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Colorectal Tumors (colorectal + tumor)

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Medical Sciences	96%

Selected Abstracts

ENDOSCOPIC MUCOSAL RESECTION AND SUBMUCOSAL DISSECTION METHOD FOR LARGE COLORECTAL TUMORS

DIGESTIVE ENDOSCOPY, Issue 2004
Yasushi Sano
ABSTRACT The goal of endoscopic mucosal resection (EMR) is to allow the endoscopist to obtain tissue or resect lesions not previously amenable to standard biopsy or excisional techniques and to remove malignant lesions without open surgery. In this article, we describe the results of conventional EMR and EMR using an insulation-tipped (IT) electrosurgical knife (submucosal dissection method) for large colorectal mucosal neoplasms and discuss the problems and future prospects of these procedures. At present, conventional EMR is much more feasible than EMR using IT-knife from the perspectives of time, money, complication, and organ preservation. However, larger lesions tend to be resected in a piecemeal fashion; and it is difficult to confirm whether EMR has been complete. For accurate histopathological assessment of the resected specimen en bloc EMR is desirable although further experience is needed to establish its safety and efficacy. Further improvements of in EMR with special knife techniques are required to simply and safely remove large colorectal neoplasms. [source]

Loss of transgelin in repeated bouts of ulcerative colitis-induced colon carcinogenesis

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2006
Marie Yeo
Abstract Though ulcerative colitis (UC)-associated colon cancer develops from dysplastic lesions caused by chronic inflammation, the specific mechanistic link between chronic inflammation and carcinogenesis in colon has not been integrated into molecular understanding. We therefore established an experimental animal model for colitic cancer, and used proteomic analysis, based on 2-DE and MALDI-TOF,MS, to identify proteins involved in colitic cancer. In our model, 6-week-old C57BL/6J mice were exposed to 15,cycles of dextran sodium sulfate (DSS), with each cycle consisting of 0.7% DSS for 1,week followed by distilled water for 10,days. Colorectal tumors developed in 22 of 24,mice (91.6%), with a tumor multiplicity of 1.727 per tumor-bearing mouse. Comparative 2-DE analysis showed that 38,protein spots were differentially expressed in colon tumors and normal colon. We identified 27 of these proteins, including GRP94, HSC70, enolase, prohibitin, and transgelin. The reduction of transgelin expression in mouse colon tumors was confirmed by Western blotting and immunohistochemistry. We also found that transgelin expression was significantly reduced in human colon tumors compared with adjacent nontumorous tissues. In conclusion, these results suggest that loss of transgelin could be a candidate for biomarker of repeated colitis-associated colon cancer. [source]

Colorectal tumors frequently express phosphorylated mitogen-activated protein kinase

APMIS, Issue 4-5 2004
SUG HYUNG LEE
Mounting evidence suggests that activation of the mitogen-activated protein (MAP) kinase pathway plays an important role in tumorigenesis. MAP kinase/ERK kinase (MEK), a crucial constituent of this pathway, is activated by phosphorylation, and the phosphorylated MEK (pMEK) in turn activates ERK kinase. The expression of pMEK has been described in some human malignancies, but not in primary human colon tumors. In this study, we analyzed the expression of pMEK in 123 colorectal tumors by immunohistochemistry. pMEK was detected either in the cytoplasm (63 cases) or nucleus (40 cases) in 93 of the 123 tumors (76%). Tubular adenomas and villous adenomas also expressed pMEK in 30% and 40% of the tumors, respectively. By contrast, the epithelial cells in the normal colonic mucosa showed no or only weak expression of pMEK in the cytoplasm. Taken together, these results indicate that MEK is frequently phosphorylated in colorectal tumors, and suggest that phosphorylation of MEK may play a role in the development of colorectal tumors. [source]

CURRENT STATUS IN THE OCCURRENCE OF POSTOPERATIVE BLEEDING, PERFORATION AND RESIDUAL/LOCAL RECURRENCE DURING COLONOSCOPIC TREATMENT IN JAPAN

