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1.
M F Melhem A I Meisler G G Finley W H Bryce M O Jones I I Tribby J M Pipas R A Koski 《Cancer research》1992,52(21):5853-5864
The myc gene family encodes nuclear phosphoproteins that are thought to play a role in the control of cellular proliferation and differentiation. We have undertaken an immunohistochemical study assessing the expression of myc gene family proteins in individual cells of normal colonic mucosa, colorectal polyps, and colorectal adenocarcinomas. We screened a panel of mouse monoclonal antibodies that we raised against recombinant human c-myc and N-myc proteins for recognition of myc proteins in paraffin tissue sections. Two of these antibodies, H120C69 and H8C150, were selected for indirect immunoperoxidase staining of tissue sections from 16 normal mucosas, 24 polyps, and 30 adenocarcinomas. In normal colon, about 25% of the cells in the lower one-third of the crypts of Lieberkühn stain for myc-related protein. This distribution resembles that of proliferating cells in the crypt. Benign hyperplastic polyps resemble normal mucosa in their myc staining pattern, with about 25% of the cells positive. In adenomatous polyps, the putative precursors of adenocarcinomas, from 50 to 100% of the cells stain positively for myc protein. In these cases, stained cells extend to the luminal surface, consistent with the previously reported expansion of the proliferation zone in these lesions. All adenocarcinomas examined had increased levels of myc protein relative to normal mucosa. The tumor cells exhibited markedly heterogeneous myc staining patterns, both among different tumors and, in some cases, within a single tumor. Comparison with Ki-67 monoclonal antibody staining indicates that myc protein expression in many tumors is uncoupled from cellular proliferation. Surprisingly, we observed increased numbers of myc-expressing cells and increased levels of myc protein in histologically normal colon directly adjacent to tumor, suggesting that many colorectal carcinomas secrete growth factors that activate gene expression in neighboring normal mucosa. 相似文献
2.
Increased expression of cyclooxygenase-2 to -1 in human colorectal cancers and adenomas, but not in hyperplastic polyps 总被引:10,自引:0,他引:10
Maekawa M; Sugano K; Sano H; Miyazaki S; Ushiama M; Fujita S; Gotoda T; Yokota T; Ohkura H; Kakizoe T; Sekiya T 《Japanese journal of clinical oncology》1998,28(7):421-426
BACKGROUND: Non-steroidal anti-inflammatory drugs can reduce the risk of
colorectal cancer. Reportedly, mRNA expression of cyclooxygenase-2 (COX-2)
is elevated in human colorectal cancers compared with accompanying normal
mucosa. The present study was undertaken to establish a simple analytical
procedure to quantify COX-2 expression levels and to characterize COX-2
expression levels in human colorectal cancers, adenomas and hyperplastic
polyps. METHODS: The combination of PCR using common primers designed in
the highly conserved regions and fluorescence-based single-strand
conformation polymorphism (F-SSCP) analysis of the products is used for
quantitative determination of the proportions of COX-2 mRNA in human
colorectal cancers, adenomas, hyperplastic polyps and accompanying normal
mucosa. RESULTS: The present F-SSCP analysis was a simple and powerful
method for quantitative determination of the proportions of COX-2 mRNA. The
proportion of COX-2 mRNA was higher in cancer tissues than in accompanying
normal mucosa in 46 of the 50 cancers. There was no significant correlation
between the increase of the COX-2 proportion and tumor location or stages.
The enhanced COX-2 expression was also observed in colorectal adenomas. On
the other hand, the proportion of COX-2 mRNA in hyperplastic polyps was not
significantly different from that in normal mucosa. CONCLUSIONS: The
proportion of COX-2 to COX-1 expression was elevated in most human
colorectal cancers and adenomas, but not in hyperplastic polyps. Therefore,
the increased proportion of COX-2 expression might be an early event in the
carcinogenesis of colorectal cancer.
相似文献
3.
