Correlation of AR, EGFR, and HER2 Expression Levels in Prostate Cancer: Immunohistochemical Analysis and Chromogenic In Situ Hybridization / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The androgen receptor (AR) plays a central role in prostate cancer. Evidence from several groups indicates that epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) may enhance AR activity in prostate cancer cell lines. This study was designed to investigate the protein expression of AR, EGFR, and HER2 and to determine whether the EGFR and HER2 genes are amplified in prostate cancer tissues. MATERIALS AND METHODS: The protein expression levels of AR, EGFR, and HER2 in a tissue microarray block of 66 prostate cancer samples were investigated by immunohistochemical analysis and chromogenic in situ hybridization was used to determine whether the EGFR and HER2 genes were amplified in these tissues. RESULTS: The AR and EGFR proteins were expressed in 59.1% and 40.9% of prostate cancers, respectively, but their expression levels were not significantly associated with clinicopathologic factors. Of the cases in which tissues were negative for EGFR protein expression, 69.2% were positive for AR protein expression; however, AR protein expression was significantly reduced (44.4%) in tissues in which EGFR protein was expressed. HER2 expression was detected in only 1 case (1.5%). No amplification of the EGFR or HER2 genes was found in prostate cancer specimens. CONCLUSION: This study was limited by small number of subjects, but it can still be inferred that the expression levels of the AR and EGFR proteins are inversely correlated in prostate cancer patients. The potential utility of EGFR and HER2 as prognostic factors or therapeutic targets warrants further study.

A Metastatic Granulocyte Colony-Stimulating Factor Producing Sarcomatoid Carcinoma of the Lung Causing Jejunal Intussusception: Report of a Case

A 75-year-old man was referred to our hospital with intestinal obstruction caused by intussusception. Abdominal computed tomography (CT) revealed seven polypoid masses in the small intestine, while chest CT revealed a mass in the right lower lobe. Preoperative laboratory tests showed white blood cell (WBC) and neutrophil differential counts of 63,630/mm3 and 95%, respectively. The serum granulocyte colony-stimulating factor (G-CSF) was 114 pg/mL, which was elevated (normal range, <18.1 pg/mL). After resection of the small bowel, the WBC count decreased to 20,510/mm3. The pathology showed a poorly differentiated carcinoma with sarcomatous components confirmed by positive immunostaining of cytokeratin (AE1/AE3) and vimentin in the small intestine. Furthermore, immunohistochemistry with specific monoclonal antibodies against G-CSF was positive. A lung biopsy revealed the same histological findings as the small intestine lesion. Therefore, the patient was diagnosed as having a G-CSF producing sarcomatoid carcinoma of the lung with metastasis to the small intestine.

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.

Combined Expression of COX-2, MMP-9, p53 and VEGF in Squamous Cell Carcinoma of the Head and Neck / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: COX-2, MMP-9, p53 and VEGF play an important role in the invasion and metastasis of tumor, and their roles are known to interact with each other. In this study, we investigated the relationship between gene protein expression and clinical parameters including synchronicity to the progression and metastasis in the head and neck squamous cell carcinoma. SUBJECTS AND METHOD: Tissue samples and clinical data were obtained from 69 head and neck squamous cell carcinoma patients who underwent surgery as initial treatment except nasopharngeal carcinoma from January 1999 to December 2003. Their primary sites were: oral cavity (12), pharynx (18) and larynx (39). Immunohistochemical stain was performed to evaluate the expression rate of COX-2, MMP-9, p53, VEGF and then expression patterns and clinical data were analysed. RESULTS: The expressions of COX-2, MMP-9, p53 and VEGF immunoreactivities were observed as 57.9%, 49.3%. 60.9% and 44.9%, respectively. MMP-9 was significantly correlated with T-stage (p=0.021) and COX-2 and p53 levels were significantly correlated with lymph node metastasis (p=0.019 and p=0.001, respectively). Multiple (2 kinds, 3 kinds, 4 kinds) expressions of gene protein were found in 31.9%, 21.7%, and 10.2%, respectively. There was a significant statistical difference between the multiple expression of gene protein to lymph node metastasis and a single expression of gene protein (p=0.030). CONCLUSION: These data suggested that COX-2, MMP-9 and p53 expression may play a role of tumor progression and metastasis in the head and neck squamous cell carcinoma. We may conclude that the synchronous gene protein expression was superior to the single gene expression in estimating progression and metastasis of the head and neck squamous cell carcinoma.