DIGESTIVE ENDOSCOPY, Issue 4 2010
Shiro Oka
Bleeding, perforation, and residual/local recurrence are the main complications associated with colonoscopic treatment of colorectal tumor. However, current status regarding the average incidence of these complications in Japan is not available. We conducted a questionnaire survey, prepared by the Colorectal Endoscopic Resection Standardization Implementation Working Group, Japanese Society for Cancer of the Colon and Rectum (JSCCR), to clarify the incidence of postoperative bleeding, perforation, and residual/local recurrence associated with colonoscopic treatment. The total incidence of postoperative bleeding was 1.2% and the incidence was 0.26% with hot biopsy, 1.3% with polypectomy, 1.4% with endoscopic mucosal resection (EMR), and 1.7% with endoscopic submucosal dissection (ESD). The total incidence of perforation was 0.74% (0.01% with the hot biopsy, 0.17% with polypectomy, 0.91% with EMR, and 3.3% with ESD). The total incidence of residual/local recurrence was 0.73% (0.007% with hot biopsy, 0.34% with polypectomy, 1.4% with EMR, and 2.3% with ESD). Colonoscopic examination was used as a surveillance method for detecting residual/local recurrence in all hospitals. The surveillance period differed among the hospitals; however, most of the hospitals reported a surveillance period of 3,6 months with mainly transabdominal ultrasonography and computed tomography in combination with the colonoscopic examination. [source]

Turcot syndrome confirmed with molecular analysis

EUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2007
C. Lebrun
Turcot syndrome is clinically characterized by the occurrence of primary brain tumor and colorectal tumor and has, in previous reports, been shown associated with germline mutations in the genes APC, MLH1, MHS6, and PMS2. To date, only few families have been documented by molecular analysis. We report two new families with Turcot syndrome to illustrate and review its characteristics and facilitate diagnosis. Molecular analysis revealed two germline mutations, one in the MLH1 gene and one in MSH2. The latter has never been describe in the literature. Personal and familial relevant anamnestic data from patients with glioma might aid in the diagnosis of genetic disorders. The subsequent molecular characterization may contribute to the appropriate care of affected patients and asymptomatic gene carriers. [source]

Endoscopic mucosal resection of colorectal tumors

DIGESTIVE ENDOSCOPY, Issue 1 2004
Yuji Inoue
It has been possible to resect early colorectal cancer by endoscopy due to the progress of colonoscopic diagnosis and technology. Therefore, most cases of colorectal mucosal cancer and benign tumor have been resected by endoscopy only. We report some techniques for endoscopic resection of colorectal tumors. The technique of endoscopic resection: (i) The B-Wave bipolar snare device: It is difficult to resect flat lesions that are not sufficiently elevated to be ligated by a usual snare. The snare of the B-Wave bipolar snare device is coated to prevent slipping on the colorectal mucosa. (ii) ,Sculpting down' polypectomy: It is difficult to resect large sessile lesions because the bases of these lesions cannot be well observed endoscopically. ,Sculpting down' polypectomy is a useful method for safe resection of such tumors. (iii) Endoscopic resection through a retroflexed scope: Under retroverted colonoscopic observation, submucosal injection and partial resection is performed. Then, under ordinary observation, complete resection of the residual tumor is performed. (iv) Endoscopic mucosal resection using a cap-fitted panendoscope (EMRC): EMRC is useful for lesions located in the lower rectum because there is no risk of free perforation. At first, submucosal injection is performed. The snare is set in the transparent cap and the lesion is aspirated into the cap. Then, it is snared and resected. [source]

Diagnosis of invasion depth in early colorectal carcinoma by pit pattern analysis with magnifying endoscopy

DIGESTIVE ENDOSCOPY, Issue 2001
Shinji Tanaka
Background: The aim of this study was to clarify whether various pit patterns on the surface of colorectal tumors are associated with various levels of submucosal invasion. Methods: We examined pathologic features of the pit pattern of the tumor surface in 457 colorectal adenomas and early carcinomas. The examinations involved the use of magnifying endoscopy with indigocarmine dye spraying or crystal violet staining methods. Regarding the pit pattern classification, we used the types I, II, IIIL, IIIS, IV, VA and VN. We subclassified the VN pit pattern according to the area of the tumor surface covered into grades A (small), B (medium) and C (large). Results: Magnifying colonoscopic observation revealed the rates of submucosal invasion associated with specific pit patterns to be 1% (3/213) for IIIL, 5% (2/42) for IIIS, 8% (4/57) for IV, 14% (13/93) for VA and 80% (42/52) for VN. The rates of submucosal massive invasion (> 400 ,m) associated with specific pit patterns was 0% (0/213) for IIIL, 0% (0/42) for IIIS, 4% (2/57) for IV, 5% (5/93) for VA and 72% (38/52) for VN. Within the VN pit pattern subclassification, the incidence of submucosal invasion , 1500 ,m was found each grade (A, B & C): 5% (1/19) for grade A, 64% (14/22) for grade B and 93% (13/14) for grade C. Conclusion: Determination of pit pattern is useful for prediction of submucosal invasion depth and for decisions concerning treatment in colorectal tumors. Lesions with VA and non-grade C VN pit patterns are candidates for total endoscopic resection. A grade C VN pit pattern is a definite indicator of severely invasive submucosal carcinoma, which is unresectable by endoscopic resection. [source]

Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development

GENES, CHROMOSOMES AND CANCER, Issue 6 2008
Kim Loh
Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways. © 2008 Wiley-Liss, Inc. [source]

Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability

GENES, CHROMOSOMES AND CANCER, Issue 3 2002
Hiroyuki Yamamoto
High-frequency microsatellite instability (MSI-H) due to defective DNA mismatch repair occurs in the majority of hereditary nonpolyposis colorectal cancers (HNPCCs) and in a subset of sporadic malignant tumors. Clinicopathologic and genotypic features of MSI-H colorectal tumors in HNPCC patients and those in sporadic cases are very similar but not identical. Correlation between the MSI phenotype and aberrant DNA methylation has been highlighted recently. A strong association between MSI and CpG island methylation has been well characterized in sporadic colorectal cancers with MSI-H but not in those of hereditary origin. To address the issue, we analyzed hereditary and sporadic colorectal cancers for aberrant DNA methylation of target genes using methylation-specific polymerase chain reaction. DNA methylation of the MLH1, CDKN2A, MGMT, THBS1, RARB, APC, and p14ARF genes was found in 0%, 23%, 10%, 3%, 73%, 53%, and 33% of 30 MSI-H cancers in HNPCC patients and in 80%, 55%, 23%, 23%, 58%, 35%, and 50% of 40 sporadic colorectal cancers with MSI-H, respectively. Cases showing methylation at three or more loci of six genes other than MLH1 were defined as CpG island methylator phenotype,positive (CIMP+), and 23% of HNPCC tumors and 53% of sporadic cancers with MSI-H were CIMP+ (P = 0.018). Differences in the extent of CpG island methylation, coupled with the differential involvement of several genes by methylation, in HNPCC tumors and sporadic MSI-H colorectal cancers may be associated with diverging developmental pathways in hereditary and sporadic cancers despite similar MSI-H phenotypes. © 2002 Wiley-Liss, Inc. [source]

Whole genome analysis for liver metastasis gene signatures in colorectal cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2007
Dong Hyuk Ki
Abstract Liver metastasis is one of the major causes of death in colorectal cancer (CRC) patients. To understand this process, we investigated whether the gene expression profiling of matched colorectal carcinomas and liver metastases could reveal key molecular events involved in tumor progression and metastasis. We performed experiments using a cDNA microarray containing 17,104 genes with the following tissue samples: paired tissues of 25 normal colorectal mucosa, 27 primary colorectal tumors, 13 normal liver and 27 liver metastasis, and 20 primary colorectal tumors without liver metastasis. To remove the effect of normal cell contamination, we selected 4,583 organ-specific genes with a false discovery rate (FDR) of 0.0067% by comparing normal colon and liver tissues using significant analysis of microarray, and these genes were excluded from further analysis. We then identified and validated 46 liver metastasis-specific genes with an accuracy of 83.3% by comparing the expression of paired primary colorectal tumors and liver metastases using prediction analysis of microarray. The 46 selected genes contained several known oncogenes and 2 ESTs. To confirm that the results correlated with the microarray expression patterns, we performed RT-PCR with WNT5A and carbonic anhydrase II. Additionally, we observed that 21 of the 46 genes were differentially expressed (FDR = 2.27%) in primary tumors with synchronous liver metastasis compared with primary tumors without liver metastasis. We scanned the human genome using a cDNA microarray and identified 46 genes that may play an important role in the progression of liver metastasis in CRC. © 2007 Wiley-Liss, Inc. [source]

Beta2-microglobulin mutations in microsatellite unstable colorectal tumors

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2007
Matthias Kloor
Abstract Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the ,2 -microglobulin (,2m) gene. To examine the implications of ,2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of ,2m mutations in MSI-H colorectal adenomas (n = 38) and carcinomas (n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of ,2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of ,2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. ,2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of ,2m expression may promote local progression of colorectal MSI-H tumors. However, no ,2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional ,2m may be necessary for distant metastasis formation in CRC patients. © 2007 Wiley-Liss, Inc. [source]