Ilmo H. Kellokumpu Leif C. Andersson Sakari J. Kellokumpu 《International journal of cancer. Journal international du cancer》1997,74(6):648-653
In contrast to normal colorectal mucosa, peanut-agglutinin(PNA)-reactive glycoconjugates are commonly expressed in most colorectal carcinomas and in some pre-malignant conditions such as adenomas and ulcerative colitis. Since enzymatically detectable galactose-β1-3-N-acetyl-galactosamine residues are found in rectal mucus obtained from patients with carcinoma of the large bowel, it was investigated here whether PNA-reactive carbohydrate structures in rectal mucus can be exploited in the detection of colorectal neoplasia. Samples of rectal mucus obtained from 261 randomly selected patients with colorectal symptoms were applied on nitrocellulose filters. The presence of PNA-reactive glycoconjugates in mucus samples was determined by a peroxidase-conjugated PNA-overlay procedure. The results were correlated to findings from total colonoscopy/surgery and histopathology. PNA-reactive carbohydrate structures were detected in 76% of patients with carcinoma (p < 0.005), in 62% of patients with adenoma (p < 0.005), in 69% of patients with inflammatory bowel disease (p < 0.005), and in 38% of patients with hyperplastic polyps (NS), in contrast to 21% of the control subjects with macroscopically normal colorectal mucosa. These results show that PNA-reactive carbohydrate alterations in rectal mucus correlates with neoplastic and hyperproliferative conditions of the colorectal mucosa. The specificity of the PNA test for colorectal neoplasia was 76%. Therefore the use of more discriminate carbohydrate probes are needed for the pre-symptomatic detection of colorectal neoplasia. Int. J. Cancer 74:648–653, 1997.© 1997 Wiley-Liss, Inc. 相似文献
4.
抑癌基因PTEN在大肠癌癌变过程中表达的实验研究 总被引:4,自引:0,他引:4
目的探讨抑癌基因PTEN的表达与大肠癌发生及浸润转移的关系。方法应用免疫组织化学EnVi-sion法原位观察正常大肠粘膜、癌旁单纯增生上皮、增生性息肉、腺瘤型息肉及癌组织中PTEN蛋白的表达。结果正常大肠粘膜均见PTEN蛋白的表达。癌旁单纯增生粘膜、增生性息肉、腺瘤型息肉及癌组织中PTEN蛋白的阳性表达率分别为92.3%、87.5%、70.6%及56.9%,其中早期癌的阳性表达率为66.7%,浸润癌的阳性表达率为55.9%。无淋巴结转移者的阳性表达率为57.5%,有淋巴结转移者为32.0%(P=0.0002)。PTEN蛋白阳性表达率随肿瘤分化程度降低而降低(P=0.028),随肿瘤Dukes分期的增加而下降,但无统计学意义(P>0.05)。结论PTEN蛋白的表达与大肠癌的发生、浸润及淋巴结转移有关,其低表达可能是大肠癌发生的一个信号。 相似文献
5.
Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis 总被引:185,自引:0,他引:185
Kawasaki H Toyoda M Shinohara H Okuda J Watanabe I Yamamoto T Tanaka K Tenjo T Tanigawa N 《Cancer》2001,91(11):2026-2032
BACKGROUND: To identify the role of survivin, a novel inhibitor of apoptosis (IAP) in colorectal tumorigenesis, the authors investigated tissue expression of survivin in human colorectal tumors including 43 hyperplastic polyps, 171 adenomas with low dysplasia, 42 adenomas with high dysplasia, and 60 carcinomas in adenoma, and examined whether the expression of survivin correlated with tumor cell apoptosis, proliferation, and angiogenesis, which is known to initiate the imbalance between cell proliferation and apoptosis. METHODS: Immunohistochemical staining for the paraffin sections by using the monoclonal antibodies, survivin, p53, bcl-2, Ki-67, and CD34, was performed by the standard avidin-biotin-peroxidase technique. The apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method, using an Apop Tag in situ detection kit. RESULTS: The immunoreactivity of survivin significantly increased in the transition from adenoma with low dysplasia to high dysplasia/carcinoma (P < 0.001). Similar changes in protein expression were observed for p53 but not for bcl-2, which was expressed throughout the colorectal tumorigenesis. This transition was associated with a significant decrease in the apoptotic index (AI) and significant increases in the Ki-67 labeling index (LI) and microvessel density (MVD; P < 0.001 for both). The expression of survivin inversely correlated with AI and was positively correlated with Ki-67 LI and MVD (P < 0.001 for both). CONCLUSIONS: These results suggest that, like p53, survivin plays an important role in transition from adenoma with low dysplasia to high dysplasia during human colorectal tumorigenesis. 相似文献
6.
