-)), Mlh1 heterozygous (Mlh1(+/-)) and wild-type (Mlh1(+/+)) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, beta-catenin and p53. RESULTS Male and female Mlh1(-/-) mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1(+/-) and Mlh1(+/+) mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of beta-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis. CONCLUSION Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.
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Affiliation(s)
- Kazuki Taniguchi
- Surgical Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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Kronberger IE, Graziadei IW, Vogel W. Small bowel adenocarcinoma in Crohn’s disease: A case report and review of literature. World J Gastroenterol 2006; 12:1317-20. [PMID: 16534894 PMCID: PMC4124452 DOI: 10.3748/wjg.v12.i8.1317] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Small bowel adenocarcinomas are remarkable for their rarity, difficult diagnosis and poor prognosis. Here we report an unusual case of a 33-year-old patient in whom infiltrative adenocarcinoma of the small bowel was diagnosed after a 10-year history of Crohn’s disease. In most previously reported cases, detection of Crohn’s disease was subsequent to that of carcinoma of the small bowel or the patients involved had an even longer history of the disease. Our literature review suggests that the risk of small bowel adenocarcinoma is higher in patients with Crohn’s disease than in the overall population. We present details on epidemiology as well as clinical and diagnostic aspects of this rare disease entity.
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Affiliation(s)
- Irmgard E Kronberger
- Department of Gastroenterology and Hepatology, Anichstrasse 35, A-6020 Innsbruck, Austria.
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27
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Zamuner SR, Bak AW, Devchand PR, Wallace JL. Predisposition to colorectal cancer in rats with resolved colitis: role of cyclooxygenase-2-derived prostaglandin d2. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 167:1293-300. [PMID: 16251413 PMCID: PMC1603786 DOI: 10.1016/s0002-9440(10)61216-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colitis markedly increases the risk of developing colon cancer, but the underlying mechanisms are not fully understood. In a rat model of colitis, alterations in epithelial secretion, proliferation, and barrier function persist long after healing has occurred. In the present study, we examined whether rats that have recovered from a bout of colitis are more susceptible to preneoplastic lesions and whether this susceptibility is mediated by cyclooxygenase (COX)-2-derived prostaglandin (PG) D2. Colitis was induced by intracolonic administration of trinitrobenzenesulfonic acid. Six weeks later, weekly treatment with the carcinogen azoxymethane was initiated. Postcolitis rats exhibited significantly more aberrant crypt foci after azoxymethane treatment than controls. The postcolitis rats also exhibited markedly increased colonic PGD2 synthesis and elevated COX-2, H-PGD synthase, and beta-catenin expression. Treatment for 1 week with a selective COX-2 inhibitor or with a selective PGD2 receptor (DP1) antagonist significantly reduced susceptibility of postcolitis rats to aberrant crypt foci development, beta-catenin expression, and mucosal thickness. The results from this animal model suggest that prolonged elevation of COX-2-derived PGD2 synthesis after resolution of colitis may contribute significantly to colitis-associated increases in colon cancer incidence. PGD2 may therefore represent a rational target for therapies directed at reducing the incidence of colitis-associated colorectal cancer.
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Affiliation(s)
- Stella R Zamuner
- Mucosal Inflammation Research Group, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1, and the Division of Gastroenterology, Kelowna General Hospital, British Columbia, Canada
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Berthelot C, Cather J, Jones D, Duvic M. Atypical CD8+ Cutaneous T-Cell Lymphoma After Immunomodulatory Therapy. ACTA ACUST UNITED AC 2006; 6:329-32. [PMID: 16507211 DOI: 10.3816/clm.2006.n.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Systemic immunomodulatory agents have recently been approved for the treatment of rheumatoid arthritis and psoriasis. Although lymphomas are known to emerge in the setting of immunosuppressive therapy, it has not been well described or established for the newer biologic immune response modifiers. Herein, we describe 2 patients who developed unusual CD8+ cutaneous lymphoproliferative disorders after treatment with efalizumab and infliximab. The mechanisms and occurrence of lymphoma after immune response modifiers are discussed.