Predicting 5-fluorouracil chemosensitivity of liver metastases from colorectal cancer using primary tumor specimens: Three-gene expression model predicts clinical response

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2006
Ryusei Matsuyama
Abstract We identified genes related to 5-fluorouracil (5-FU) sensitivity in colorectal cancer and utilized these genes for predicting the 5-FU sensitivity of liver metastases. Eighty-one candidate genes involved in 5-FU resistance in gastric and colon cancer cell lines were previously identified using a cDNA microarray. In this study, the mRNA expression levels of these 81 selected genes and the genes of 5-FU-related enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyltransferase (OPRT), were measured using real-time quantitative RT-PCR assays of surgically resected materials from primary colorectal tumors in 22 patients. Clinical responses were estimated by evaluating the effects of 5-FU-based hepatic artery injection (HAI) chemotherapy for synchronous liver metastases. Four genes (TNFRSF1B, SLC35F5, NAG-1 and OPRT) had significantly different expression profiles in 5-FU-nonresponding and responding tumors (p < 0.05). A "Response Index" system using three genes (TNFRSF1B, SLC35F5 and OPRT) was then developed using a discriminate analysis; the results were well correlated with the individual chemosensitivities. Among the 11 cases with positive scores in our response index, 9 achieved a reduction in their liver metastases after 5-FU-based chemotherapy, whereas only 1 of the 11 cases with negative scores responded well to chemotherapy. Our "Response Index" system, consisting of TNFRSF1B, SLC35F5 and OPRT, has great potential for predicting the efficacy of 5-FU-based chemotherapy against liver metastases from colorectal cancer. © 2006 Wiley-Liss, Inc. [source]

BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2005
Nobunao Ikehara
Abstract To understand the role of BRAF dysfunction in the carcinogenesis and progression/development of colorectal tumors, the authors investigated genetic alterations in the BRAF gene in human colorectal neoplasms as well as the effects of an RAS inhibitor in BRAF -mutant cells. Seven colon cancer cell lines and 116 colorectal tumors (34 adenomas and 82 adenocarcinomas) were analyzed. Genetic alterations in the BRAF and K- ras genes were examined using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. The growth-inhibitory and apoptosis-inducing effects of the FTI-277 RAS inhibitor in colon cancer cell lines were analyzed as well. An immunohistochemical study was also performed to investigate the correlations between the clinicopathologic parameters involved in the Ki-67 labeling index and the number of apoptotic bodies in tumor cells. FTI-277 did not suppress the proliferation of BRAF -mutant cells (WiDr and TCO), but remarkably inhibited the growth of K- ras mutant cells (LoVo). Interestingly, LoVo cells underwent apoptosis by FTI-277 in a dose-dependent manner, whereas WiDr cells were resistant to this agent. In tumor samples, BRAF mutations were found in 1 (3.0%) of 33 adenomas and 6 (7.2%) of 83 adenocarcinomas. No tumor exhibited mutations in both the BRAF and K- ras genes. Neither BRAF nor K- ras mutations correlated with the Ki-67 labeling index immunohistochemically. However, the number of apoptotic bodies was significantly decreased in the BRAF -mutant tumors. Mutation in the BRAF gene may contribute to colorectal carcinogenesis by upregulating the antiapoptotic role of the RAS/RAF/MEK/ERK pathway. © 2005 Wiley-Liss, Inc. [source]

Magnitude and polarization of P53-specific T-helper immunity in connection to leukocyte infiltration of colorectal tumors

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2003
Sjoerd H. van der Burg
Abstract The tumor antigen p53 is mutated frequently and overexpressed in colorectal cancer. As a result, patients with this type of cancer commonly display p53-specific T-helper (Th) immunity. Examination of the cytokines produced by these Th-cells showed that a majority of the proliferative p53-specific T cell cultures produced none of the key cytokines (IFN,, TNF,, IL-4, IL-5 or IL-10), indicating that these p53-specific Th-responses are not polarized. In patients who exhibited p53-specific reactivity against multiple p53-epitopes, non-polarized responses could be found side by side with polarized Th-responses that produced INF, or other cytokines such as IL-10. Patients who exhibited p53-specific IFN,-producing Th cell-immunity before surgical excision of the tumor displayed higher numbers of tumor infiltrating intraepithelial leukocytes (p = 0.04) than patients lacking such responses, suggesting that the systemic presence of p53-specific Th-cells positively affects local tumor-immunity. Our data concerning the polarization-state of p53-specific Th immunity in colorectal cancer patients support the use of vaccine formulations that induce strong Th1-polarized p53-specific immunity to ensure proper (re-)programming of the anti-tumor response. © 2003 Wiley-Liss, Inc. [source]

