Expression of Bcl-2 and c-ErbB-2 in colorectal neoplasia

Several studies have been demonstrated the value of c-ErbB-2 and Bcl-2 in predicting the biological behaviour of tumors. The aim of this study was to investigate Bcl-2 and c-ErbB-2 expression in colorectal carcinomas and the correlation between their presence and other clinicopathologic parameters. Eighty-six colorectal carcinomas and 17 adenomas were stained with Bcl-2 and c-ErbB-2 immunohistochemically. Staining patterns were assessed semi-quantitatively and correlated with tumor size, Duke s classification, tumor differentiation, mucinous characteristic and anatomic locations. We detected Bcl-2 expression in 10 of 17 adenomas (58.8 %) and 31 of 86 carcinomas (36.04 %). Positive staining in normal mucosa was observed only in the compartment of cryptic cells. However neither the difference in the rates of Bcl-2 positivity in adenoma and carcinoma groups, nor the correlation with other mentioned clinicopathological parameters, were found statistically significant. Bcl-2 expression was found to be significantly high in mucinous carcinomas. Expression of c-ErbB-2 was observed in 12 of 86 (13.95 %) carcinomas. It was not detected in adenomas and normal mucosa. Although the incidence of c-ErbB-2 in nonmucinous carcinoma was higher than that of mucinous carcinoma, this was not significant. In addition we were unable to show any significant relation between c-ErbB-2 expression and other clinicopathologic features. Our result suggest that c-ErbB-2 protein expression in colorectal carcinomas, is not very frequent event. There is no correlation between c-ErbB-2 expression and malignant potential of colorectal carcinomas. Higher expressions of Bcl-2 in adenomas than carcinomas suggest us a possible role of Bcl-2 in early carcinogenesis of colon. However since we were unable to find any significant correlation between Bcl-2 expression and other parameters the impact of this gene on biological behavior is still unclear for us.     

Chromogranin-A expression in gastric and colon cancer tissues.

We studied the expression of chromogranin A (CgA) in human gastric (n = 17) and colorectal (n = 18) adenocarcinomas by nucleic acid hybridization and immunohistochemical analyses using a specific monoclonal antibody (MAb) to human chromogranin A (CgA). Some corresponding adjacent non-malignant mucosal tissues were also examined. Results: (1) Northern blotting: of 3 normal gastric mucosas examined, 2 (67%) had an easily detected signal for expression of CgA. Only one of 14 gastric carcinomas (7%) and one of 18 colorectal carcinomas (6%) had easily detected RNA signals. (2) Immunohistochemical staining: all non-malignant samples of gastric and colonic mucosa contained CgA-positive neuroendocrine (NE) cells. Two of 17 (12%) gastric adenocarcinomas, and 3 of 18 (17%) of colorectal adenocarcinomas contained CgA-positive tumor cells. Interestingly, the positive cases detected by immunohistochemistry included both cases detected by Northern blotting. Of the 5 cases detected by immunohistochemistry, 2 gastric cancers and 1 rectal carcinoma contained many diffusely scattered positive cells, occurring singly or in small clusters, while 2 colorectal carcinomas contained only occasional single CgA-positive tumor cells. In one of the positive gastric cases, a well-differentiated adenocarcinoma arising in a tubular adenoma, both the adenomatous and the carcinomatous elements contained positively staining cells. Our specific assays for CgA indicate that (1) a NE cell component, either diffusely scattered or occasional, occurs in about 15% of gastric and colorectal tumors; (2) there is no correlation between the presence of NE cells and degree of tumor differentiation; and (3) because only a minority of the tumor cells in positive cases stain for CgA, immunohistochemistry is a more sensitive method than Northern blotting.     