Intravascular Leiomyosarcoma of the Femoral Vein: A Case Report

Intravascular leiomyosarcomas of the femoral vein are extremely rare. Our patient was initially diagnosed with a deep vein thrombosis based on ultrasonography and venography. The thrombectomy specimen consisted of typical spindle cells with variable anaplasia arranged in a fasciculating and interlacing pattern. The final diagnosis was proved to be an intravascular leiomyosarcoma confirmed by immunohistochemical studies for smooth muscle actin, desmin, vimentin, CD34 and CD68.

Immunohistochemical Study of the C-erbB-2, COX-2, MMP-9, p53 and VEGF Expressions in Hepatobiliary and Pancreatic Adenocarcinoma

PURPOSE: Researching the inhibitors of the gene products that participate in the multistep carcinogenetic events of human cancer is important for chemoprevention or adjuvant cancer therapy. This study was performed to search for basic data for the chemoprevention or adjuvant therapy of human hepatobiliary and pancreatic adenocarcinoma, and we wanted to evaluate the coexpression of each gene product and the relationship between the expression of each gene product and the clinocopathologic factors and the prognosis. METHODS: The following formalin-fixed paraffin embedded surgical specimens were immunohistochemically stained by the avidin-biotin complex method for C-erbB-2, COX-2, MMP-9, p53 and VEGF. There were 15 cases of intrahepatic cholangiocarcinoma, 12 cases of metastatic adenocarcinoma in the liver, 15 cases of gallbladder adenocarcinoma, 25 cases of extrahepatic bile duct adnocarcinoma involving the ampullary region and 20 cases of pancreatic ductal adenocarcinoma. RESULTS: Varying frequencies of the overexpressions of the five gene products in the hepatobiliary and pancreatic adenocarcinomas were noted. Although the coexpression of the five gene products was observed to various degrees, the VEGF expression was statistically correlated with the expressions of COX-2 (in the intrahepatic cholangiocarcinoma) MMP-9 (in the glalbladder adenocarcinoma) and p53 (in the extrahepatic bile duct and pancreatic duct adenocarcinoma) (P<0.05). There was also statistical correlation between the C-erbB-2 and COX-2 expressions and the clinical stage of adenocarcinoma of the extrahepatic bile ducts (P<0.05). CONCLUSION: These results suggest that the overexpression of the five gene products was one of the important multistep carcinogenetic events, and the VEGF expression might play an important role in the coexpression of other gene products of hepatobiliary and pancreatic adenocarcinoma.

Prognostication by Cluster Analysis of COX-2, MMP-9 and P53 Expression and?by Clinico-pathologic Correlation Analysis in Non-small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: In pathogenesis and prognosis of lung cancer, significance of enormous types of genetic expression were very compounding and undetermined. We performed this study to search association between clinical characteristics and expression of COX-2, MMP-9 and p53 in non-small cell lung cancer. METHODS: Ninety-one patients with adenocarcinoma or squamous cell carcinoma were enrolled. We had searched clinical data retrospectively and performed immunohistochemical staining for COX-2, MMP-9 and p53. We had analyzed significance of these three genes in clinical features and prognosis for survival. RESULTS: 1) In squamous cell carcinoma, male was predominant and was significantly correlated with smoking. 2) Major prognostic determinants for overall survival were curative resection. 3) Expression of COX-2 was more frequent in adenocarcinoma than in squamous cell carcinoma. 4) Negative staining of COX-2, MMP-9 and p53 was more frequent in squamous cell carcinoma than adenocarcinoma. 5) Survival duration was longer in the group with positive expression of p53 and negative for COX-2 and MMP-9 (median duration of survival = 165.6 weeks) than groups with the other expressional patterns. 6) Significant correlation was found between expression of MMP-9 and COX-2. In squamous cell carcinoma, expression of MMP-9, COX-2 and mutant p53 were mutually correlated. 7) COX-2 expression was significant prognostic factor for survival in resected cancer group. In unresected inoperable non-small cell lung cancer group, MMP-9 was statistically significant prognostic factor for overall survival. CONCLUSION: COX-2 and MMP-9 might have some roles for progression or prognosis in some selected patients with non-small cell lung cancer. COX-2 and MMP-9 may have some roles for disease progression or prognosis in selected patients with NSCLC.