Analysis of the human APC mutation spectrum in a saccharomyces cerevisiae strain with a mismatch repair defect

INTERNATIONAL JOURNAL OF CANCER, Issue 5 2003
Kazunori Otsuka
Abstract Somatic APC mutations in colorectal tumors with an RER phenotype reflect excessive frameshift mutations, especially in simple repetition tracts within the coding sequence. Because this type of mutation is characteristic of cells with a deficient DNA MMR system, the APC mutation signature of RER tumors may be attributable to a defect in the MMR system. However, there is little experimental evidence to prove that the spectrum of mutations and the APC gene distribution are directly influenced by MMR system defects. We therefore examined the mutation spectrum of the MCR of the APC gene after transfection into both MMR-proficient and MMR-deficient yeast strains and compared it with a previously reported human APC mutation database. Small insertions or deletions in mono- or dinucleotide repeats were more common in the MMR-deficient than in the MMR-proficient strain (91.2% vs. 38.1%, Fisher's exact test p < 0.0001). Furthermore, the 2 mutation hot spots, 4385,4394(AG)5 and 4661,4666(A)6, found in the yeast system corresponded with those in human tumors. Combining our data with those from human tumors, there appears to be hypermutable mutations in specific simple repetitive sequences within the MCR, which are more prevalent in MMR-deficient cells and RER tumors than in MMR-proficient cells and non-RER tumors. We therefore consider that the differences in the spectra of RER and non-RER tumors are attributable at least in part to the MMR system of the host cells. © 2002 Wiley-Liss, Inc. [source]

Low expression of XIAP-associated factor 1 in human colorectal cancers

JOURNAL OF DIGESTIVE DISEASES, Issue 1 2005
Tian Le MA
OBJECTIVE: Eight cellular homologs of the inhibitors-of-apoptosis proteins (IAP) have been identified in humans and of them, the X-linked IAP (XIAP) is the most potent. XIAP-associated factor 1 (XAF1) is a newly discovered XIAP-binding protein that negatively regulates the caspase-inhibiting activity of XIAP. It is either not expressed or present at extremely low levels in many cancer cell lines. The aims of the present study were: (i) to investigate the expression of XAF1 in human colorectal cancers (CRC) both in vitro and in vivo, and (ii) to evaluate the possibility of XAF1 as a new tumor marker. METHODS: The expression of XAF1 in four human colon cancer cell lines (Colo205, Colo320, SW1116, LoVo) and in samples from 70 patients with CRC was analyzed by reverse transcriptase-polymerase chain reaction. XAF1 concentrations were also detected in the peripheral circulation of the 70 patients, as well as three traditional circulating cancer-associated antigens. RESULTS: A low concentration of XAF1 mRNA was detectable in the three colon cancer cell lines other than Colo205, which showed the strongest expression of XAF1. The expression of XAF1 in tissue was relatively lower in primary CRC compared with a relatively higher level in benign colorectal tumors (P < 0.01). Although the XAF1 expression in circulation of those with CRC was also lower than in those with benign tumors, there was no statistical significance (P > 0.05). CONCLUSIONS: The present results suggest that the low expression of XAF1 in tumor tissue coincides with a similar level in the peripheral circulation, which contributes at least part to the malignant behavior of CRC. Integrating the XAF1 relative expression value with the other three traditional tumor biomarkers created a four-parameter assay that significantly improved the rate of diagnosis of CRC. [source]

Dysplasia and carcinoma development in a repeated dextran sulfate sodium-induced colitis model