目的 探讨细胞分化抑制因子-1(Id-1)、细胞增殖核抗原Ki-67在宫颈上皮内瘤变(CIN)组织中的表达及其与CIN病变程度的关系.方法 选取经病理学确诊的109例CIN患者的CIN组织为CIN组,选取经病理学确诊的60例健康妇女的正常宫颈黏膜组织为正常对照组,采用免疫组化SP染色方法检测两组标本中Id-1、Ki-67蛋白的表达,并探讨Id-1、Ki-67蛋白表达与CIN分级的关系.结果 CIN组的Id-1、Ki-67蛋白阳性表达率分别为34.86%、43.12%,均明显高于正常对照组的6.67%、10.00%(P﹤0.001);CINⅠ级、CINⅡ级、CINⅢ级与Id-1蛋白阳性表达率呈正相关(r=0.818,P﹤0.05);CINⅠ级、CINⅡ级、CINⅢ级与Ki-67蛋白阳性表达率呈正相关(r=0.794,P﹤0.05).结论 Id-1、Ki-67蛋白在CIN组织中的阳性表达率增高,并且与CIN病变程度具有相关性. 相似文献
7.
Fecal Adnab-9 binding as a risk marker for colorectal neoplasia 总被引:1,自引:0,他引:1
Adnab-9 binding in colonic tissue and effluent has been associated with an increased risk for colorectal neoplasia. We investigated if fecal binding by Adnab-9 may be used as a marker for colorectal neoplasia. A fecal-Adnab-9 ELISA was performed on samples of 249 patients and colonoscopic pathology results correlated. Fecal Adnab-9 binding was seen in 63% of patients with colorectal neoplasia (59% with colorectal cancer and 83% with adenoma), 33% with inflammatory bowel disease, 0% with hyperplastic polyps and 10% of controls. We conclude that fecal Adnab-9 binding is a promising risk marker for colorectal neoplasia. 相似文献
8.
OPN/CD44v6 overexpression in laryngeal dysplasia and correlation with clinical outcome 总被引:2,自引:0,他引:2
Staibano S Merolla F Testa D Iovine R Mascolo M Guarino V Castellone MD Di Benedetto M Galli V Motta S Melillo RM De Rosa G Santoro M Celetti A 《British journal of cancer》2007,97(11):1545-1551
Laryngeal dysplasia is a common clinical concern. Despite major advancements, a significant number of patients with this condition progress to invasive squamous cell carcinoma. Osteopontin (OPN) is a secreted glycoprotein, whose expression is markedly elevated in several types of cancers. We explored OPN as a candidate biomarker for laryngeal dysplasia. To this aim, we examined OPN expression in 82 cases of dysplasia and in hyperplastic and normal tissue samples. OPN expression was elevated in all severe dysplasia samples, but not hyperplastic samples, with respect to matched normal mucosa. OPN expression levels correlated positively with degree of dysplasia (P=0.0094) and negatively with disease-free survival (P<0.0001). OPN expression was paralleled by cell surface reactivity for CD44v6, an OPN functional receptor. CD44v6 expression correlated negatively with disease-free survival, as well (P=0.0007). Taken as a whole, our finding identify OPN and CD44v6 as predictive markers of recurrence or aggressiveness in laryngeal intraepithelial neoplasia, and overall, point out an important signalling complex in the evolution of laryngeal dysplasia. 相似文献
9.
目的探讨CDX2、PTEN、Ki-67在结直肠癌中的表达及其与DNA倍体的相互关系。方法采用免疫组织化学SP法检测50例结直肠癌组织和10例癌旁的正常肠黏膜组织中CDX2、PTEN及硒-67的表达,运用流式细胞术(FCM)对50例结直肠癌组织做DNA倍体分析。结果结直肠癌和正常肠黏膜组织CDX2的阳性率分别为82%(41/50)和100%(10/10),差异有统计学意义(P〈0.05)。PTEN在两组的表达阳性率分别为64%(32/50)和90%(9/10),差异有统计学意义(P〈0.05)。二者与肿瘤的TNM分期、组织分级、淋巴结转移、原发灶浸润程度相关。CDX2和PTEN与Ki-67呈负相关(r=-0.254,r=-0.340)。二倍体肿瘤中CDX2的表达明显高于异倍体组(93.75%:76.47%),而PTEN在两组表达中差异无统计学意义。结论CDX2与FFEN呈正相关,二者与Ki-67呈负相关,在调节肠上皮细胞增生分化方面PTEN对CDX2有调控作用。CDX2的下降与肿瘤恶性程度、预后有关。 相似文献
10.