Prognostic significance of alpha-1-antitrypsin in early stage of colorectal carcinomas

We have previously shown that human colorectal carcinoma cell lines, RCM-1 and CoCM-1, synthesize alpha-1-antitrypsin (alpha 1-AT) in culture. We have studied immunohistochemically the incidence of alpha 1-AT on histologic sections from paraffin-embedded tissues of surgically resected colorectal carcinomas and their metastatic foci, polypectomized adenomas, and normal mucosae. alpha 1-AT was detected in 89 (61%) of 145 carcinomas (including 14 carcinomas in adenoma), and 12 (39%) of 31 adenomas. But only 2 (4%) of 55 normal colorectal mucosae were positive for alpha 1-AT. In metastatic tumor cells of colorectal carcinomas in lymph nodes and other organs, alpha 1-AT positivity was 60% and 82%, respectively. The incidence of alpha 1-AT was markedly higher in advanced adenocarcinomas than in early ones and more frequent in adenocarcinomas of right side (including transverse colon) than those of left side and rectum, regardless of their histological malignancy grades. In mucinous carcinomas the frequency was greater (8 of 9 cases) than in conventional adenocarcinomas. Clinical follow-up of the patients with colorectal carcinomas suggested that alpha 1-AT positivity in Dukes' stage A/B tends to correlate with unfavorable prognosis irrespective of the grade of histologic differentiation of carcinoma, but there is no significant relation in Dukes' stage C/D. Our findings suggest that alpha 1-AT in colorectal carcinoma is related to the invasive and metastatic capacity. It may thus serve as a biologic marker for prognosis of colorectal carcinomas at relatively early stages (Dukes' stage A/B).     

Expression of cripto-1 in human colorectal adenomas and carcinomas is related to the degree of dysplasia

The expression and localization of cripto-1 (CR-1) and epidermal growth factor receptor (EGFR) were assessed by immunocytochemistry in 41 human colorectal carcinomas, 57 adenomas, 9 hyperplastic polyps and in 98 noninvolved colonic mucosa samples that were adjacent to adenoma and/or carcinoma. Thirty-two (78.0%) and 19 (46%) carcinomas showed staining for CR-1 and EGFR, respectively, whereas 24 (42.0%) and 25 (43.8%) of the adenoma samples were reactive with the anti-CR-1 and anti-EGER antibodies, respectively. Two (22.2%) and 1 (11.1%) of the hyperplastic polyps demonstrated moderate levels of staining with anti-CR-1 and anti-EGFR antibodies. In contrast, none of the normal, noninvolved colonic mucosa samples reacted with the CR-1 antibody, whereas only 1 (1.0%) reacted with the EGFR antibody. Between EGFR and CR-1 expression, there was no significant association within either adenomas or carcinomas. A significant difference in the incidence for CR-1 expression was observed between adenomas and carcinomas (p<0.001). Within adenomas, the frequency of CR-1 was related to the histological degree of atypia. Immunostaining for p53 was also observed in 10 (24%) of the carcinomas, in 10 (17%) of the adenomas and in none of the hyperplastic polyps nor colonic mucosa samples. No statistically significant difference for p53 staining was observed between the adenomas and carcinomas. However, adenomas with moderate atypia exhibited relatively strong positive staining for p53 (p<0.05) compared to either adenomas with mild or severe atypia. A slight trend (p<0.05) for coexpression of p53 and CR-1 was detected in adenomas but not in carcinomas. These data demonstrate that CR-1 is a tumor marker for colon carcinomas and additionally that the expression of CR-1 may be an important factor in the early stages of colon cancer development during the adenomacarcinoma transition.     

Decreased expression of DNA-dependent protein kinase, a DNA repair protein, during human colon carcinogenesis.

DNA-dependent protein kinase (DNA-PK), consisting of a catalytic subunit (DNA-PKcs) and the Ku70 and Ku86 proteins, participates in the repair of DNA double-strand breaks (DSBs). We assessed its expression immunohistochemically in normal human colon tissue, colon adenomas, colon carcinomas, and normal tissue distant from carcinomas. Normal colonocytes expressed all DNA-PK proteins. Compared with the expression in normal tissue [176.62 +/- 18.56 (the intensity of expression x the percentage of cells expressing this protein), mean + SE], the expression of Ku70 was significantly reduced in adenomas (36.62 +/- 11.09; P < 0.001) and carcinomas (85.68 +/- 15.76; P < 0.01), as was the expression of Ku86 [(113.10 +/- 10.22 versus 41.66 +/- 14.71 in adenomas (P < 0.01) or versus 85.68 +/- 15.76 in carcinomas (P < 0.05)]. The expression of DNA-PKcs was not significantly changed. The marked underexpression of Ku70 and Ku86 starting at the adenoma stage may be crucial to the development of colon cancer.     

