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Angiogenesis in Inflammatory Bowel Disease. Int J Inflam 2015; 2015:970890. [PMID: 26839731 PMCID: PMC4709626 DOI: 10.1155/2015/970890] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/07/2015] [Accepted: 12/08/2015] [Indexed: 12/24/2022] Open
Abstract
Angiogenesis is an important component of pathogenesis of inflammatory bowel disease (IBD). Chronic inflammation and angiogenesis are two closely related processes. Chronic intestinal inflammation is dependent on angiogenesis and this angiogenesis is modulated by immune system in IBD. Angiogenesis is a very complex process which includes multiple cell types, growth factors, cytokines, adhesion molecules, and signal transduction. Lymphangiogenesis is a new research area in the pathogenesis of IBD. While angiogenesis supports inflammation via leukocyte migration, carrying oxygen and nutrients, on the other hand, it has a major role in wound healing. Angiogenic molecules look like perfect targets for the treatment of IBD, but they have risk for serious side effects because of their nature.
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Funagayama M, Kondo K, Chijiiwa K, Kataoka H. Expression of hepatocyte growth factor activator inhibitor type 1 in human hepatocellular carcinoma and postoperative outcomes. World J Surg 2011; 34:1563-71. [PMID: 20213201 DOI: 10.1007/s00268-010-0517-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Hepatocyte growth factor activator inhibitor type 1 (HAI-1), one of the Kunitz-type serine protease inhibitors, has an important role in cancer progression through regulation of the activity of hepatocyte growth factor. HAI-1 is expressed in hepatocellular carcinoma (HCC) to various degrees. Investigation of the relationship between HAI-1 expression and clinicopathological features of HCC may contribute to improved treatment outcomes for HCC through understanding the mechanism of tumor progression or improvement in the prediction of tumor malignancy. METHODS The study included 121 HCC patients treated surgically from 1996 to 2005. We performed immunohistological examination for HAI-1 in resected HCC specimens by use of anti-human HAI-1 monoclonal antibody. Clinicopathological features, including postoperative overall survival (OS) and disease-free survival (DFS) rates, were compared between the immunoreaction positive and negative groups. RESULTS The immunoreaction positive group included 38 patients (31%), and the negative group included 83 patients (69%). OS and DFS rates were significantly higher in the HAI-1 negative group than in the positive group. HAI-1 positivity related to multiplicity, vascular invasion, and characteristics of advanced tumor stage. In multivariate analysis, expression of HAI-1 was a significant independent prognostic tumor factor. CONCLUSIONS Expression of HAI-1 in HCC cells is associated with poor prognosis for HCC patients. HAI-1 may be important in HCC progression and may be a new prognostic factor for HCC.
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Affiliation(s)
- Mayumi Funagayama
- Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
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Antalis TM, Shea-Donohue T, Vogel SN, Sears C, Fasano A. Mechanisms of disease: protease functions in intestinal mucosal pathobiology. ACTA ACUST UNITED AC 2007; 4:393-402. [PMID: 17607295 PMCID: PMC3049113 DOI: 10.1038/ncpgasthep0846] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2007] [Accepted: 04/20/2007] [Indexed: 12/16/2022]
Abstract
Of all our organ systems, the gastrointestinal tract contains the highest levels of endogenous and exogenous proteases (also known as proteinases and peptidases); however, our understanding of their functions and interactions within the gastrointestinal tract is restricted largely to nutrient digestion. The gut epithelium is a sensor of the luminal environment, not only controlling digestive, absorptive and secretory functions, but also relaying information to the mucosal immune, vascular and nervous systems. These functions involve a complex array of cell types that elaborate growth factors, cytokines and extracellular matrix (ECM) proteins, the activity and availability of which are regulated by proteases. Proteolytic activity must be tightly regulated in the face of diverse environmental challenges, because unrestrained or excessive proteolysis leads to pathological gastrointestinal conditions. Moreover, enteric microbes and parasites can hijack proteolytic pathways through 'pathogen host mimicry'. Understanding how the protease balance is maintained and regulated in the intestinal epithelial cell microenvironment and how proteases contribute to physiological and pathological outcomes will undoubtedly contribute to the identification of new potential therapeutic targets for gastrointestinal diseases.