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Affiliation(s)
- Cindy Berthelot
- University of Texas Medical School Southwestern, Dallas, 77030, USA
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29
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Costello CM, Mah N, Häsler R, Rosenstiel P, Waetzig GH, Hahn A, Lu T, Gurbuz Y, Nikolaus S, Albrecht M, Hampe J, Lucius R, Klöppel G, Eickhoff H, Lehrach H, Lengauer T, Schreiber S. Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays. PLoS Med 2005; 2:e199. [PMID: 16107186 PMCID: PMC1188246 DOI: 10.1371/journal.pmed.0020199] [Citation(s) in RCA: 158] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2004] [Accepted: 05/09/2005] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The differential pathophysiologic mechanisms that trigger and maintain the two forms of inflammatory bowel disease (IBD), Crohn disease (CD), and ulcerative colitis (UC) are only partially understood. cDNA microarrays can be used to decipher gene regulation events at a genome-wide level and to identify novel unknown genes that might be involved in perpetuating inflammatory disease progression. METHODS AND FINDINGS High-density cDNA microarrays representing 33,792 UniGene clusters were prepared. Biopsies were taken from the sigmoid colon of normal controls (n = 11), CD patients (n = 10) and UC patients (n = 10). 33P-radiolabeled cDNA from purified poly(A)+ RNA extracted from biopsies (unpooled) was hybridized to the arrays. We identified 500 and 272 transcripts differentially regulated in CD and UC, respectively. Interesting hits were independently verified by real-time PCR in a second sample of 100 individuals, and immunohistochemistry was used for exemplary localization. The main findings point to novel molecules important in abnormal immune regulation and the highly disturbed cell biology of colonic epithelial cells in IBD pathogenesis, e.g., CYLD (cylindromatosis, turban tumor syndrome) and CDH11 (cadherin 11, type 2). By the nature of the array setup, many of the genes identified were to our knowledge previously uncharacterized, and prediction of the putative function of a subsection of these genes indicate that some could be involved in early events in disease pathophysiology. CONCLUSION A comprehensive set of candidate genes not previously associated with IBD was revealed, which underlines the polygenic and complex nature of the disease. It points out substantial differences in pathophysiology between CD and UC. The multiple unknown genes identified may stimulate new research in the fields of barrier mechanisms and cell signalling in the context of IBD, and ultimately new therapeutic approaches.
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Affiliation(s)
- Christine M Costello
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Nancy Mah
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Robert Häsler
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Philip Rosenstiel
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | | | - Andreas Hahn
- 3Department of Computational Biology and Applied Algorithmics, Max-Planck-Institute for Informatics, Saarbrücken, Germany
| | - Tim Lu
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Yesim Gurbuz
- 4Institute of Pathology, University Hospital Schleswig Holstein, Kiel, Germany
| | - Susanna Nikolaus
- 5Department of General Internal Medicine, University Hospital Schleswig Holstein, Kiel, Germany
| | - Mario Albrecht
- 3Department of Computational Biology and Applied Algorithmics, Max-Planck-Institute for Informatics, Saarbrücken, Germany
| | - Jochen Hampe
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Ralph Lucius
- 6Institute of Anatomy, University Hospital Schleswig Holstein, Kiel, Germany
| | - Günther Klöppel
- 4Institute of Pathology, University Hospital Schleswig Holstein, Kiel, Germany
| | - Holger Eickhoff
- 7Max-Planck-Institute for Molecular Genetics, Berlin, Germany
| | - Hans Lehrach
- 7Max-Planck-Institute for Molecular Genetics, Berlin, Germany
| | - Thomas Lengauer
- 3Department of Computational Biology and Applied Algorithmics, Max-Planck-Institute for Informatics, Saarbrücken, Germany
| | - Stefan Schreiber
- 1Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany
- *To whom correspondence should be addressed. E-mail:
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30