Immunohistochemical Study of C-erbB-2 and VEGF Expression in Non-Small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: Mutated or deregulated expression of C-erbB-2 causes this gene to function as a potent oncogene. Vascular endothelial growth factor (VEGF) is a crucial angiogenic molecule in lung cancer. Both C-erbB-2 and VEGF can promote growth, proliferation and metastasis in non-small cell lung cancer (NSCLC). The purpose of this study was to investigate evaluate the relationship between the expressions of the C-erbB-2 and VEGF genes using immunohistochemistry. MATERIALS AND METHODS: Ninety-five patients with NSCLC were involved (60 squamous cell carcinoma and 35 adenocarcinoma). The formalin-fixed paraffin embedded specimens were immunohistochemically stained for C-erbB-2 and VEGF using the avidin-biotin complex method. RESULTS: Positive C-erbB-2 expression was observed more often in adenocarcinomas than squamous cell carcinomas (p<0.05). Although the immunohistochemical expressions of C-erbB-2 and VEGF in non-small-cell lung cancer showed increased tendencies at an advanced stage, the correlation between early and advanced cancers was insignificant. In adenocarcinomas, the expressions of VEGF and C-erbB-2 were significantly (p<0.05). CONCLUSION: The overexpression fo C-erbB-2 was significantly higher in adenocarcinomas than squamous cell carcinomas, and correlated with the expression of VEGF in adenocarcinomas of the lungs.

Immunohistochemical Study of COX-2, VEGF, CD34 and MMP-9 Expression in Colonic Adenocarcinoma

PURPOSE: The aim of this study was to analyse expression of COX-2, VEGF, CD34 and MMP-9 in colonic adenocarcinoma, and correlate this expression with clinicopathologic parameters. METHODS: Tumor sections of 66 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the colon were immunohistochemically stained using antihuman-COX-2, VEGF, CD34 and MMP-9 antibodies. For the evaluation of COX-2, VEGF and MMP-2 expression, those cases showing the respective antigen expression in more than 10% of the tumor cells were considered to be positive. Microvessel density (MVD) by CD34 expression was evaluated as the number of vessels per high-power field(X200). The mean value for the three fields were recorded as the MVD for each tumor. RESULTS: Although COX-2 expression was not correlated with any clinicopathologic factors, it showed the increased expression according to T-stage, lymph node metastasis and clinical staging. Microvessel density with CD34 expression was correlated with lymph node metastasis and clinical staging. MMP-9 expression was correlated with clinical stage. Microvessel density was correlated with COX-2, VEGF and MMP-9 expression. CONCLUSION: This results indicate that angiogenesis is a complex process that involves multiple factors including COX-2, VEGF, CD34 & MMP-9, and suggest that microvessel density with COX-2 and MMP-9 expression are related to tumor progression and metastasis of colonic adenocarcinoma.

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.

Cathepsin D expression in the tumor cells and juxta-tumoral stromal cells of T1 invasive ductal carcinoma, Nos / 한국유방암학회지

INTRODUCTION: Cathepsin D (CD) is a lysosomal protease that can be used as an important prognostic cytosolic factor for breast cancer. Its over-expression in breast cancer cells and in the host stromal cells in the tumor has been proposed as being a poor prognostic indicator. However, its prognostic value is still being debated. Therefore, CD expression needs to be examined in more relevant subsets of tissue in order to refine its prognostic significance and the clinical applications. METHODS: Regardless of the lymph node status, 110 T1 invasive ductal carcinomas of the breast were immunohistochemically evaluated for the CD expression using rabbit anti-cathepsin D monoclonal antibody. This study separately assessed the expression of CD in the invasive component (IDC), in the in situ component (DCIS), and in the juxtatumoral stromal cells (JTSC). The CD expression level in these three kinds of tissues were correlated with the nuclear grade, ER, PR, c-erb-B2, p53, the N stage, the T stage, and the 5 year metastasis-free survival. RESULTS: Positive CD expression in the JTSC was associated with the T stage (p = 0.001) and the N stage (p = 0.029), whereas positive CD expression in the DCIS and IDC was not. In addition, strong CD expression in the JTSC correlated with the nuclear grade of the invasive component (p = 0.024). In all three components, no statistically significant correlation was found between the biomarker (ER, PR, cerb-B2, p53) and the CD expression. On univariate analysis, positive expression in the JTSC was correlated with a poor 5 year- metastasis free survival (p = 0.007), but the positive expression in the IDC and DCIS was not. CONCLUSION: CD expression of the JTSC could represent the N stage, the T stage, and the nuclear grade of T1 IDC. Whether or not it would have an independent influence on the prognosis of T1 IDC, CD expression in the JTSC is probably an indicator of the tumor virulence. CD expression in the JTSC will provide an important clue for the development of new CD targeted therapies, and it will serve as an important criterion for selecting the appropriate candidates for these future targeted therapies.