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2002
Isao Okayasu
Abstract Background: As an important mechanism underlying the increased risk of colorectal carcinoma development in patients with long-standing ulcerative colitis, promotion as a result of the regenerative process has been proposed. In the present study, a dysplasia-carcinoma sequence in a novel repeated colitis model in mice is documented. Methods: Repeated colitis was induced by nine administration cycles of 3% dextran sulfate sodium (DSS; molecular weight, 54 000): each administration cycle comprised 3% DSS for 7 days followed by distilled water for the subsequent 14 days, to give conditions similar to the clinically observed active and remission phases in humans. Results: Multiple colorectal tumors (nine low- and four high-grade dysplasias and two carcinomas) developed in 25 mice. These neoplastic lesions consisted of tubular structures, presenting as various types of elevated, flat and depressed tumor, similar to those in ulcerative colitis patients. A time-course study with assessment of the severity of colitis and in vivo bromodeoxyuridine uptake during a single 3% DSS administration cycle revealed a high level of regenerative activity in the colitis-affected mucosal epithelia. Conclusion: Thus, with the present repeated colitis model, regeneration and neoplastic lesions were apparent, the biological features of which provide evidence of a colorectal dysplasia,invasive carcinoma sequence in ulcerative colitis. [source]

Alcohol and Colorectal Cancer: The Role of Alcohol Dehydrogenase 1C Polymorphism

ALCOHOLISM, Issue 3 2009
Nils Homann
Background:, Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C (ADH1C) exists resulting in different acetaldehyde concentrations following ethanol oxidation. Methods:, To evaluate whether the association between alcohol consumption and colorectal tumor development is modified by ADH1C polymorphism, we recruited 173 individuals with colorectal tumors diagnosed by colonoscopy and 788 control individuals without colorectal tumors. Genotyping was performed using genomic DNA extracted from whole blood followed by polymerase chain reaction. Results:, Genotype ADH1C*1/1 was more frequent in patients with alcohol-associated colorectal neoplasia compared to patients without cancers in the multivariate model controlling for age, gender, and alcohol intake (odds ratio = 1.674, 95% confidence interval = 1.110,2.524, 2-sided p from Wald test = 0.0139). In addition, the joint test of the genetic effect and interaction between ADH1C genotype and alcohol intake (2-sided p = 0.0007) indicated that the difference in ADH1C*1 polymorphisms between controls and colorectal neoplasia is strongly influenced by the alcohol consumption and that only individuals drinking more than 30 g ethanol per day with the genotype ADH1C*1/1 had an increased risk for colorectal tumors. Conclusions:, These data identify ADH1C homozygosity as a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day and emphasize the role of acetaldehyde as a carcinogenic agent in alcohol-related colorectal carcinogenesis. [source]

Hypermethylation status of APC inversely correlates with the presence of submucosal invasion in laterally spreading colorectal tumors

MOLECULAR CARCINOGENESIS, Issue 1 2008
Kazuo Hashimoto
Abstract Little is known about epigenetic alterations in laterally spreading colorectal tumors (LSTs). The goal of the present study was to elucidate the epigenetic background of LSTs and compare the methylation status of DNA CpG islands (CGIs) with clinicopathologic features. Methylation of MINT1, MINT2, MINT31, p16, O6 -methylguanine-DNA methyltransferase (MGMT), adenomatous polyposis coli (APC), and human MutL homologue 1 (hMLH1) in 42 LSTs was assessed by methylation-specific polymerase chain reaction (MSP) and compared with clinicopathologic parameters. The frequency of hypermethylation was 12.5% (4/32) for MINT1, 40.0% (16/40) for MINT2, 25.0% (10/40) for MINT31, 25.7% (9/35) for p16, 7.7% (3/39) for hMLH1, 26.5% (9/34) for MGMT, and 35.9% (14/39) for APC. APC methylation was inversely associated with submucosal invasion (P,=,0.034), which was not found in any of 14 LST cases with APC methylation, whereas submucosal invasion was present in 8 of 25 (32.0%) cases without APC methylation. These data suggest that hypermethylation of APC could be a predictive marker for the absence of submucosal invasion of LSTs. © 2007 Wiley-Liss, Inc. [source]

Colorectal carcinoma development in inducible nitric oxide synthase-deficient mice with dextran sulfate sodium-induced ulcerative colitis