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Kohno H, Suzuki R, Sugie S, Tanaka T. Beta-Catenin mutations in a mouse model of inflammation-related colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sodium sulfate. Cancer Sci 2005; 96:69-76. [PMID: 15723650 PMCID: PMC11159258 DOI: 10.1111/j.1349-7006.2005.00020.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In a previous study, we developed a novel mouse model for colitis-related carcinogenesis, utilizing a single dose of azoxymethane (AOM) followed by dextran sodium sulfate (DSS) in drinking water. In the present study, we investigated whether colonic neoplasms can be developed in mice initiated with a single injection of another genotoxic colonic carcinogen 1,2-dimethylhydrazine (DMH), instead of AOM and followed by exposure of DSS in drinking water. Male crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10, 20 or 40 mg/kg body weight) of DMH and 1-week oral exposure (2% in drinking water) of a non-genotoxic carcinogen, DSS. All animals were killed at week 20, histological alterations and immunohistochemical expression of beta-catenin, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) were examined in induced colonic epithelial lesions (colonic dysplasias and neoplasms). Also, the beta-catenin gene mutations in paraffin-embedded colonic adenocarcinomas were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. The incidences of colonic neoplasms with dysplastic lesions developed were 100% with 2.29+/-0.95 multiplicity, and 100% with 10.38+/-4.00 multiplicity in mice given DMH at doses of 10 mg/kg or 20 mg/kg and 2%DSS, respectively. Although approximately half of the mice given DMH at a dose of 40 mg/kg bodyweight were dead after 2-3 days after the injection, mice who received DMH 40 mg/kg and 2%DSS had 100% incidence of colonic neoplasms with 9.75+/-6.29 multiplicity. Immunohistochemical investigation revealed that adnocarcinomas, induced by DMH at all doses and 2%DSS, showed positive reactivities against beta-catenin, COX-2 and iNOS. In DMH/DSS-induced adenocarcinomas, 10 of 11 (90.9%) adenocacrcinomas had beta-catenin gene mutations. Half of the mutations were detected at codon 37 or 41, encoding serine and threonine that are direct targets for phosphorylation by glycogen synthase kinase-3beta. The present results suggests that, as in the previously reported model (AOM/DSS) our experimental protocol, DMH initiation followed by DSS, may provide a novel and useful mouse model for investigating inflammation-related colon carcinogenesis and for identifying xenobiotics with modifying effects.
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Affiliation(s)
- Hiroyuki Kohno
- Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan.
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31
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Getliffe KM, Al Dulaimi D, Martin-Ruiz C, Holder RL, von Zglinicki T, Morris A, Nwokolo CU. Lymphocyte telomere dynamics and telomerase activity in inflammatory bowel disease: effect of drugs and smoking. Aliment Pharmacol Ther 2005; 21:121-31. [PMID: 15679761 DOI: 10.1111/j.1365-2036.2005.02311.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The chromosome instability observed in peripheral blood lymphocytes in ulcerative colitis could be a biomarker of cancer susceptibility. AIM To determine whether accelerated telomere shortening could explain chromosome instability and assess the effect of drugs and smoking on telomere dynamics in these cells. METHODS Peripheral blood lymphocytes were isolated from ulcerative colitis, Crohn's disease and non-inflammatory bowel disease control patients. Telomere lengths were measured by quantitative real-time polymerase chain reaction. After activation and cell separation, telomerase activity and human telomerase reverse transcriptase messenger ribonucleic acid were measured by telomerase repeat amplification protocol enzyme-linked immunosorbent serological assay and quantitative real-time polymerase chain reaction, respectively. RESULTS Age-related telomere loss in peripheral blood lymphocytes was similar in ulcerative colitis, Crohn's disease and control patients. Telomerase activity decreased with age in all groups and correlated positively with telomere length (r = 0.489, P = 0.006). Among Crohn's disease patients, azathioprine was associated with decreased telomerase activity (0.66 vs. 1.54, P = 0.026, P < 0.05) and smoking was associated with decreased human telomerase reverse transcriptase mRNA expression (10.5 vs. 33.3, P = 0.036, P < 0.05). CONCLUSIONS Telomere shortening is not accelerated and therefore cannot be the cause of the chromosome instability observed in ulcerative colitis peripheral blood lymphocytes. Azathioprine and cigarette smoking modify telomerase expression in these cells.
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Affiliation(s)
- K M Getliffe
- Department of Biological Sciences, University of Warwick, Coventry, UK
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32
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Wang JG, Wang DF, Lv BJ, Si JM. A novel mouse model for colitis-associated colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sulfate sodium. World J Gastroenterol 2004; 10:2958-62. [PMID: 15378773 PMCID: PMC4576252 DOI: 10.3748/wjg.v10.i20.2958] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To develop an efficient animal colitis-associated carcinogenesis model and to detect the expression of β -catenin and p53 in this new model.