Expression of Cyclins (D1, A, E, and B1) in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced Rat Bladder Carcinogenesis

BACKGROUND: Cell cycle deregulation plays a major role in chemical multistage carcinogenesis.Therefore, the evaluation of cell cycle proteins is important. METHODS: In order to induce carcinogenesis in the rat urinary bladder, 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)was administered to male Sprague-Dawley rats for 30 weeks. Expressions of cyclin D1, A, E, and B1 were examined by immunohistochemical stainings. RESULTS: Urothelial cell hyperplasia appeared at 5 weeks, followed by papilloma at 10 weeks. Superficial carcinoma was observed at 20 weeks, and invasive carcinoma developed in 40% (4/10) of the rats at 30 weeks. Expressions of cyclin D1 and A increased sequentially from normal mucosa throughhyperplasia, papilloma, and carcinoma (p<0.01). Expressions of cyclin D1, B1 and cyclin Ewere higher in invasive carcinomas than in superficial carcinomas (p<0.01). In contrast, therewas no significant difference in the expression of cyclin B1 between hyperplasia, papillomaand superficial carcinoma. CONCLUSIONS: The present results indicate the important roles of cyclin D1 and A in the development of BBN-induced urothelial carcinoma of rats. Aberrantexpression of cyclin B1 and E may contribute to the progression from superficial to invasivebladder cancer rather than tumorigenesis.

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

BACKGROUND: Amplifications of the HER-2/neu oncogene and the Topoisomerase II-alpha gene are important determiners of the response to chemotherapy in the breast cancer. For detecting HER-2/neu amplification, fluorescent in situ hybridization and immunohistochemistry are currently regarded as standard methods. Chromogenic in situ hybridization (CISH) is investigated as a new modification of in situ hybridization. The purpose of this study is to compare the efficacy of CISH and immunohistochemistry (IHC) in detecting HER-2/neu oncogene amplification and to investigate the prognostic significance of the HER-2/neu oncogene and the Topoisomerase II-alpha gene in breast cancer. METHODS: Using CISH and IHC the amplifications and protein expressions of the HER-2/neu oncogene were studied on paraffin sections of 43 infiltrating duct carcinomas. The expression of the Topoisomerase II-alpha gene was studied immunohistochemically. RESULTS: Of the 43 infiltrating duct carcinomas, amplifications of the HER-2/neu oncogene by CISH were observed in 8 cases (18.6%), and the HER-2/neu protein was deemed overexpressed by IHC in 9 cases (20.9%). The amplifications of the HER-2/neu oncogene showed a statistically significant correlation with tumor size, histological grade, and the Topoisomerase II-alpha index. The Topoisomerase II-alpha index showed a statistically significant correlation with tumor size, lymph node status, stage, histologic grade, and estrogen receptor status. CONCLUSIONS: CISH is a useful alternative for determining HER-2/neu amplification, especially for confirming the immunohistochemical staining results. HER-2/neu amplification and the Topoisomerase II-alpha gene index may be prognostic factors of breast cancer.