Association of Bcl-2 protein expression with gallbladder carcinoma differentiation and progression and its relation to apoptosis

BACKGROUND: Bcl-2 protein is believed to play a role in neoplasia by inhibiting tumor cell apoptosis. To assess its contribution to gallbladder tumorigenesis and cancer progression, an immunohistochemical study was performed. METHODS: Fifteen adenomas and 68 adenocarcinomas were immunohistochemically and histopathologically investigated for the relation of Bcl-2 expression to p53 status, apoptosis (apoptotic index, AI), and proliferation activity (mitotic index, MI; Ki-67 labeling index, Ki-67 LI). RESULTS: The Bcl-2 score, based on intensity and extent, decreased in the order of adenoma, well-differentiated, and moderately to poorly differentiated adenocarcinoma. Early stage carcinomas demonstrated significantly higher Bcl-2 scores than their advanced counterparts (P < 0.05). On the other hand, p53 score, MI, Ki-67 LI, and AI increased in the same order. The Bcl-2 negative adenocarcinomas displayed higher AI and AI-to-MI ratios than the Bcl-2 positive group, especially in the early stage, well-differentiated lesions. A significantly positive correlation between MI(r=0.549) or Ki-67 LI(r = 0.446) and AI was observed. In early stage carcinomas, adenomatous components in the lesions were found more frequently in the polypoid lesions than in the nonpolypoid lesions (P < 0.05). CONCLUSIONS: Expression of Bcl-2 protein in gallbladder tumors appears to be positively associated with tumor cell differentiation and inversely with tumor progression. It may thus play a role in regulating carcinoma growth, especially in the early stage of tumorigenesis. It is believed that the polypoid carcinomas may arise from preexisting adenomas but the nonpolypoid carcinomas may arise as de novo carcinoma.     

Prognostic value of circulating chromogranin A and soluble tumor necrosis factor receptors in advanced nonsmall cell lung cancer

BACKGROUND: Increased levels of chromogranin A (CgA), a protein secreted by many neuroendocrine cells, have been detected in sera of patients with neuroendocrine tumors or renal, hepatic, or heart failure. In patients with heart failure, serum CgA correlates with tumor necrosis factor-alpha (TNF) and soluble TNF receptors (sTNF-Rs), with important prognostic implications. The prognostic value of CgA and sTNF-Rs was investigated in advanced nonsmall cell lung cancer (NSCLC), a histologically heterogeneous group of tumors that may undergo neuroendocrine differentiation. METHODS: CgA and sTNF-Rs were analyzed in the sera of 88 patients with NSCLC before chemotherapy by enzyme-linked immunoadsorbent assay (ELISA) and in tumors by immunohistochemistry. RESULTS: Thirteen percent of patients had CgA values greater than the highest value observed in normal subjects (distribution range, 9-724 ng/mL and 28-196 ng/mL, respectively). Immunohistochemical studies showed no correlation between CgA expression in tumors and serum levels. Conversely, circulating CgA was associated with worse Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P = .0005), more advanced stage (P = .042), and survival, with CgA being an independent prognostic factor of poor outcome (hazards ratio [HR] 1.31 for 100 ng/mL increase; 95% confidence interval [95% CI], 1.08-1.60 [P = .0071]). sTNF-R1 and sTNF-R2 were also associated with ECOG PS (P = .0001 and P = .02, respectively). sTNF-Rs was weakly correlated with circulating CgA (r = 0.39 for TNF-R1 and r = 0.40 for TNF-R2), suggesting a regulatory link between sTNF-Rs and CgA secretion. CONCLUSIONS: Increased serum levels of CgA in NSCLC are independent from protein expression in tumors and more likely related to neuroendocrine response associated with worsening of patient condition. In addition to ECOG PS and stage, CgA is an independent indicator of poor prognosis.     