METHODS: Dysplasia and cancer were investigated in mice pretreated with a single intraperitoneal injection of 20 mg/kg body mass of 1,2-dimethylhydrazine prior to three repetitive oral administrations of 30 g/L dextran sulfate sodium to give conditions similar to the clinically observed active and remission phases. Immunohistochemical staining of β - catenin and p53 was performed on paraffin-imbedded specimens of animals with cancer and/or dysplasia, those without dysplasia and the normal control animals.
RESULTS: At wk 11, four early-invasive adenocarcinomas and 36 dysplasia were found in 10 (90.9%) of the 11 mice that underwent 1,2-dimethylhydrazine-pretreatment with 3 cycles of 30 g/L dextran sulfate sodium-exposure. Dysplasia and/or cancer occurred as flat lesions or as dysplasia-associated lesion or mass (DALM) as observed in humans. Colorectal carcinogenesis occurred primarily on the distal portion of the large intestine. No dysplasia and/or cancer lesion was observed in the control groups with 1,2-dimethylhydrazine pretreatment or 3 cycles of 30 g/L dextran sulfate sodium exposure alone. Immunohistochemical investigation revealed that β -catenin was translocated from cell membrane to cytoplasm and/or nucleus in 100% of cases with dysplasia and neoplasm, while normal membrane staining was observed in cases without dysplasia and the normal control animals. Nuclear expression of p53 was not detected in specimens.
CONCLUSION: A single dose of procarcinogen followed by induction of chronic ulcerative colitis results in a high incidence of colorectal dysplasia and cancer. Abnormal expression of β -catenin occurs frequently in dysplasia and cancer. This novel mouse model may provide an excellent vehicle for studying colitis-related colon carcinogenesis.
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Affiliation(s)
- Jian-Guo Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China.
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33
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Mannick EE, Bonomolo JC, Horswell R, Lentz JJ, Serrano MS, Zapata-Velandia A, Gastanaduy M, Himel JL, Rose SL, Udall JN, Hornick CA, Liu Z. Gene expression in mononuclear cells from patients with inflammatory bowel disease. Clin Immunol 2004; 112:247-57. [PMID: 15308118 DOI: 10.1016/j.clim.2004.03.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2003] [Accepted: 03/17/2004] [Indexed: 01/16/2023]
Abstract
OBJECTIVES Discovery of Nod2 as the inflammatory bowel disease 1 (IBD1) susceptibility gene has brought to light the significance of mononuclear cells in inflammatory bowel disease pathogenesis. The purpose of this study was to examine changes in gene expression in peripheral blood mononuclear cells in patients with untreated Crohn's disease (CD) and ulcerative colitis (UC) as compared to patients with other inflammatory gastrointestinal disorders and to healthy controls. METHODS We used a 2400 gene cDNA glass slide array (MICROMAX) to examine gene expression in peripheral blood mononuclear cells from seven patients with Crohn's disease, five patients with ulcerative colitis, 10 patients with other inflammatory gastrointestinal disorders, and 22 age- and sex-matched controls. Results. Novel categories of genes differentially expressed in Crohn's disease and ulcerative colitis patients included genes regulating hematopoietic cell differentiation and leukemogenesis, lipid raft-associated signaling, the actin cytoskeleton, and vesicular trafficking. CONCLUSIONS Altered gene expression in mononuclear cells may contribute to inflammatory bowel disease pathogenesis.