Polyamine biosynthetic activity was assessed in various colorectal tissue samples consisting of noninvolved mucosa, benign adenomatous polyps and adenocarcinomas taken at surgery from a total of 40 patients. Ornithine decarboxylase (ODC) displayed a gradient of enzyme activity (i.e., adenocarcinoma greater than polyps greater than mucosa) which seemed to correlate positively with the neoplastic status of the tissue. In 10 of the patients, samples were obtained for all three tissue types. Five of these exhibited a clear repetition of the trends in enzyme activity seen with the mixed patient tissue sampling whereas the remainder differed by having the highest ODC activity in the polyps. In nine of the ten cases, ODC activity was substantially lower in the mucosa than in either of the neoplastic lesions. Trends in enzyme activity were the same for tissues obtained from either the colon or rectum. The ODC activity in adenocarcinomas could not be correlated with histologic differentiation, stage or site of the disease, however, in samples from female patients (all postmenopausal) the activity was elevated over normal mucosa to a greater extent (ten-fold) than in male patients (seven-fold). S-adenosylmethionine decarboxylase activity was assessed in 27 of the 40 patients and found to follow the same distribution as ODC; however, the mean value differences +/- SEM between tissues were less distinct. In general, tissue polyamine pool analysis of these same specimens reflected the levels of ornithine and S-adenosylmethionine decarboxylase activities. Overall, the data reveal an increase in polyamine biosynthetic activity in colorectal neoplasms, relative to surrounding mucosa, which may correlate with (1) progression of the neoplastic process, (2) the proportion of proliferating cells, (3) the rate of cell proliferation, or (4) a combination of two or all of these possibilities. 相似文献
11.
Over-expression and abnormal intracellular location of the product of the oncogene c-myc in colonic dysplasia and neoplasia may be related to alterations in epigenetic mechanisms controlling the functioning of this gene. We have investigated the methylation patterns of the c-myc oncogene in human colorectal tissue representing various stages of dysplasia and neoplasia, including metastasis to liver, omentum and lymph node. Comparison of normal and neoplastic tissues from the same patient showed a decrease in methylation in a specific CCGG site in the third exon of c-myc through the progression from normal via dysplastic to neoplastic and metastatic tissue. Quantitative analysis revealed that in colonic adenocarcinomas an average of 66.1% and in metastatic deposits 83.1% of the myc gene DNA was hypomethylated at this site, as compared to a value of 9.2% in normal colonic mucosa. Adenomatous polyps showed an average value of 50.5% and hyperplastic polyps, 24.8%. The results suggest that partial hypomethylation of the c-myc gene third exon is associated with cell proliferation, and that deregulation of proliferation may be linked to the high levels of hypomethylation, presumably involving both copies of the gene in some cells, which occur at a relatively early stage in neoplastic progression. 相似文献
12.
Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis 总被引:22,自引:0,他引:22
Yu HG Yu LL Yang Y Luo HS Yu JP Meier JJ Schrader H Bastian A Schmidt WE Schmitz F 《Oncology》2003,65(1):37-45
OBJECTIVE: To identify the role of RelA/nuclear factor-kappa B, an important inhibitor of apoptosis in colorectal tumorigenesis, we examined the expression of RelA in normal colorectal mucosa (n = 10), colorectal adenomas (n = 30) and colorectal adenocarcinomas (n = 30). Furthermore, the association of RelA expression with tumor cell apoptosis, proliferation, and expression of Bcl-2/Bcl-x(L )was also studied. METHODS: Paraffin sections were stained with monoclonal antibodies directed against RelA, Bcl-2, Bcl-x(L), and Ki-67 to assess protein expression patterns in normal, adenomatous and colon cancer tissue. Apoptotic cells were detected by terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling (TUNEL) using an in situ detection kit. RESULTS: The results of immunohistochemical staining revealed that expression of RelA, Bcl-2, Bcl-x(L), and Ki-67 labeling index (LI) significantly increased in the transition from adenoma with low dysplasia to adenocarcinoma. This transition was associated with a significant decrease in the apoptotic index (AI) and a significant increase in the Ki-67 LI. The expression of RelA correlated inversely with the AI and correlated positively with the expression of Bcl-2, Bcl-x(L), and Ki-67 LI in the transition from low-grade dysplasia to adenocarcinoma. CONCLUSION: Our results suggest that increased expression of RelA/nuclear factor-kappa B plays an important role in the transition from colorectal adenoma with low-grade dysplasia to adenocarcinoma in the pathogenesis of colon cancer in humans. 相似文献
13.
