Immunohistochemical Studies of Fascin, MMP-9 Overexpression, and Proliferating Index as Prognostic Factors in Cases of a Colon Adenocarcinoma

PURPOSE: The malignant conversion of epithelial cells involves alterations in the expression and the function of cell-matrix and cell-cell adhesive systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Here, the author studies the prevalence and the potential clinical significance of fascin and Matrix metalloproteinase-9 (MMP-9) expression in relation to the progression of colon adenocarcinoma and of tumor cell proliferation as measured by using the topoisomerase II-alpha (Topo II-alpha) index. METHODS: Relatively well-preserved paraffin-embedded tissues of 120 cases of colon adenocarcinomas were immunohistochemically stained for fascin, MMP-9, and Topo II-alpha expression. A reaction was determined as being positive when more than 10% of the cells were positive for fascin, and/or MMP-9. The Topo II-alpha index is defined as the positive number of tumor cells divided by the total number of tumor cells counted times 100. At least 1,000 cells were counted for this analysis. A chi-square test, by using Epi info 2000, for Fascin and/or MMP-9 and a two-sided test for the Topo II-alpha index were employed with a significance of P65 yr, P=0.028), tumor grading (P=0.009), and lymph node metastases (P=0.005). However, MMP-9 immunoreactivity was not statistically associated with age, gender, tumor stage, or lymph node metastases. Fascin expression was statistically associated with MMP-9 expression, especially for left colon adenocarcinomas (P=0.0032). Although the topo II-alpha proliferating index was associated with lymph node metastasis (P<0.01), this result was not statistically associated with Fascin or MMP-9 expression. CONCLUSION: Fascin expression may be closely linked with tumor grading and lymph node metastasis of more aggressive colon adenocarcinomas and partly associated with MMP-9 expression in tumor invasion. However, further studies of fascin expression as an independent prognostic factor are required for the determination of significant relationships with other clinicopathologic indices.

Amplification of the HER-2/neu Oncogene and Topoisomerase II-alpha by Chromogenic in Situ Hybridization in Breast Cancer

PURPOSE: HER-2/neu is the most frequently amplified oncogene in breast cancer. Topoisomerase II-alpha is a key enzyme in DNA replication and it is a molecular target for many anti-cancer drugs that are called topo II inhibitors; in addition, it is a new marker of proliferation. Because of the physical proximity of the ER-2/neu and topoisomerase II-alpha genes, co-amplification of the HER-2/neu and topoisomerase II-alpha may be important determinates of the response to chemotherapy for advanced breast cancer patients. METHODS: We studied the correlation of gene amplification of HER-2/neu and topoisomerase II-alpha by chromogenic in situ hybridization (CISH) in 43 infiltrating duct carcinomas of the breast. The over-expression of HER-2/neu protein and the staining index for the proliferation marker of topoisomerase II-alpha were examined immunohistochemically. The correlations between the status of HER-2/neu and topoisomerase II-alpha and the other clinicopathologic variables such as tumor size, lymph node metastasis, TNM stage, histologic grade, nuclear grade, and the estrogen receptor and progesteron receptor were investigated. RESULTS: Of the 43 infiltrating ductal carcinomas, the amplifications of HER-2/neu and topoisomerase II-alpha by CISH were observed in 8 cases (18.6%) and 14 cases (32.6%), respectively. Amplification of HER-2/neu showed the statistically significant correlations with tumor size, histologic grade and the topoisomerase II-alpha staining index. Amplification of topoisomerase II-alpha showed statistically significant correlations with axillary lymph node metastasis, the stage, the nuclear grade and the estrogen receptor status. CONCLUSION: These data suggest that amplification of HER-2/neu oncogene and topoisomerase II-alpha by CISH may be valuable for determining the response to chemotherapy, and detection of HER-2/neu and topoisomerase II-alpha in tumor sections may have prognostic value in human breast cancer.