EphB2 expression across 138 human tumor types in a tissue microarray: high levels of expression in gastrointestinal cancers.

PURPOSE: To comprehensively evaluate ephrin receptor B2 (EphB2) expression in normal and neoplastic tissues. EphB2 is a tyrosine kinase recently implicated in the deregulation of cell-to-cell communication in many tumors. EXPERIMENTAL DESIGN: EphB2 protein expression was analyzed by immunohistochemistry on tissue microarrays that included 76 different normal tissues, >4,000 samples from 138 different cancer types, and 1,476 samples of colon cancer with clinical follow-up data. RESULTS: We found most prominent EphB2 expression in the intestinal epithelium (colonic crypts) with cancer of the colorectum displaying the highest EphB2 positivity of all tumors. Positivity was found in 100% of 118 colon adenomas but in 33.3% of 45 colon carcinomas. EphB2 expression was also observed in 75 tumor categories, including serous carcinoma of the endometrium (34.8%), adenocarcinoma of the esophagus (33.3%), intestinal adenocarcinoma of the stomach (30.2%), and adenocarcinoma of the small intestine (70%). The occasional finding of strong EphB2 positivity in tumors without EphB2 positivity in the corresponding normal cells [adenocarcinoma of the lung (4%) and pancreas (2.2%)] suggests that deregulation of EphB2 signaling may involve up-regulation of the protein expression. In colon carcinoma, loss of EphB2 expression was associated with advanced stage (P < 0.0001) and was an indicator of poor overall survival (P = 0.0098). CONCLUSIONS: Our results provide an overview on the EphB2 protein expression in normal and neoplastic tissues. Deregulated EphB2 expression may play a role in several cancer types with loss of EphB2 expression serving as an indicator of the possible pathogenetic role of EphB2 signaling in the maintenance of tissue architecture of colon epithelium.     

Differential expression in normal-adenoma-carcinoma sequence suggests complex molecular carcinogenesis in colon

The majority of colon cancers develop from pre-existing adenomas. We analyzed the expression profiles in the sequence of normal colon crypts, adenomas and early-stage carcinomas using microdissected cells from tubular adenomas with foci of malignant transformation. Differentially expressed genes were detected between normal-adenoma and adenoma-carcinoma, and were grouped according to the patterns of expression changes in the sequence. Down-regulated genes in the sequence included PLA2G2A, TSPAN1, PDCD4, FCGBP, AATK, EPLIN, FABP1, AGR2, MTUS1, TSC1, galectin 4 and MT1F. PLA2G2A has been shown to suppress colon tumorigenesis in mice, but the pathobiological role in humans has been controversial. Our data showed continuous down-regulation of PLA2G2A in the sequence supporting an implication in human colon cancer. Tumor suppressor and/ or proapoptotic activities have also been reported in other genes. Up-regulated genes included ribosomal proteins, IER3 and TPR. TGF-beta2 and matrix metalloproteinase 23B were up-regulated in carcinoma but not in adenoma, supporting the pathobiological roles in malignant transformation. Differentially expressed genes partly coincided with those in the adenoma-carcinoma sequence of the stomach, which was published previously, suggesting a partial overlap between the adenoma-carcinoma sequences of the colon and stomach.     