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Affiliation(s)
| | | | | | | | - Alessio Fasano
- Correspondence, Mucosal Biology Research Center, University of Maryland School of Medicine, Room S345, HSF II Building, 20 Penn Street, Baltimore, MD 21201, USA,
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Chidlow JH, Shukla D, Grisham MB, Kevil CG. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am J Physiol Gastrointest Liver Physiol 2007; 293:G5-G18. [PMID: 17463183 DOI: 10.1152/ajpgi.00107.2007] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Angiogenesis is now understood to play a major role in the pathology of chronic inflammatory diseases and is indicated to exacerbate disease pathology. Recent evidence shows that angiogenesis is crucial during inflammatory bowel disease (IBD) and in experimental models of colitis. Examination of the relationship between angiogenesis and inflammation in experimental colitis shows that initiating factors for these responses simultaneously increase as disease progresses and correlate in magnitude. Recent studies show that inhibition of the inflammatory response attenuates angiogenesis to a similar degree and, importantly, that inhibition of angiogenesis does the same to inflammation. Recent data provide evidence that differential regulation of the angiogenic mediators involved in IBD-associated chronic inflammation is the root of this pathological angiogenesis. Many factors are involved in this phenomenon, including growth factors/cytokines, chemokines, adhesion molecules, integrins, matrix-associated molecules, and signaling targets. These factors are produced by various vascular, inflammatory, and immune cell types that are involved in IBD pathology. Moreover, recent studies provide evidence that antiangiogenic therapy is a novel and effective approach for IBD treatment. Here we review the role of pathological angiogenesis during IBD and experimental colitis and discuss the therapeutic avenues this recent knowledge has revealed.
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Affiliation(s)
- John H Chidlow
- Department of Pathology, LSU Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA
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Park EC, Hayata T, Cho KWY, Han JK. Xenopus cDNA microarray identification of genes with endodermal organ expression. Dev Dyn 2007; 236:1633-49. [PMID: 17474120 DOI: 10.1002/dvdy.21167] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The endoderm is classically defined as the innermost layer of three Metazoan germ layers. During organogenesis, the endoderm gives rise to the digestive and respiratory tracts as well as associated organs such as the liver, pancreas, and lung. At present, however, how the endoderm forms the variety of cell types of digestive and respiratory tracts as well as the budding organs is not well understood. In order to investigate the molecular basis and mechanism of organogenesis and to identify the endodermal organ-related marker genes, we carried out microarray analysis using Xenopus cDNA chips. To achieve this goal, we isolated the Xenopus gut endoderm from three different stages of Xenopus organogenesis, and separated each stage of gut endoderm into anterior and posterior regions. Competitive hybridization of cDNA between the anterior and posterior endoderm regions, to screen genes that specifically expressed in the major organs, revealed 915 candidates. We then selected 104 clones for in situ hybridization analysis. Here, we report the identification and expression patterns of the 104 Xenopus endodermal genes, which would serve as useful markers for studying endodermal organ development.
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Affiliation(s)
- Edmond Changkyun Park
- Division of Molecular and Life Sciences, Pohang University of Science and Technology, Kyungbuk, Republic of Korea
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Popov SV, Markov PA, Nikitina IR, Petrishev S, Smirnov V, Ovodov YS. Preventive effect of a pectic polysaccharide of the common cranberry Vaccinium oxycoccos L. on acetic acid-induced colitis in mice. World J Gastroenterol 2006; 12:6646-51. [PMID: 17075978 PMCID: PMC4125670 DOI: 10.3748/wjg.v12.i41.6646] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [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
AIM: To study isolation and chemical characterization of pectin derived from the common cranberry Vaccinium oxycoccos L. (oxycoccusan OP) and the testing of its preventive effect on experimental colitis.
METHODS: Mice were administrated orally with OP two days prior to a rectal injection of 5% acetic acid and examined for colonic damage 24 h later. Colonic inflammation was characterized by macroscopical injury and enhanced levels of myeloperoxidase activity measured spectrophotometrically with o-phenylene diamine as the substrate. The mucus contents of the colon were determined by the Alcian blue dye binding method. Vascular permeability was estimated using 4% Evans blue passage after i.p. injection of 0.05 mol/L acetic acid.
RESULTS: In the mice treated with OP, colonic macroscopic scores (1.1 ± 0.4 vs 2.7, P < 0.01) and the total square area of damage (10 ± 2 vs 21 ± 7, P < 0.01) were significantly reduced when compared with the vehicle-treated colitis group. OP was shown to decrease the tissue myeloperoxidase activity in colons (42 ± 11 vs 112 ± 40, P < 0.01) and enhance the amount of mucus of colitis mice (0.9 ± 0.1 vs 0.4 ± 0.1, P < 0.01). The level of colonic malondialdehyde was noted to decrease in OP-pretreated mice (3.6 ± 0.7 vs 5.1 ± 0.8, P < 0.01). OP was found to decrease the inflammatory status of mice as was determined by reduction of vascular permeability (161 ± 34 vs 241 ± 21, P < 0.01). Adhesion of peritoneal neutrophils and macrophages was also shown to decrease after administration of OP (141 ± 50 vs 235 ± 37, P < 0.05).