Immunohistochemical Study of Metallothionein Expression in Colonic Adenocarcinoma: Correlation with p53, Topoisomerase II-alpha Expression and Apoptosis

PURPOSE: Although immunohistochemically detectable metallothionein (MT) overexpression has been described in proliferation epithelial tumor cells, the clinical significance of the expression remains to be elucidated. Therefore, the present article is focused on evaluating the possible significance of MT expression in colonic adenocarcinoma and its relationship with p53 overexpression, Topoisomerase II-alpha as new cell proliferating marker and apoptosis. METHODS: The following formalin-fixed paraffin embedded surgical or biopsied samples were immunohistochemically stained for MT, p53 and topoisomerase II-alpha, and performed in situ TUNEL method for evaluation of apoptotic cell ; normal control mucosa (78 cases), tubular adenomas (20 cases) and adenocarcinomas with various degree of differentiation (78 cases). RESULTS: The MT immunohistochmical reactivity was decreased in colonic adenocarcinoma than that of normal glandular epithelial and tubular adenoma, with the frequency of MT expression in colonic adenocarcinoma depending upon tumor differentiation only. But the frequency of p53 expression was correlated with T-stage, lymph node metastasis and clinical staging, while topoisomerase II-alpha expression and apoptosis in colonic adenocarcinoma were correlated with lymph node metastasis and clinical staging. The immunohistochemical expression of MT and p53 expression in colonic adenocarcinoma was inversely correlated. Also, the inverse correlation between MT expression and expression of toposiomerase II-alpha indices and apoptotic indices were noted. CONCLUSION: These data suggest that MT expression may play a role in proliferative activity and apoptosis in colonic adenocarcinoma. Although MT expression is correlated to tumor differentiation, further studies of a possibility of prognostic factor, such as p53, are required for the determination of significant relationships in other clinicinopathologic indices.

Altered Expression of DNA Topoisomerase IIalpha, Ki-67, p53 and p27 in Non-Hodgkin's Lymphoma

BACKGROUND: Topoisomerase II (TOPO II) is an enzyme that separates intertwined chromosomes during DNA synthesis by transiently breaking and joining DNA strands. The level of TOP II is one of the determinants of cellular sensitivity to anti-tumor drugs in non-Hodgkin's lymphoma patients. The alpha form of TOPO II has been recently used as a marker of cellular proliferation. High levels of TOPO IIalpha are expressed in aggressive and proliferative tumors. METHODS: This study was designed to evaluate the relationship between TOPO IIalpha expression and clinicopathological parameters including age, gender, the serum LDH level, the serum beta2-microglobulin level and stage, or expressions, of Ki-67, p53 and p27, in non-Hodgkin's lymphoma. We analyzed forty-one biopsied tissue specimens from patients with non-Hodgkin's lymphoma. RESULTS: The expression of TOPO IIalpha increased with the clinical stage and it was correlated with Ki-67 and p53 expressions. However, TOPO IIalpha expression did not have any significant correlation with age, gender, the serum LDH level, the serum 2-microglobulin level and the p27 expression. CONCLUSIONS: TOPO IIalpha expression is a useful marker of cellular proliferation and it may serve as a prognostic factor of a tumor's progression and aggressiveness in non-Hodgkin's lymphomas.

The Immunohistochemical Expression of DNA Topoisomerase II-alpha and E2F-1 in the Breast Carcinoma and Their Relationship with Clinicopathologic Factors