MOLECULAR CARCINOGENESIS, Issue 5 2007
Darren N. Seril
Abstract The overproduction of reactive oxygen and nitrogen species (RONS) may play an important role in ulcerative colitis (UC)-associated carcinogenesis. In order to study the role of nitric oxide (NO) in UC-associated colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS-induced and iron-enhanced model of chronic UC in inducible nitric oxide synthase (iNOS)-deficient mice. Female wild-type C57BL/6 (iNOS+/+) and iNOS,/, mice were administered 1% DSS (w/v) through the drinking fluid for 15 DSS cycles and fed twofold iron-enriched diet. Colorectal inflammation and mucosal ulceration of moderate severity were observed in both iNOS+/+ and iNOS,/, mice. Similar tumor incidence and multiplicity in the colon were observed that 15 out of 23 (65.2%) iNOS+/+ mice developed colorectal tumors with a tumor multiplicity of 1.47,±,0.17 (mean,±,SE) after 15 DSS cycles, and 13 out of 19 (68.4%) iNOS,/, mice developed colorectal tumors with a tumor multiplicity of 2.08,±,0.21. Histopathologically, the tumors were confirmed to be well-differentiated adenocarcinomas. Nitrotyrosine, an indicator of peroxynitrite-caused protein modification, was detectable by immunohistochemistry in inflammatory cells and epithelial cells of the colon in iNOS+/+ and iNOS,/, mice, and no difference in staining intensity was observed between the two groups. Immunostaining for endothelial NOS (eNOS) was observed in lamina propria macrophages and colonic blood vessels, and eNOS protein levels were increased in the inflamed colon. These results show that there is no difference in UC-associated cancer development in iNOS+/+ and iNOS,/, mice, and suggest that in the absence of iNOS, other factors, such as eNOS, may play a role in nitrosative stress and UC-associated carcinogenesis in this model system. © 2006 Wiley-Liss, Inc. [source]

Differential expression of hMLH1 in sporadic human colorectal cancer tumors and distant metastases

APMIS, Issue 11 2009
NICOLAI BALLE LARSEN
Somatic defects in the mismatch repair system constitute an important pathway in colorectal carcinogenesis. We have examined the expression of mismatch repair proteins in sporadic stage IV colorectal tumors and their derived metastases. Sporadic tumors were further examined for differences in expression between the tumor transition zone and the invasive front. Expression of hMSH2, hMLH1, and hPMS2 was screened immunohistochemically in 92 stage IV tumors and derived liver metastases. In cases with loss of mismatch repair protein expression, lymph node metastases were also examined. Clinicopathological parameters and Ki-67 staining indexes were evaluated and compared. Four tumors displayed a complete loss of hMLH1/hPMS2 expression at the transition zone; however, three of these expressed both proteins at the invasive front and in liver and lymph node metastases. A further four were predominantly hMLH1/hPMS2 negative at the transition zone, but with distinct subclones of hMLH1/hPMS2-expressing cells at the transition zone. All of these tumors expressed hMLH1/hPMS2 at the invasive front and in liver metastases, with three also expressing hMLH/hPMS2 in lymph node metastases. No significant difference in the proliferative index was observed for the hMLH1/hPMS2-compromised group. In stage IV tumors re-expression of hMLH1/hPMS2 occurred, leading to different patterns of expression within the primary tumor and between tumor and metastases. This may have functional importance for the chemosensitivity of metastases compared to the primary tumor. [source]

Colorectal tumors frequently express phosphorylated mitogen-activated protein kinase

Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care,Correlations with food intake, metabolism, exercise capacity, and hormones

CANCER, Issue 10 2005
Marita Fouladiun M.D.
Abstract BACKGROUND Several investigations that yielded different results in terms of net changes in body composition of weight-losing cancer patients have been reported that employed a variety of methods based on fundamentally different technology. Most of those reports were cross-sectional, whereas to the authors' knowledge there is sparse information available on longitudinal follow-up measurements in relation to other independent methods for the assessment of metabolism and performance. METHODS For the current report, the authors evaluated time course changes in body composition (dual-energy X-ray absorptiometry) with measurements of whole body and regional distribution of fat and lean tissue in relation to food and dietary intake, host metabolism (indirect calorimetry), maximum exercise capacity (walking test), and circulating hormones in cancer patients who were receiving palliative care during 4,62 months of follow-up. The entire cohort comprised 311 patients, ages 68 years ± 3 years who were diagnosed with solid gastrointestinal tumors (84 colorectal tumors, 74 pancreatic tumors, 73 upper gastrointestinal tumors, 51 liver-biliary tumors, 3 breast tumors, 5 melanomas, and 21 other tumor types). RESULTS Decreased body weight was explained by loss of body fat, preferentially from the trunk, followed by leg tissue and arm tissue, respectively. Lean tissue (fat-free mass) was lost from arm tissue, whereas trunk and leg tissue compartments increased, all concomitant with declines in serum albumin, increased systemic inflammation (C-reactive protein, erythrocyte sedimentation rate), increased serum insulin, and elevated daily caloric intake; whereas serum insulin-like growth factor 1 (IGF-1), resting energy expenditure, and maximum exercise capacity remained unchanged in the same patients. Serum albumin levels (P < 0.001), whole body fat (P < 0.02), and caloric intake (P < 0.001) predicted survival, whereas lean tissue mass did not. Daily intake of fat and carbohydrate was more important for predicting survival than protein intake. Survival also was predicted by serum IGF-1, insulin, leptin, and ghrelin levels (P < 0.02 , P < 0.001). Serum insulin, leptin, and ghrelin (total) levels predicted body fat (P < 0.001), whereas IGF-1 and thyroid hormone levels (T3, free T3) predicted lean tissue mass (P < 0.01). Systemic inflammation primarily explained variation in lean tissue and secondarily explained loss in body fat. Depletion of lean arm tissue was related most to short survival compared with the depletion of lean leg and trunk tissue. CONCLUSIONS The current results demonstrated that body fat was lost more rapidly than lean tissue in progressive cancer cachexia, a phenomenon that was related highly to alterations in the levels of circulating classic hormones and food intake, including both caloric amount and diet composition. The results showed importance in the planning of efficient palliative treatment for cancer patients. Cancer 2005. © 2005 American Cancer Society. [source]