Pattern of epithelial cell proliferation in colorectal mucosa of normal subjects and of patients with adenomatous polyps or cancer of the large bowel 总被引:11,自引:0,他引:11
M Ponz de Leon L Roncucci P Di Donato L Tassi O Smerieri M G Amorico G Malagoli D De Maria A Antonioli N J Chahin 《Cancer research》1988,48(14):4121-4126
Microautoradiography has been largely used to characterize the proliferative activity of colorectal mucosa. We used this technique in a large series of patients with polyps or cancer of the large bowel and in normal controls with the following objectives: (a) to define the normal pattern of cell replication in different tracts of the large bowel; (b) to compare the proliferative activity of colonic crypts in patients with colorectal cancer or polyps with that of controls; (c) to evaluate replicative activity of colorectal mucosa in the close vicinity and at distance from a neoplastic mass. Specimens of colorectal mucosa were taken during endoscopy (controls and polyps) or at surgery (cancer). During histological examination each intestinal hemicrypt was divided into five equal longitudinal compartments from the base to the surface and the labeled cells in each compartment were counted. In controls, total labeling index (ratio of labeled to total cells) and labeling index per crypt compartment showed only minor differences between the various large bowel tracts. Total labeling index tended to be higher in patients with polyps or cancer than in controls (13.5 +/- 0.4 and 12.5 +/- 0.4, respectively, versus 11.3 +/- 0.5). Labeling index per crypt compartment in the most superficial portions of the crypt (compartments 3 to 5) was significantly higher in the two groups of patients with tumors than in controls. This was particularly evident in the fifth compartment (the most superficial), in which labeled cells were observed in 15.8% (three subjects out of 19) of controls but in 71% (15 out of 21) and 87.5% (14 out of 16) of polyp and cancer patients, respectively. In patients with colorectal cancer there were not significant differences of cell proliferation between mucosal samples taken at various distances from the tumor margin; however, increased cell replication, especially in the most superficial portions of the crypt, has been observed. In conclusion, a significant upwards expansion of the proliferative zone of intestinal glands has been observed in patients with either polyps or cancer of the large bowel. In particular, labeling of the fifth compartment seems to possess the highest discriminatory power between subjects with or without intestinal neoplasms. Hyperproliferation of the entire colonic mucosa seems to be a common feature in patients with colorectal cancer. 相似文献
14.
The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature. 总被引:3,自引:0,他引:3
In recent years, an alternative pathway of colorectal cancer development has been described in which serrated polyps replace the traditional adenoma as the precursor lesion. Importantly, serrated polyps and a subset of colorectal cancer show largely nonoverlapping mutation profiles to those found in adenomas and the majority of colorectal cancer. These genetic alterations include activating mutation of the BRAF proto-oncogene and widespread gene promoter hypermethylation (CpG island methylator phenotype or CIMP). Up to 15% of colorectal cancer is likely to develop on the basis of a strong genetic predisposition. The two most well-characterized syndromes, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (Lynch syndrome), both develop via the adenoma-carcinoma pathway and together account for approximately one third of familial colorectal cancer. We have recently described 11 families in which there is evidence that the genetic predisposition to autosomal dominant colorectal cancer is linked to the serrated pathway. This condition, serrated pathway syndrome, and the related condition, hyperplastic polyposis, the presentation of which suggests a recessive mode of inheritance, represent two syndromes in which BRAF mutation and methylation co-occur within serrated precursor lesions. Further, CIMP is observed in the normal colonic mucosa of individuals with hyperplastic polyposis consistent with a field defect in epigenetic regulation. The spectrum of serrated neoplasia may also implicate the apparently sporadic and later onset subset of colorectal cancer with high levels of microsatellite instability. The tendency for these lesions to be multiple, associated with smoking, and to show frequent BRAF mutation and CIMP points to a defect that may result from interactions between the environment and a weakly penetrant genetic alteration. 相似文献
15.