PURPOSE: Clinical courses of breast cancer are very different, and concern for finding a predictable marker of breast carcinomas has increased. This study focused on the relationship between the expressions of DNA topoisomerase II-alpha as a proliferative marker, and E2F-1 as a transcription factor, with clinicopathological factors of infiltrating duct carcinomas of the breast. METHODS: We investigated the expressions of E2F-1 and DNA topoisomerase II-alpha in 43 patients with infiltrating ductal carcinomas using immunohistochemical staining, and the results were analyzed with regard to clinicopathological parameters. RESULTS: Among 43 infiltrating ductal carcinomas, 24 (55.8%) were immunohistochemically negative on E2F-1 and 19 (44.2%) were positive. The expression of E2F-1 correlated with increased tumor size, positive axillary lymph node meta stasis and high stage. The topoisomerase II-alpha index correlated with increased tumor size, positive lymph node metastasis, high stage, high histological grade and negative estrogen receptor. The expression of E2F-1 and the topo II-alpha index were significantly correlated. CONCLUSION: These results suggest that the expressions of DNA topoisomerase II-alpha and E2F-1 play some role as prog nostic factors for infiltrating duct carcinomas of the breast, but much more study will be required.

The Immunohistochemical Expression of E2F-1 Protein and DNA Topoisomerase II-alpha E2F-1 Protein in Colorectal Cancer and Their Relationship with Clinicopathologic Factors

PURPOSE: E2F-1 is a transcriptor that converts G1 to S in the cell cycle, and Topoisomerase II-alpha is a key enzyme in the metabolism of DNA, and an indicator of cell replication. The purpose of this study was to evaluate the clinical validity of E2F-1 and Topoisomerase II-alpha as prognostic factors in colorectal cancer. METHODS: The expressions of E2F-1 and Topoisomerase II-alpha were studied immunohistochemically using tumor specimen sections fixed with formalin and paraffin-embedded for 84 cases of colorectal cancer. The correlation between E2F-1 and Topoisomerase II-alpha expressions, and their relationship with the clinicopathological factors, such as tumor differentiation, tumor invasion, lymph node metastasis and tumor stage were investigated. RESULTS: Of the 84 specimens, 43 (51.2%) were immunohistochemically negative for E2F-1, and 41 (48.8%) were positive. The expression of E2F-1 correlated with poor tumor differentiation, increased lymph node metastasis and high tumor stage. The expression of Topoisomerase II-alpha also correlated with poor tumor differentiation, increased lymph node metastasis and high tumor stage. The E2F-1 and Topoisomerase II-alpha expressions indices were significantly correlated. CONCLUSION: These results suggest that the expressions of E2F-1 and DNA Topoisomerase II-alpha may play a role as a prognostic factor for colorectal cancer, but further studies will be required for its comfirmation.

Expression of c-erbB-2 Oncoprotein and DNA Topoisomerase II-alpha in Premalignant Lesions and Invasive Squamous Cell Carcinomas of the Uterine Cervix / 대한산부인과학회잡지

OBJECTIVE: The relationship was studied between expression of c-erbB-2 oncoprotein and topoisomerase II-alpha as proliferating marker in precancerous lesions and invasive squamous carcinomas of the uterine cervix. METHODS: Total 81 formalin-fixed, paraffin-embedded sections of low-grade intrasquamous lesion (22 cases), high-grade intraepithelial lesions (42 cases) and invasive squamous cell carcinomas (17 cases) in the uterine cervix were stained by immunohistochemistry for expression of the c-erbB-2 oncoprotein and topoisomerase II-alpha. RESULTS: The expression of c-erbB-2 oncoprotein and staining index (mean+/-S.D) of topoisomerase II-alpha were statistically significant between precancerous lesions and invasive carcinoma. The expression of c-erbB-2 oncoprotein has correlation with staining index (mean+/-S.D) of topoisomerase II-alpha. CONCLUSION: There results suggest that the expression of c-erbB-2 protein has relationship with progression of squamous lesions and topoisomerase II-alpha is an useful proliferating marker in the uterine cervix. And, the expression of c-erbB-2 protein has correlation with expression of topoisomerase II-alpha.