CONCLUSION: Thus, a preventive effect of pectin from the common cranberry, namely oxycoccusan OP, on acetic acid-induced colitis in mice was detected. A reduction of neutrophil infiltration and antioxidant action may be implicated in the protective effect of oxycoccusan.
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Affiliation(s)
- Sergey V Popov
- Department of Molecular Immunologby and Biotechnology, Institute of Physiology, Komi Science Centre, the Urals Branch of the Russian Academy of Sciences, 50 Pervomaiskaya str., Syktyvkar 167982, Russia.
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Sasaki M, Ikeda H, Kataoka H, Nakanuma Y. Augmented expression of hepatocytes growth factor activator inhibitor type 1 (HAI-1) in intrahepatic small bile ducts in primary biliary cirrhosis. Virchows Arch 2006; 449:462-71. [PMID: 16941151 DOI: 10.1007/s00428-006-0257-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2006] [Accepted: 06/17/2006] [Indexed: 12/16/2022]
Abstract
The repair system of damaged biliary mucosa was not fully clarified so far in primary biliary cirrhosis (PBC). Given that related factors of the hepatocyte growth factor (HGF) such as HGF activator (HGFA) and HGFA inhibitor type 1 (HAI-1) participate in the repair of injured gastrointestinal mucosa, we investigated the involvement of the HGF/HGFA/HAI-1 system in PBC and control livers. The expression of HGFA, HAI-1, and c-Met was examined in PBC livers (n=24), diseased livers (control, n=30), and normal livers (n=15) by immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction. We examined the expression of HGFA, HAI-1, and c-Met, and the effect of HGF administration on cell proliferation and wound healing, and HAI expression in cultured mouse biliary epithelial cells (BECs). HAI-1 expression was faint in control livers, whereas it was significantly augmented in damaged small bile ducts, bile ductules, and periportal hepatocytes in PBC (p<0.05). HGFA and c-Met were homogeneously expressed in BECs in PBC and control livers. HAI-1 expression was increased at the front of wound healing and the treatment with HGF-enhanced HAI-1 expression, cell proliferation, and wound healing in cultured BECs. HGF/HGFA/HAI-1 system may participate in biliary mucosal repair as reported in gastrointestinal mucosal repair.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan.
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Saleem M, Adhami VM, Zhong W, Longley BJ, Lin CY, Dickson RB, Reagan-Shaw S, Jarrard DF, Mukhtar H. A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1. Cancer Epidemiol Biomarkers Prev 2006; 15:217-27. [PMID: 16492908 DOI: 10.1158/1055-9965.epi-05-0737] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Matriptase, a type II transmembrane serine protease is involved in angiogenesis, degradation of extracellular matrix, and in the progression of some epithelial cancers. Here, we establish the clinical significance of matriptase and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), during the progression of human prostate cancer (CaP). METHODS The expression patterns of matriptase and HAI-1 were determined in primary cultures of normal human prostate epithelial (NHPE) cells, human CaP cells LNCaP, DU-145, CWR22Rnu1, and PC-3, and in tissue samples of 172 patients with normal prostate, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and adenocarcinoma of different tumor grades. RESULTS The protein and mRNA levels of matriptase were significantly higher in all carcinoma cells as compared with NHPE cells. Conversely, all CaP cells exhibited a reduced expression of HAI-1 as compared with NHPE cells. A progressive increase in the protein levels of matriptase was observed with increasing tumor grade in CaP specimens as compared with normal and BPH tissue specimens. Tissue samples of normal prostate exhibited a high constitutive protein level of HAI-1 compared with BPH and low-grade cancer with a progressive loss with increasing tumor grade. CONCLUSION The increased expression of matriptase and loss of HAI-1 may be an important event during the progression of CaP in humans. We suggest that the ratio of these two gene products may serve as a promising biomarker for CaP progression and a potential marker for establishing the efficacy of therapeutic and chemopreventive interventions.