Expression of p53, p21waf1/cip1, Cyclin D1 and Rb in Gastric Epithelial Proliferative Lesions

BACKGROUND: Aberrations of cell cycle-related genes have been reported to contribute to the formation and development of various human tumors. To investigate the gastric carcinogenesis, the expression of cell cycle-related genes (p53, p21wafl/cipl, cyclin D1 and Rb protein) compared to the morphological changes of gastric epithelial lesions were studied. METHODS: The expression of p53, p21wafl/cipl, cyclin D1 and Rb protein was immunohistochemically studied in a series of surgical specimens including the 36 normal/regenerating lesions and the 127 gastric epithelial proliferative lesions (GEPLs). The gastric epithelial proliferative lesions consisted of 25 regenerating epithelia with atypias (REAs), 27 low grade gastric dysplasias (LGDs), 17 high grade dysplasias (HGDs), 24 early gastrc carcinomas (EGCs), and 34 advanced gastric carcinomas (AGCs). RESULTS:The frequency of p53 protein overexpression was significantly associated with histologic grades of GEPLs (p=0.031); occurring in 4% of REAs, in 14.8% of LGDs, in 23.5% of HGDs, in 41.7% of EGCs and 58.9% of AGCs. The p21 wafl/cipl immunohistochemical reaction showed superficial eccentric positivity, representing an inverse correlation with histologic grades of GEPLs (p=0.04); occurring in 83.4% of normal/regenerating lesions, in 80% of REAs, in 74.1% of LGDs, in 29.4% of HGDs, 20.8% of EGCs and 8.8% of AGCs. Although Cyclin D1 and Rb proteins were expressed highly in the GEPLs, the frequency of both proteins were insignificantly associated with histologic grades of GEPLs (p=0.092). However, cases with both the Rb and cyclin D1 positivity were increased with statistical significance along histologic grades of GEPLs (p=0.044). CONCLUSIONS: The altered expression of p53, p21, Rb, and cyclin D1 was considered to be related to dysplastic progression and advancement of malignancy in GEPLs. Therefore, immunohistochemical studies of cell cycle related proteins and a combined analysis may be useful for estimating and following up cases of GEPLs.

Expression of DNA Topoisomerase II-alpha as a Proliferating Marker in Urothelial Carcinoma of Urinary Bladder based on World Health Organization/International Society of Urological Pathology Consensus Classification: A Correlation with Expression of Ki-67

BACKGROUND: DNA topoisomerase II-alpha is linked with active cell proliferation in mammalian cells. The aim of this study was to examine the relationship between the expression of DNA topoisomerase II-alpha as a proliferating marker, and the expression of Ki-67 and apoptosis in urothelial carcinoma of urinary bladder based on World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification. METHODS: 73 urothelial carcinomas of the urinary bladder after transurethral resection and 25 carcinomas after radical cystectomy were investigated for histologic grading based on WHO and WHO/ISUP consensus classification. Formalin fixed, paraffin embedded tissue of 98 specimens from 73 patients were immunohistochemically stained for DNA topoisomerase II-alpha and Ki-67, and in situ TdT-mediated dUTP-biotin nick end labeling method for evaluation of apoptotic cells was performed. For each case, a DNA topoisomerase II-alpha, Ki-67, and apoptotic indices were determined. RESULTS: The histologic grades of 73 cases based on the WHO grading system were 21.9% (16 cases) in grade 1, 65.8% (48 cases) in grade 2, and 12.3% (9 cases). 5.5% (4 cases) of papillary neoplasm of low malignant potential, 47.9% (35 cases) of urothelial carcinoma of low grade, and 46.6% (34 cases) in urothelial carcinoma of high grade were reclassified using the WHO/ISUP consensus classification. Histologic grades based on two grading systems were correlated to invasion and stage (p<0.05). DNA topoisomerase II-alpha, Ki-67, and apoptotic indices were correlated to histologic grades based on two grading system and invasion. Also, the correlation of DNA topoisomerase II-alpha and Ki-67 indices, and DNA topoisomerase II-alpha and apoptotic indices were significant, respectively. CONCLUSIONS: DNA topoisomerase II-alpha appears to be an useful marker for assessing the proliferation potential of urothelial carcinoma of in the urinary bladder.