Expression of Topoisomerase II-alpha and c-erbB-2 in Breast Cancer

PURPOSE: Topoisomerase II-alpha is a key enzyme in DNA replication and a molecular target for many anti-cancer drugs. The C-erbB-2 oncogene (HER-2/neu) is the most frequently amplified oncogene in breast cancer. Because of the physical proximity of c-erbB-2 and topoisomerase II-alpha, co-amplification of the c-erbB-2 and topoisomerase II-alpha may occur. To investigate the clinical significance of the topoisomerase II-alpha and c-erbB-2, the correlation between topoisomerase II-alpha and c-erbB-2 was examined by immunohistochemical staining in 43 invasive ductal breast carcinomas and its relationship with other prognostic factors. METHODS: Topoisomerase II-alpha and c-erbB-2 expression was studied immunohistochemically using sections of formalin fixed, paraffin-embedded tumor specimens from 43 invasive ductal breast carcinomas. The correlation between topoisomerase II-alpha and c-erbB-2 expression, and its relationship with the clinicopathological factors such as the tumor size, lymph node metastasis, TNM stage, histological grade, nuclear grade, estrogen receptors and progesteron receptors was investigated. RESULTS: C-erbB-2 was expressed in 9 (20.9%) out of the 43 infiltrating ductal carcinoma cases. Among the prognostic factors, the tumor size, lymph node metastasis, tumor stage, nuclear grade, status of progesteron receptors and estrogen receptors did not significantly correlated with c-erbB-2 expression. The tumor size, lymph node metastasis, tumor stage, histological grade, and the absence of estrogen receptors displayed a significant relationship with the increase in the topoisomerase-alpha index. However, the topoisomerase II-alpha index did not correlate with the nuclear grade and the status of progesterone receptors. The topoisomerase II-alpha index was slightly higher in the c-erbB-2 positive expression cases compared to c-erbB-2 negative expression cases but this increase was not significant (P=0.503). CONCLUSION: These results suggest that topoisomerase II-alpha may play some role as a prognostic factor, but further investigation is needed.

Expression of Topoisomerase II-alpha and c-erbB-2 in Breast Cancer / 한국유방암학회지

PURPOSE: Topoisomerase II-alpha is a key enzyme in DNA replication and a molecular target for many anti-cancer drugs. The C-erbB-2 oncogene (HER-2/neu) is the most frequently amplified oncogene in breast cancer. Because of the physical proximity of c-erbB-2 and topoisomerase II-alpha, co-amplification of the c-erbB-2 and topoisomerase II-alpha may occur. To investigate the clinical significance of the topoisomerase II-alpha and c-erbB-2, the correlation between topoisomerase II-alpha and c-erbB-2 was examined by immunohistochemical staining in 43 invasive ductal breast carcinomas and its relationship with other prognostic factors. METHODS: Topoisomerase II-alpha and c-erbB-2 expression was studied immunohistochemically using sections of formalin fixed, paraffin-embedded tumor specimens from 43 invasive ductal breast carcinomas. The correlation between topoisomerase II-alpha and c-erbB-2 expression, and its relationship with the clinicopathological factors such as the tumor size, lymph node metastasis, TNM stage, histological grade, nuclear grade, estrogen receptors and progesteron receptors was investigated. RESULTS: C-erbB-2 was expressed in 9 (20.9%) out of the 43 infiltrating ductal carcinoma cases. Among the prognostic factors, the tumor size, lymph node metastasis, tumor stage, nuclear grade, status of progesteron receptors and estrogen receptors did not significantly correlated with c-erbB-2 expression. The tumor size, lymph node metastasis, tumor stage, histological grade, and the absence of estrogen receptors displayed a significant relationship with the increase in the topoisomerase-alpha index. However, the topoisomerase II-alpha index did not correlate with the nuclear grade and the status of progesterone receptors. The topoisomerase II-alpha index was slightly higher in the c-erbB-2 positive expression cases compared to c-erbB-2 negative expression cases but this increase was not significant (P=0.503). CONCLUSION: These results suggest that topoisomerase II-alpha may play some role as a prognostic factor, but further investigation is needed.