Frank A Sinicrope Elizabeth Half Jeffrey S Morris Patrick M Lynch Jason D Morrow Bernard Levin Ernest T Hawk Deborah S Cohen Gregory D Ayers L Clifton Stephens 《Cancer epidemiology, biomarkers & prevention》2004,13(6):920-927
BACKGROUND: Celecoxib was shown to regress colorectal adenomas in familial adenomatous polyposis (FAP) patients relative to placebo. To address the mechanism of polyp regression, we determined whether celecoxib can modulate cell proliferation, apoptosis, and prostaglandin E(2) (PGE(2)) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number. MATERIALS AND METHODS: Colorectal mucosal biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg twice daily) or placebo administration (6 months). Residual paraffin-embedded adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling indices and their ratios were calculated in superficials (s) and nonsuperficial (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences were calculated. PGE(2) levels were analyzed by mass spectroscopy (normal, n = 64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated with previously determined mean percentage reductions in colorectal polyp number. RESULTS: In adenomas, a reduction in the superficial proliferative activity i.e., Ki-67(s) labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AI(s))/nonsuperficial apoptotic index (AI(ns))] was found to correlate with reduced polyp counts in that higher apoptotic ratios correlated with better response to celecoxib (r = 0.71, P = 0.004). Furthermore, the AI(s)/Ki-67(s) ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AI(s) (r = 0.33, P = 0.053) and polyp regression was found. PGE(2) levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009; PGE(2), r = 0.50, P = 0.059) within individual patients. CONCLUSION: Suppression of cell proliferation and an increased apoptotic ratio, as well as the ratio of apoptosis to cell proliferation, accompany polyp regression in a chemoprevention trial in FAP patients. These findings suggest potential mechanisms for the efficacy of celecoxib and warrant further study of these biomarkers as intermediate endpoints in FAP patients. 相似文献
16.
Nagothu KK Jaszewski R Moragoda L Rishi AK Finkenauer R Tobi M Naumoff JA Dhar R Ehrinpreis M Kucuk O Majumdar AP 《Cancer Detection and Prevention》2003,27(4):297-304
Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation. 相似文献
17.
Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. 总被引:12,自引:0,他引:12
A M De Marzo V L Marchi E S Yang R Veeraswamy X Lin W G Nelson 《Cancer research》1999,59(16):3855-3860
Somatic changes in CpG dinucleotide methylation occur quite commonly in human cancer cell DNA. Relative to DNA from normal human colonic cells, DNA from human colorectal cancer cells typically displays regional CpG dinucleotide hypermethylation amid global CpG dinucleotide hypomethylation. The role of the maintenance DNA methyltransferase (DNMT1) in the acquisition of such abnormal CpG dinucleotide methylation changes in colorectal cancer cells remains controversial; in one study, 60-200-fold increases in DNMT1 mRNA expression were detected in colorectal polyps and cancers relative to normal colonic tissue [W. S. El-Deiry et al., Proc. Natl. Acad. Sci. USA, 88: 3470-3474, 1991], whereas in another study, only small increases in DNMT1 mRNA expression, commensurate with differences in cell proliferation accompanying colonic tumorigenesis, were observed [P. J. Lee et al., Proc. Natl. Acad. Sci. USA, 93: 10366-10370, 1996]. To definitively ascertain whether abnormal DNMT1 expression might accompany human colorectal carcinogenesis, we subjected a series of normal and neoplastic colonic tissues to immunohistochemical staining using a polyclonal antiserum raised against a DNMT1 polypeptide. A concordance of DNMT1 expression with the expression of PCNA and other cell proliferation markers, such as Ki-67 and DNA topoisomerase IIalpha, was observed in normal colonic epithelial cells and in cells comprising other normal epithelia and lymphoid tissues. The polypeptide p21, which has been reported to undermine DNMT1 binding to proliferating cell nuclear antigen at DNA replication sites, was not expressed by normal colonic cells containing DNMT1 and other cell proliferation markers. In adenomatous polyps, although DNMT1 expression coincided with the expression of other cell proliferation markers, many DNMT1-expressing cells also expressed p21. The fidelity of DNMT1 expression was further undermined in colorectal carcinomas, in which a striking heterogeneity in DNMT1 expression, with some carcinoma cells containing very high DNMT1 levels and others containing very low DNMT1 levels, was observed. These results indicate that human colorectal carcinogenesis is accompanied by a progressive dysregulation of DNMT1 expression and suggest that abnormalities in DNMT1 expression may contribute to the abnormal CpG dinucleotide methylation changes characteristic of human colorectal carcinoma cell DNA. 相似文献
18.