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Suzuki R, Kohno H, Sugie S, Tanaka T. Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate. Cancer Sci 2004; 95:721-7. [PMID: 15471557 PMCID: PMC11159186 DOI: 10.1111/j.1349-7006.2004.tb03252.x] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2004] [Revised: 07/26/2004] [Accepted: 08/02/2004] [Indexed: 12/16/2022] Open
Abstract
Previously, we proposed a novel mouse model for colitis-related colon carcinogenesis using azoxymethane (AOM) and dextran sodium sulfate (DSS) (Cancer Sci 2003; 94: 965-73). In the current study, sequential analysis of pathological alterations during carcinogenesis in our model was conducted to establish the influence of inflammation caused by DSS on colon carcinogenesis in this model. Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight) and given 2% (w/v) DSS in the drinking water for 7 days, starting 1 week after the AOM injection. They were sequentially sacrificed at weeks 2, 3, 4, 5, 6, 9, 12, and 14 for histopathological and immunohistochemical examinations. Colonic adenomas were found in 2 (40% incidence and 0.40 +/- 0.49 multiplicity) of 5 mice at week 3 and colon carcinomas developed in 2 (40% incidence and 2.00 +/- 3.52 multiplicity) of 5 mice at week 4. Their incidence gradually increased with time and reached 100% (6.20 +/- 2.48 multiplicity) at week 6. At week 14, the multiplicity of adenocarcinoma was 9.75 +/- 2.49 (100% incidence). In addition, colonic dysplasia was noted at all time-points. The scores of colonic inflammation and nitrotyrosine immunohistochemistry were extremely high at early time-points and were well correlated. Our results suggest that combined treatment of mice with AOM and DSS generates neoplasms in the colonic mucosa via dysplastic lesions induced by nitrosative stress.
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Affiliation(s)
- Rikako Suzuki
- Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-8471, Japan
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35
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Craven M, Simpson JW, Ridyard AE, Chandler ML. Canine inflammatory bowel disease: retrospective analysis of diagnosis and outcome in 80 cases (1995-2002). J Small Anim Pract 2004; 45:336-42. [PMID: 15266855 DOI: 10.1111/j.1748-5827.2004.tb00245.x] [Citation(s) in RCA: 174] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The case records of 80 dogs in which idiopathic inflammatory bowel disease (IBD) had been diagnosed were reviewed, and owners were contacted for follow-up information using a telephone questionnaire. The types of IBD encountered were lymphocytic (n=6), lymphocytic-plasmacytic (n=38), eosinophilic (n=6) and mixed inflammation (n=30). Prednisolone, sulphasalazine, metronidazole and tylosin were the most frequently prescribed medications. At follow-up, 21 dogs (26 per cent) were classified as being in remission (for a median of 14 months), 40 dogs (50 per cent) had intermittent clinical signs (for a median of 17 months) and three dogs (4 per cent) had uncontrolled disease (for a median of 19 months). Ten dogs (13 per cent) had been euthanased due to refractory IBD and four of these had entered remission for a median of 21 months prior to developing severe relapse and refractoriness to further treatment. Six dogs (8 per cent) had been euthanased or had died for reasons unrelated to IBD. Hypoalbuminaemia at the time of diagnosis was significantly associated with a negative outcome (P=0.0007). No association was found between the site (P=0.75), type (P=0.44) and severity (P=0.75) of disease. Dietary change to single protein and carbohydrate commercial diets had no association with outcome (P=0.12). Owner assessment of quality of life at follow-up was significantly associated with outcome (P=0.006).
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Affiliation(s)
- M Craven
- University of Edinburgh, Hospital for Small Animals, Easter Bush Veterinary Centre, Roslin, Midlothian EH25 9RG
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36
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Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 2003; 94:965-73. [PMID: 14611673 PMCID: PMC11160237 DOI: 10.1111/j.1349-7006.2003.tb01386.x] [Citation(s) in RCA: 553] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
To develop an efficient animal model for colitis-related carcinogenesis, male Crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic colonic carcinogen, azoxymethane (AOM), and a 1-week oral exposure (2% in drinking water) to a non-genotoxic carcinogen, dextran sodium sulfate (DSS), under various protocols. At week 20, colonic neoplasms (adenocarcinomas, 100% incidence with 5.60 +/- 2.42 multiplicity; and adenomas, 38% incidence with 0.20 +/- 0.40 multiplicity) with dysplastic lesions developed in mice treated with AOM followed by DSS. Protocols in which AOM was given during or after DSS administration induced a few tubular adenomas or no tumors in the colon. Immunohistochemical investigation of such dysplasias and neoplasms revealed that all lesions were positive for beta-catenin, cyclooxygenase-2 and inducible nitric oxide synthase, but did not show p53 immunoreactivity. The results indicate that 1-week administration of 2% DSS after initiation with a low dose of AOM exerts a powerful tumor-promoting activity in colon carcinogenesis in male ICR mice, and may provide a novel mouse model for investigating colitis-related colon carcinogenesis and for identifying xenobiotics with modifying effects.
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Affiliation(s)
- Takuji Tanaka
- The First Department of Pathology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293.
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