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Affiliation(s)
- Mohammad Saleem
- Department of Dermatology, Laboratory of Medicine, University of Wisconsin, 1300 University Avenue, Medical Sciences Center, B-25, Madison, Wisconsin 53706, USA
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Nakahira R, Mizuno S, Yoshimine T, Nakamura T. The loss of local HGF, an endogenous gastrotrophic factor, leads to mucosal injuries in the stomach of mice. Biochem Biophys Res Commun 2006; 341:897-903. [PMID: 16476577 DOI: 10.1016/j.bbrc.2006.01.091] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2006] [Accepted: 01/12/2006] [Indexed: 12/28/2022]
Abstract
The stomach is constantly exposed to mechanical and chemical stresses. Under persistent damages, epithelial cell proliferation is required to maintain mucosal integrity. Nevertheless, which ligand system(s) is physiologically involved in gastric defense remains unclear. Herein, we provide evidence that HGF is a key "natural ligand" to reverse gastric injury. The injection of cisplatin in mice led to the loss of HGF in the gastric interstitium, associated with the decrease in proliferating epithelium and the progression of mucotitis. When c-Met tyrosine phosphorylation was abolished by anti-HGF IgG, mucosal cell proliferation became faint, leading to delayed recovery from mucotitis, and vice versa in cases of HGF supplementation. Our findings indicate that: (1) HGF/c-Met signal on mucosa is needed to restore gastric injuries; and (2) the loss of local HGF leads to manifestation of gastric lesions. This study provides a rationale that explains why HGF supplement is useful for reversing gastric diseases.
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Affiliation(s)
- Rie Nakahira
- Division of Molecular Regenerative Medicine, Department of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Yamadaoka 2-2-B7, Suita 565-0871, Japan
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Di Caro S, Tao H, Grillo A, Franceschi F, Elia C, Zocco MA, Gasbarrini G, Sepulveda AR, Gasbarrini A. Bacillus clausii effect on gene expression pattern in small bowel mucosa using DNA microarray analysis. Eur J Gastroenterol Hepatol 2005; 17:951-960. [PMID: 16093873 DOI: 10.1097/00042737-200509000-00011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Probiotics are widely used for the cure or prevention of several clinical conditions. However, clinical decisions need to be substantiated by an analysis of the complex bacteria-host interplay in the intestinal lumen. AIMS To identify the gene expression pattern induced by Bacillus clausii in the intestinal mucosa of healthy individuals. METHODS Six male patients (mean age 38+/-5 years) affected by endoscopically confirmed mild oesophagitis were treated for one month with esomeprazole, and were randomly selected to receive or not B. clausii (groups I and II, respectively). Duodenal biopsies were taken pre and post-treatment to identify the modification of gene expression, using the GeneChip Human U133A array. To validate the microarray analysis, real-time reverse transcriptase-polymerase chain reaction (PCR) of five target genes was performed. RESULTS After B. clausii administration, a total of 158 and 265 genes were up and downregulated, respectively. Quantitative PCR confirmed the microarray data. B. clausii mainly affected the expression of genes involved in immune response and inflammation, apoptosis and cell growth, cell differentiation, cell-cell signalling, cell adhesion, signal transcription and transduction. CONCLUSIONS Our data represent the first global analysis of B. clausii effects on the gene expression profile in normal intestine, and provide the basis to identify the mechanisms by which these agents interact with the host and exert their beneficial effects. Future studies are needed to clarify the B. clausii-induced gene pattern in the clinical disorders in which probiotics have proved to be effective.
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Affiliation(s)
- Simona Di Caro
- Department of Gastroenterology, Catholic University, Rome, Italy
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Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T. Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Crit Rev Oncol Hematol 2005; 53:35-69. [PMID: 15607934 DOI: 10.1016/j.critrevonc.2004.09.004] [Citation(s) in RCA: 187] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/14/2004] [Indexed: 12/22/2022] Open
Abstract
Hepatocyte growth factor plays multiple roles in cancer, by acting as a motility and invasion stimulating factor, promoting metastasis and tumour growth. Furthermore, it acts as a powerful angiogenic factor. The pivotal role of this factor in cancer has indicated HGF as being a potential target in cancer therapies. The past few years have seen rapid progress in developing tools in targeting HGF, in the context of cancer therapies, including development of antagonists, small compounds, antibodies and genetic approaches. The current article discusses the potential value of HGF and its receptor as targets in cancer therapies, the current development in anti-HGF research, and the clinical value of HGF in prognosis and treatment.
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Affiliation(s)
- Wen G Jiang
- Metastasis and Angiogenesis Research Group, University Department of Surgery, Wales College of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
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