Correlation of bcl-2 oncoprotein immunohistochemical expression with proliferation index and histopathologic parameters in colorectal neoplasia

Thebcl-2oncogene plays an important role in carcinogenesis by inhibiting cell death (apoptosis). It was initially discovered in follicular B cell lymphoma with t(14,18), and subsequently found in other malignant and premalignant lesions. Alteration of the normal controls of cell proliferation is also a significant factor in the multistep process of tumorigenesis. The proliferative activity of a given lesion is commonly valuated by MIB1, a monoclonal antibody to Ki67 proliferation antigen. Immuno-histochemical (IHC) staining expression of bcl-2 and Ki67 was retrospectively investigated in a series of 52 colorectal carcinomas and 56 adenomas according to the avidin-biotin-complex method. The aim of the study was twofold: 1) to investigate any correlation between MIB1 and bcl-2 immunostaining expression in colonic adenomas and carcinomas, 2) to identify any relationship between either marker and several histopathologic parameters including tumor size, pathologic stage, lymph node metastasis, angio-lymphatic invasion, tumor grade and differentiation in colon carcinomas. Bcl-2 was consistently higher in adenomas than in carcinomas. There were 44/56 (78.6%) adenomas, and 27/52 (51.9%) carcinomas positive for bcl-2 (p=0.004).The mean Ki67 labeling index (LI) was 30.05+/-7.6 and 38.12+/-11.01 in adenomas and carcinomas, respectively (p=0.0001). Expression of bcl-2 in carcinoma was significantly associated with a lower mean Ki67 LI and with favorable histopathologic parameters. We conclude that bcl-2 oncoprotein expression is probably an early step in the process of colon carcinogenesis, and its expression may be associated with a favorable clinical course. Furthermore, an inverse relationship exists between bcl-2 and Ki67 in colonic neoplasia. Evaluation of bcl-2 and Ki67 IHC expression in colonic carcinoma should be performed prospectively to determine if their expression is of value in predicting the clinical course in these patients.     

Liver fatty acid binding protein expression in colorectal neoplasia

Liver fatty acid binding protein is a member of the fatty acid binding group of proteins that are involved in the intracellular transport of bioactive fatty acids and participate in intracellular signalling pathways, cell growth and differentiation. In this study we have used proteomics and immunohistochemistry to determine the changes in liver fatty acid binding protein in colorectal neoplasia. Comparative proteome analysis of paired samples colorectal cancer and normal colon identified consistent loss of liver fatty acid binding protein (L-FABP) in colorectal cancer compared with normal colon. To identify the changes in liver fatty acid binding protein expression during colorectal cancer development and progression the cell-specific expression of L-FABP was determined by immunohistochemistry in a series of colorectal cancers and colorectal adenomas. Decreased L-FABP immunoreactivity was significantly associated with poorly differentiated cancers (P<0.001). In colorectal adenomas there was a significant trend towards decreased staining of L-FABP in the larger adenomas (P<0.001). There was consistent L-FABP immunostaining of normal surface colonocytes. This study demonstrates that loss of L-FABP occurs at the adenoma stage of colorectal tumour development and also indicates that L-FABP is a marker of colorectal cancer differentiation.     

Neuroendocrine differentiation in colorectal carcinomas: assessing its prognostic significance

AIMS AND BACKGROUND: There is evidence that colorectal carcinomas with extensive neuroendocrine features have a substantially worse prognosis than those without, but the frequency and clinical significance of neuroendocrine features in conventional carcinomas has not been settled since few studies have been performed, with conflicting results. The aim of the study was to investigate neuroendocrine differentiation in colorectal carcinomas in relation to its prognostic significance. METHODS: In 50 patients with colorectal carcinoma, the extent and intensity of staining with each of the three antibodies (chromogranin A, neuron-specific enolase and synaptophysin) were determined and correlated with the histologic type, grade, stage of the tumor and survival time ot the patients. RESULTS: We observed chromogranin A expression in 38%, neuron-specific enolase expression in 26%, and synaptophysin expression in 6% of the tumors. Chromogranin A was the most frequently and strongly expressed marker in our study. Of the three antibodies studied, only chromogranin A positivity was correlated with grade and stage of the tumors and was associated with a decreased effect on survival. CONCLUSIONS: Our results show that chromogranin A is the most sensitive and specific neuroendocrine marker. Chromogranin A positivity appears to bear a poor prognosis in patients with colorectal cancers.     