DNA Topoisomerase II-alpha as a marker of cell proliferation in endocrine and other neoplasms.

DNA topoisomerases are enzymes that are able to link and unlink DNA strands. They are classified as type I or type II topoisomerase if they catalyze transient single-strand (topo I) or double-strand (topo II) DNA breaks. Topo II-alpha has been used as a proliferation marker and it can also serve as a molecular target for a variety of anticancer drugs that are used clinically.Topo II-alpha expression is similar to MIB1 immunoreactivity in breast, ovarian, cervix, gastric, endometrial, adrenocortical, and hematological malignancies. In a study of adrenocortical tumors with metastases topo II was significantly higher than in tumors without metastases.Studies of topo II-alpha expression may provide information about the biological behavior of specific tumors and may also provide insights into the role that this enzyme plays in the response of human cancers to topo II-targeted anticancer drugs.

Expression of Ki-67 and Topoisomerase IIa in Human Middle Ear Cholesteatoma Epithelium / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Cholesteatoma is a destructive lesion of the middle ear or mastoid process. The development of human cholesteatoma is due to the altered control of cellular proliferation in part, which tilts the balance toward the aggressive, invasive growth of squamous epithelium within the middle ear. Many efforts were performed to prove overproliferative characteristics of cholesteatoma using various proliferation markers. Nonetheless, trigger site of overproliferation within the overgrowing epithelium of cholesteatoma is still ill defined. MATERIALS AND METHODS: In this study, we used the monoclonal antibody Ki-67 and Topoisomerase II, a marker of active proliferation, on frozen sections obtained from 12 cholesteatoma samples and observed expression of these markers in three different regions, from normal meatal skin, transitional zone and cholesteatoma sac. RESULTS: The results were interpreted on the basis of nuclear staining and percentage of positively stained cells (labeling index). We found that labeling indices of cholesteatoma and transitional zone were significantly increased compared with that of normal meatal skin. CONCLUSION: This result suggested that initiating of overproliliferation of cholesteatoma epithelium started from the transitional zone.

Clinical Usefulness of Flow Cytometric Measurement of P-glycoprotein, Glutathione S-Transferase pie and Topoisomerase II alpha Expression in Adult Acute Myelogenous Leukemia / 대한혈액학회지

BACKGROUND: P-glycoprotein (PGP) is capable of expelling cytotoxic drugs from cytosol and the overexpression mediates drug resistance. However not all resistant leukemic cells express PGP. High expression of glutathione S-transferasepie (GSTpie) is related to clinical outcome following chemotherapy. Topoisomerase IIalpha (topo IIalpha) is a major target of anthracyclines for the treatment of leukemia. METHODS: To evaluate the relation of PGP, GSTpie and topo IIalpha expression to treatment outcome, PGP, GSTpie and topo IIalpha expression were analysed by flow cytometry using mono clonal antibodies (anti-JSB1, anti-GSTpie and anti-topo IIalpha) in 33 cases of de novo acute myelogenous leukemia. RESULTS: In patients with AML, the frequency of patients with high expression of PGP was 57.6% (19/33). The complete remission (CR) rate and mean survival duration were significantly different between patients with high expression and those with low expression of PGP (31.6 vs 92.9%, P=0.001; 83 vs 341 days, P=0.011). The frequency of patients with high expression of GST pie was 60.6% (20/33). The CR rate and mean survival duration were significantly different between patients with high expression and those with low expression of GSTpie (40.0 vs 84.6%, P=0.011; 115 vs 343 days, P=0.021). The frequency of patients with high expression of topo IIalpha is 78.8% (26/33) and treatment outcome was not related to topo IIalpha expression. In multivariate analysis with age, WBC count, PGP and GSTpie, PGP expression was an independent prognostic factor for treatment outcome. CONCLUSION: The flow cytometric measurement of PGP and GSTpie expression can be useful for the prediction of treament outcome following chemotherapy and PGP can be used as aprognostic factor in AML.