探讨在大肠癌发生发展过程中自噬基因Beclin1的表达及其与增殖、凋亡相关基因之间的关系。方法:采用免疫组化检测29例正常大肠黏膜、60例大肠腺瘤、19例腺瘤恶变及50例大肠癌组织中Beclin1、Bcl-2、Caspase-9、Caspase-3及Ki-67蛋白的表达。结果:1)Beclin1在大肠癌中的阳性表达率高于正常大肠黏膜,但与大肠癌的组织学分化无关,与淋巴结转移有关;2)Bcl-2在大肠腺瘤、腺瘤恶变及大肠癌组织中的表达高于正常大肠黏膜,且与大肠癌的组织学分化及转移有关;Caspase-9与大肠癌的癌变有关,但与组织学分化和淋巴结转移无关;Caspase-3在正常大肠黏膜中的阳性表达高于其他组,无淋巴结转移组高于淋巴结转移组,但与大肠癌的组织学分化无关;3)Ki-67在正常大肠黏膜、大肠腺瘤、腺瘤恶变及大肠癌中的表达逐渐增高,差异有统计学意义,且与大肠癌的组织学分化和淋巴结转移有关。结论:1)自噬可能与大肠癌的发生有关,但随着肿瘤的进展,自噬能力降低可能会促进其侵袭转移。2)大肠癌发生发展过程中,在癌细胞无限增殖的同时,自噬、凋亡通过内在的分子机制相互协调转化,使癌细胞逃脱了机体正常的清除机制,向恶性方向发展。 相似文献
19.
Luca Roncucci Erika Mora Francesco Mariani Serena Bursi Annalisa Pezzi Giuseppina Rossi Monica Pedroni Davide Luppi Luisa Santoro Sebastiano Monni Antonio Manenti Angela Bertani Alberto Merighi Piero Benatti Carmela Di Gregorio Ponz Maurizio de Leon 《Cancer epidemiology, biomarkers & prevention》2008,17(9):2291-2297
Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in x100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean +/- SD, 2.7 +/- 2.0 versus 1.4 +/- 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 +/- 15.5 versus 11.9 +/- 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis. 相似文献
20.
Michael Selgrad Jan Jacob Koornstra Lucia Fini Marloes Blom Rong Huang Edward B Devol Wytske Boersma-van Ek Gerard Dijkstra Robert C Verdonk Steven de Jong Ajay Goel Sharenda L Williams Richard L Meyer Elizabeth B Haagsma Luigi Ricciardiello C Richard Boland 《Clinical cancer research》2008,14(20):6717-6721
PURPOSE: Liver transplant recepients (LTRs) have an increased risk of colorectal neoplasia. The mechanism responsible for this is unknown. JCV encodes for TAg and has been implicated in colorectal carcinogenesis. We hypothesized that the use of immunosuppression in LTRs facilitates activation of JCV and is responsible for the increased risk of neoplasia. EXPERIMENTAL DESIGN: JCV TAg DNA and protein expression were determined in normal colonic epithelium (n = 15) and adenomatous polyps (n = 26) from LTRs and compared with tissue samples from control patients (normal colon, n = 21; adenomas, n = 40). Apoptosis and proliferation were determined by M30 and Ki-67 immunoreactivity, respectively. RESULTS: JCV TAg DNA was found in 10 of 15 (67%) of normal colonic mucosa from LTRs compared with 5 of 21 (24%) of control normal mucosa (P = 0.025). JCV TAg DNA was detected in 16 of 26 (62%) of the adenomas from LTRs and in 20 of 40 (50%) of control adenomas. JCV TAg protein was expressed in 13 of 26 (50%) adenomas from LTRs versus 2 of 40 (5%) of adenomas from controls (P < 0.001). In adenomas from LTRs, the mean proliferative activity was higher compared with controls (60.3 +/- 3.2% versus 42.7 +/- 2.8%, P < 0.001), whereas mean apoptotic indices were lower in LTRs (0.29 +/- 0.08% versus 0.39 +/- 0.06%, P = 0.05). CONCLUSIONS: The presence of JCV in the colorectal mucosa and adenomas from LTRs, in concert with the use of immunosuppressive agents, suggests that JCV may undergo reactivation, and the subsequent TAg protein expression might explain the increased risk of colorectal neoplasia in LTRs. 相似文献