Comparative study of plasminogen activator antigens in colonic carcinomas and adenomas

The correlation between malignant transformation and increased PA synthesis or secretion has been examined in a variety of cell lines. To study the relationship between content and composition of PAs and colorectal neoplasms, we measured u-PA and t-PA antigen levels in normal mucosa, tubular adenoma, adenocarcinoma in adenoma, and adenocarcinoma, using a sensitive sandwich enzyme immunoassay. This assay was very sensitive and was not hindered by the presence of serine protease inhibitors. Both adenomas and carcinomas had higher u-PA antigen levels than normal mucosa. The u-PA antigen level of adenomas was lower than that of carcinomas. Antigen level of t-PA, however, was lower in both adenomas and carcinomas compared with that in normal mucosa, the values being lowest in carcinomas. Two cases of carcinoma in adenoma had PA contents similar to those of carcinomas. u-PA antigen level of adenomas with dysplastic epithelium was higher than that of adenomas without dysplastic epithelium. Therefore, the increase of u-PA content in adenomas could be a parameter of malignant changes in adenomas.     

神经内分泌分化与p53对非小细胞肺癌预后的影响

目的探讨神经内分泌(neuroendocrine,NE)分化标志物嗜铬蛋白A(CgA)、突触素(Syn)、神经内分泌颗粒和p53对非小细胞肺癌(non-small cell lung carcinoma,NSCLC)预后的影响。方法62例NSCLC进行含铂类方案新辅助化疗1~2个周期,然后手术治疗,以免疫组化法检测术后标本中NE分化标志物CgA、Syn及p53,以电镜观察标本中神经内分泌颗粒,随访3年,结果采用SPSS11.0统计软件,进行生存率分析。结果p53及NE分化标志物联合p53对非小细胞肺癌患者的无病生存期在统计学上均有显著性差异(P<0.05),NE( )p53(-)患者生存率较高。说明p53和NE分化联合p53与非小细胞肺癌患者的预后有关。结论神经内分泌分化和p53两者联合,用于非小细胞肺癌患者无进展生存期评价具有一定的临床价值。     

VEGF expression in the colorectal adenoma-carcinoma sequence

Angiogenesis is essential for tumor growth and metastasis. It is controlled by multiple factors, one of the most important being vascular endothelial growth factor (VEGF). VEGF and p53 expression were evaluated in 16 hyperplastic polyps, 35 solitary tubular and tubulovillous adenomas, and 47 cases of sporadic colorectal carcinomas arising on the basis of preexisting adenomas, using immunohistochemistry. In parallel, angiogenesis was assessed by the Chalkley score (CS) method. VEGF positivity was detected in 19/47 carcinoma cases (40%). In the respective adenomatous part of the tumor, VEGF positivity was detected in 11/47 cases (23%). Carcinomas arising from VEGF-positive adenomas were mostly VEGF positive (10/11, 91%), whereas in 28/36 (78%) carcinomas arising from VEGF-negative adenomas VEGF expression was not detected. CS was higher in VEGF-positive compared with VEGF-negative carcinomas (9.1 +/- 1.8 and 7.8 +/- 2.3, respectively, p < 0.05), whereas there was no statistically significant difference between the CS in the VEGF-negative and VEGF-positive adenomatous part of the tumor (3.3 +/- 1.8 and 4.3 +/- 2.3, respectively). Nuclear p53 positivity was detected in 26/47 (55%) cases in the cancerous part and in 14/47 (29%) cases in the adenomatous part of the tissue, and no significant correlation with VEGF expression was observed. We conclude that VEGF associates with angiogenesis in colorectal cancer, and its pattern of expression in adenomas is maintained in the arising carcinomas. Further investigation is warranted to clarify whether these findings could be used as indicators of prognosis in screening programs or in patients with limited stage disease where the usefulness of adjuvant therapies with either cytotoxic drugs or inhibitors of angiogenesis is still unclear.     