Intra-tumoral interleukin-6 down-regulation system and genetic mutations of tumor suppressor genes in colorectal carcinoma

CANCER, Issue 5 2002
Chikao Miki M.D.
Abstract BACKGROUND The interleukin (IL)-1-IL-6 network, the most potent cascade of pro-inflammatory cytokines, plays an autocrine role in tumor growth. The IL-1-IL-6 network is down-regulated by a phased cytokine inhibitor IL-1 receptor antagonist (ra) and an anti-inflammatory cytokine IL-10. The current study evaluated this down-regulation system in colorectal carcinoma and its relation to the genetic alteration of tumor suppressor genes. METHODS Seventy-four specimens of primary colorectal carcinoma and normal mucosa were collected to measure tissue concentrations of cytokines. Polymerase chain reaction amplification was performed to investigate the loss of heterozygosity of the microsatellite markers on chromosomes 17p and 18q. RESULTS The IL-1ra/IL-6 ratio in the carcinoma specimens was lower than ratios in adenomas and normal mucosae and decreased with disease progression. The IL-1ra/IL-6 ratio in early cancers tended to be lower than that in adenomas and normal mucosae. However, the tissue concentrations of IL-1, and IL-10 were not associated with any clinicopathologic parameters. The tissue IL-1ra concentration correlated with that of IL-6 only in adenomas and early cancers. Immunohistochemically, IL-1ra and IL-6 were localized in the tumor cytoplasm. A reduced tissue IL-1ra/IL-6 ratio in the carcinomas correlated with poor prognosis and was associated with the loss of heterozygosity of the microsatellite markers on chromosomes 18q. CONCLUSIONS There is an IL-6-IL-1ra network system in colorectal tumors, but this system deteriorates with carcinogenesis and tumor growth. The deterioration of this network system was associated with the allelic loss of a portion of chromosome 18q, reflecting the genetic alteration of tumor suppressor genes. Cancer 2002;94:1584,92. © 2002 American Cancer Society. DOI 10.1002/cncr.10324 [source]

Frameshift Mutations at Mononucleotide Repeats in RAD50 Recombinational DNA Repair Gene in Colorectal Cancers with Microsatellite Instability

CANCER SCIENCE, Issue 6 2001
Tsuneo Ikenoue
To identify additional genes targeted for microsatellite instability (MSI), we search for human genes which contain mononucleotide repeats in their coding region, selected 7 genes (RAD50, DNA-PKcs, FLASH, Apaf-1, XPG, CtIP, and MLSN1), and analyzed frameshift mutations in them. Here we report that 60% (3 out of 5) of human colorectal cancer cell lines exhibiting a high frequency of MSI (MSI-H) and 46% (6 out of 13) of MSI-H primary colorectal tumors had mutations in the (A)9 repeat of RAD50 recombinational repair gene. In contrast, no frameshift mutations were found in any of the 5 MSI-negative colorectal cancer cell lines, 8 colorectal tumors exhibiting a low frequency of MSI (MSI-L), or 28 MSI-negative colorectal tumors. No mutations were found in the mononucleotide repeats of 6 other genes, even in MSI-H cancers. These results suggest that RAD50 frameshift mutations may play a role in the tumorigenesis of MSI-H colorectal cancers. [source]