Intestinal histopathology and in situ postures of Gymnophalloides seoi in experimentally infected mice

The intestinal histopathology and in situ postures of Gymnophalloides seoi (Digenea: Gymnophallidae) were studied using C3H/HeN and C57BL/6 mice as experimental hosts; the effects of immunosuppression were also observed. The metacercariae isolated from naturally infected oysters, 300 or 1,000 in number, were infected orally to each mouse, and the mice were killed at days 3-21 post-infection (PI). In immunocompetent (IC) mice, only a small number of flukes were found in the mucosa of the duodenum and jejunum during days 3-7 PI, with their large oral suckers pinching and sucking the root of villi. The intestinal mucosa showed mild villous atrophy, crypt hyperplasia, and inflammations in the villous stroma and crypt, with remarkable goblet cell hyperplasia. These mucosal changes were almost restored after days 14-21 PI. In immunosuppressed (IS) mice, displacement as well as complete loss of villi adjacent to the flukes was frequently encountered, otherwise the histopathology was generally mild, with minimal goblet cell hyperplasia. In these mice, numerous flukes were found, and it seemed that they were actively moving and rotating in situ. Several flukes were found to have invaded into the submucosa, almost facing the serosa. These results indicate that in IC mice the intestinal histopathology caused by G. seoi is generally mild, and the flukes do not penetrate beyond the mucosa, however, in IS mice, the flukes can cause severe destruction of neighboring villi, and some of them invade into the submucosa.

Expression of p53, CD44v6 and VEGF in Gastric Adenocarcinomas

PURPOSE: The p53 protein is a tumor supressor gene, and its mutation is associated with biologic aggressiveness. CD44v6, one of the CD44 family, is a cell surface glycoprotein that plays a role in cancer invasion and metastasis. Vascular endothelial growth factor (VEGF) is another recently identified growth factor with significant angiogenic properties. The purpose of this study was to investigate p53, CD44v6, and VEGF expressions to determine whether degree of expression was related to pathological parameters such as Lauren's classification, depth of invasion, and lymph node metastasis. MATENRIALS AND METHODS: Immunohistochemical stains of p53, CD44v6, and VEGF in formalin-fixed paraffin-embedded tissue sections of 125 gastric adenocarcinomas were done. RESULTS: The overall expression rates of p53, CD44v6, and VEGF were 54.4% (68/125), 36.8% (46/125), and 48.0% (60/ 125), respectively. The p53, not CD44v6 and VEGF was higher in intestinal-type gastric carcinomas by Lauren's classification. The expressions of p53, CD44v6, and VEGF were statistically correlated with depth of tumor invasion. The expression of CD44v6 was higher in the lymph node metastatic group than in the negative group. The p53 expression was significantly associated with VEGF expression. CONCLUSIONs: These data suggest that the expressions of p53, CD44v6, and VEGF are biologically related to malignancy. The p53 and CD44v6 expressions are independent; however, p53 gene mutation is one of the contributing factors to VEGF expression in gastric adenocarcinoma.

Expression of Glutathione S-Transferase, E-Cadherin, and Catenins during N,N-Diethylnitrosamine-Induced Hepatocarcinogenesis in Rat Liver

N,N-Diethylnitrosamine (DEN) has been proved to have carcinogenic potential in the initiation or promotion stage and the transformed cells proliferate to form preneoplastic nodules which are positive for placental form of glutathione S-transferase (GST-P). E-Cadherin, a member of the cadherin family, is expressed in epithelial cells. To evaluate the role of adhesion molecules (E-Cadherin, alpha-catenin, and beta-catenin), which have not been well understood in carcinogenesis, we investigated the changes of E-cadherin, alpha-Catenin and beta-Catenins by immunohistochemistry and immunoblotting in DEN-induced hepatocarcinogenesis of rat liver. In addition, the sequential analysis of histopathology and the expression of GST-P were also examined. Immunoreactive areas for GST-P were gradually increased from early period of carcinogenesis and strong GST-P positive foci were noted in various lesions, especially in the clear cell and eosinophilic cell nodules. Immunohistochemically, the E-Cadherin expression was increased in DEN-treated preneoplastic nodules in 4 and 10 weeks and hepatocellular carcinomas displayed relatively reduced expression compared with the hyperplastic nodules. But alpha- and beta-catenin expression was increased in hyperplastic nodules and hepatocellular carcinomas. Immunoblotting studies revealed that the level of alpha-catenin (cytosol and membranous fraction) was overexpressed in hyperplastic nodules as well as hepatocellular carcinomas, which showed markedly increased expression. The membranous fraction of beta-catenin was markedly increased in 10 weeks of DEN treatment and slightly reduced in hepatocellular carcinomas. These findings suggest that during DEN-induced hepatocarcinogenesis, the clear cell and eosinophilic cell nodules expressing GST-P in their cytoplasm are early transformed cell nodules. The altered expression of E-Cadherin and catenins is closely related with tumor propagation. Loss or reduced expression of E-cadherin may play a role in the progression of late hyperplastic nodule to hepatocellular carcinoma in DEN-induced rat hepato carcinogenesis.