Matrix Metalloproteinase-9 Expression in the Normal Mucosa–Adenoma–Dysplasia–Adenocarcinoma Sequence of the Colon

It has been proposed that matrix metalloproteinases (MMPs) play a role in tumor invasion. We determined protein expression of matrix metalloproteinase-9 (MMP-9) in colorectal cancer (CRC), corresponding normal mucosa and colorectal adenomas. For confirmation of immunohistochemical results MMP-9 TaqMan RT-PCR analysis was performed. Expression of MMP-9 was determined on paraffin embedded biopsy sections by immunohistochemistry in 31 CRC patients (from cancer tissue and corresponding normal mucosa) and in 30 patients with adenoma (nine adenomas with high grade of dysplasia). MMP-9 immunostaining was determined semi-quantitatively. For Taqman RT-PCR analyses normal mucosa (n = 5), adenoma without (n = 6) and with high grade dysplasia (n = 7) and CRC (n = 10) were investigated. Statistical analysis with ANOVA, LSD test and correlation analysis were performed. P value of <0.05 was considered significant. The MMP-9 expression in CRC was significantly higher compared to adenomas or the normal mucosa (P = 0.001). Significantly higher expression of MMP-9 has been observed in adenomas with high grade dysplasia compared to other adenomas or normal colon (P < 0.001). Diffuse strong MMP-9 expression was present in tumor as well as in stromal cells. In adenoma samples, dysplastic epithelial cells showed moderate intensive cytoplasmic MMP-9 expression, with a clear-cut differentiation between dysplastic and non-dysplastic areas. Staining intensity correlated with the grade of CRC. We demonstrate a significantly higher expression of MMP-9 in adenoma with high grade dysplasia-CRC sequence as compared to normal tissue. The over-expression of MMP-9 strongly suggests its association with colorectal carcinogenesis.     

Angiogenesis and p53 expression in the colorectal adenoma-carcinoma sequence

Angiogenesis, the formation of new vessels, is essential for tumor growth and metastasis. Mutations of p53 tumor suppressor gene are frequent and play an important role in colorectal oncogenesis. A role of p53 as an angiogenesis inhibitor has also been proposed. We evaluated angiogenesis and p53 expression in 16 hyperplastic polyps, 35 solitary tubular and tubulovillous adenomas, and 47 cases of sporadic colorectal carcinomas arising on the basis of preexisting adenomas, with standard immunohistochemical techniques. The mean microvessel density (MVD) in carcinomas was significantly higher compared with the respective adenomatous part of the same tumor (27.9 vs. 7; P=0.0001). Linear regression analysis of MVD between cancerous and adenomatous areas showed a significant correlation (P = 0.0001, r = 0.56), raising the possibility that carcinomas arising from better vascularized adenomas might show increased vascularity. The MVD was significantly higher in stage C compared with stage A cases (P=0.04). p53 positivity was detected in 26 of 47 cancerous (55%) and in 14 of 47 adenomatous areas (30%; P = 0.0002). All carcinomas arising from p53-positive adenomas were also p53 positive. p53 positivity associated with a higher MVD in adenomas (P = 0.02), but not in carcinomas (P = 0.78). We conclude that angiogenesis and p53 play a critical role in colorectal neoplasia, and the process of malignant transformation in tumors arising from highly angiogenic adenomas, particularly those carrying p53 mutations, is accelerated with rapid tumor progression from stage to stage, indicating a more aggressive tumor phenotype.     

增殖抑制基因在结直肠癌中的表达及其意义

 目的 探讨增殖抑制基因（HSG）在结直肠癌中的表达及其意义。方法 应用免疫组化法检测HSG在结直肠正常粘膜、良性病变及恶性肿瘤组织中HSG的不同表达变化。结果 正常粘膜、良性腺瘤、结直肠癌组HSG的阳性表达率分别为94．2％、74．2％和50．9％，与正常粘膜组和良性腺瘤组比较，结直肠癌组HSG表达率下降，差异有统计学意义（P〈0．05）；HSG蛋白表达与肿瘤分化程度无相关性（P〉0．05），而与肿瘤淋巴结转移和临床病理分期密切相关（P〈0．05）。结论 结直肠癌组织中HSG蛋白表达显著低于良性腺瘤和正常粘膜组织，提示HSG蛋白在结直肠癌演变中具有重要意义。