Correlation of Expression of E-Cadherin, alpha-Catenin, beta-Catenin, and Clinicopathologic Parameters in Colorectal Adenocarcinomas

The E-cadherin, alpha-catenin, and beta-catenin expressions were immunohistochemically investigated in paraffin-embedded materials of 80 cases of colorectal adenocarcinomas. The staining similar to normal colorectal mucosa with preserved strong membranous staining pattern was considered normal or preserved expression. The X2 test was used to analyse the statistical correlation of cadherin/catenin expression with clinicopathologic parameters and the Breslow test for the correlation with survival length. Normal colorectal mucosa showed strong membranous expression of cadherin/catenin complex. The reduced E-cadherin, alpha-catenin, and beta-catenin expression were found in 53/80 (66.3%), 46/80 (57.5%), and 44/80 (55.5%) cases of colorectal cancers examined, respectively. There were significant correlations between E- cadherin and alpha -catenin (p=0.035), and between alpha-catenin and beta-catenin (p=0.013). The reduced E-cadherin expression was associated with histologic dedifferentiation, tumor depth, lymph node metastasis, clinical stage (p<0.05), poor clinical outcome in stage II (p=0.016) and the reduced alpha-catenin expression with lymph node metastasis and clinical stage (p<0.05). Reduced expression of two or more proteins was correlated with lymph node matastasis, histologic dedifferentiation, clinical stage, and survival (p<0.05). The present study demonstrates a significant down-regulation of E-cadherin and alpha-catenin expression in colorectal cancer is associated with tumor invasiveness, histologic dedifferentiation, lymph node metastasis, and clinical stage. These results suggest that E-cadherin and alpha-catenin may be useful markers of invasiveness, lymph node metastatic potential, and clinical stage and of value as prognostic markers in the earlier stage. Further studies are needed to confirm the prognostic value of these cadherin/catenin complex.

Expression of Prostatic Carcinoma Oncogene PTI - 1 in Prostatic Carcinoma , Prostatic Intraepithelial Neoplasia and Benign Prostatic Hyperplasia Using in situ PCR / 대한암학회지

PURPOSE: Prostatic tumor induced gene-1 (PTI-1) is a mutated human EF-la and putative prostatic carcinoma tumor-inducing oncogene, that is differently expressed in prostatic cancer and benign prostatic hyperplasia. And, it is more sensitive marker than prostate- specific antigen (PSA) for detecting human prostate cancer in the bloodstream. This study invastigated the expression of PTI-1 in paraffin embedded tissue of prostatic carcinoma, prostatic intraepithelial neoplasia, and benign prostatic hyperplasia using in situ PCR. MATERIALS AND METHODS: we evaluated expression of PTI-1 in prostatic carcinoma with prostatic intraepithelial neoplasia (PIN) of 32 cases, benign hyperplasia of 20 cases, high grade transitional cell carcinoma of 10 cases and colon cancer of 10 cases for control group. Also, the immunohistochemical staining for PSA was performed to comparison with clinical value of PSA. RESULTS: The serum level of PSA was closely related to stage and Gleason score (p < 0.05). However, the results of immunohistochemical stains were variable to stage and Gleason score. PTI-1 using in situ PCR expressed in 50% of prostatic carcinoma, 41% of prostatic intraepithelial neoplasia, 10% of benign hyperplasia and colon cancer (p < 0.05). No expression is observed in transitional cell carcinoma. In prostatic carcinoma, PTI-1 expressed in 43.8% (7/16) of stage II, 50.0% (5/10) of stage III, and 66.7% (4/6) of stage IV (p<0.05). In PIN, expression of PTI-1 was similar to prostatic carcinoma (p<0.05). CONCLUSION: PTI-1 represented a relatively sensitive marker for prostatic carcinoma and PIN, indicator of prostatic carcinoma progression.