Cyclooxygenase-2 Expression is not a Marker of Poor Survival in Lung Cancer

Objective: Cyclooxygenase-2 (COX-2) has been claimed to play role in carcinogenesis and be related to a badprognosis in tumours. The aim of this study was to investigate the relationship between COX-2 expression andclinical and pathological parameters in early and advanced stage lung cancer patients. Materials and Methods: Atotal of 73 patients with lung cancer (27 adenocarcinomas, 33 squamous cell carcinomas, 4 large cell carcinomasand 9 small cell cancer) were analysed retrospectively. COX-2 expression was evaluated by immunohistochemistryin resection materials or lung biopsies. Tumor cells demonstrating more intense staining than smooth muscle andendothelial cells were recorded as COX-2 positive. We investigated the correlation between increased COX-2expression and histological type of the tumor, the stage of the disease and survival. Results: COX-2 expressionwas observed in 55% of the adenocarcinomas, 45% of the squamous cell carcinomas and 22% of the small cellcarcinomas. No correlation was apparent between COX-2 expression and disease stage, histological type and thesurvival. Conclusion: The results of this study do not support COX-2 expression as an independent prognosticfactor in lung cancer. However, since results of the literature are different, further studies made in larger seriesare needed.     

Elevated content of osteopontin in plasma and tumor tissues of patients with laryngeal and hypopharyngeal carcinoma associated with metastasis and prognosis

The aim of this study was to evaluate the usefulness of osteopontin (OPN) expression level in plasma and tumor tissues of patients with laryngeal and hypopharyngeal squamous-cell carcinoma for predicting metastasis and survival of this tumor. The OPN expression in tumor tissues was detected by immunohistochemical staining in a tissue microarray of laryngeal and hypopharyngeal carcinomas, and the OPN level in plasma was measured by ELISA. The expression levels of OPN in plasma and tumor tissues were associated with clinicopathological features and survival of laryngeal and hypopharyngeal carcinomas. Results showed that the OPN expression quantitation either in tissues or plasma was significantly correlated with differentiation and lymphatic metastasis of the laryngeal and hypopharyngeal carcinoma. Elevated OPN level of plasma and tissues was significantly associated with poor survival. In conclusion, elevated OPN level in plasma and tumor tissues was significantly associated with metastasis and survival of laryngeal and hypopharyngeal carcinomas. Elevated OPN level in plasma and tumor tissues may become a useful indicator of prognosis for laryngeal and hypopharyngeal cancers.     

Expression of hyaluronan in normal and dysplastic bronchial epithelium and in squamous cell carcinoma of the lung

A series of 85 lung/bronchial tissue samples from 76 patients consisting of normal, metaplastic and dysplastic epithelium and different types of lung carcinomas were analyzed for the distribution of hyaluronan (HA), using a biotinylated hyaluronan binding complex as an HA-specific probe. The normal pseudo-stratified columnar bronchial epithelium was either negative for HA or displayed a weak staining around the basal cells. The epithelia of serous and mucous bronchial glands were HA negative whereas the submucosal connective tissue was strongly positive. In metaplastic, dysplastic and carcinoma in situ lesions the whole epithelium from basal to uppermost cells expressed HA on plasma membranes. Epithelial HA was also found in squamous cell carcinomas, but not in adenocarcinomas, carcinoid tumors or small cell carcinomas of the lung. Whereas epithelial HA was present in all lesions of the squamous cell type, the staining intensity displayed great local variability in 50% of the cases with severe dysplasia, carcinoma in situ and squamous cell carcinomas. In squamous cell carcinomas, such an irregular staining pattern was significantly associated with poor differentiation. Our results indicate that the expression of HA in different bronchial lesions and lung tumors is restricted to those showing squamous cell differentiation, being absent from other types of lung carcinomas. The increase of HA-depleted areas in poorly differentiated squamous cell carcinomas emphasizes the important role of HA in tumor differentiation. HA on carcinoma cell surface may influence tumor growth and metastatic behavior. Int. J. Cancer (Pred. Oncol.) 79:251–255, 1998.© 1998 Wiley-Liss, Inc.     

Prognostic value of differential expression of Laminin-5 gamma2 in oral squamous cell carcinomas: correlation with survival

In oral squamous cell carcinomas of the head and neck, Laminin-5 gamma2 has been associated with tissue invasion, lymph node metastasis and histopathological grading. In the present study, we compared the expression of the subunit gamma2 of Laminin-5 under normal, dysplastic and invading epithelia in 65 biopsies previously diagnosed for oral squamous cell carcinoma. The number of gamma2-positive cells were analyzed in relation to patients' survival, tumor grading, size of the lesion, TNM stage, histopathological pattern of invasion and inflammatory reaction. Biopsies of oral squamous cell carcinomas were deparaffinised, processed for antigen unmasking procedures and stained with antibody anti-Laminin-5 gamma2. By light microscopy, 4 optical fields of x200 were selected in three different areas including normal, dysplastic and invading epithelia. Positive cells were counted and divided into three categories, which included <20 cells, between 21 and 50 cells and >50 stained cells. Patient survival was analyzed by Kaplan-Mayer curves. gamma2-positive cells were found in the basal layer of dysplastic epithelium, within inflammatory infiltrate, at the margins of differentiated invading islands and at the forefront of undifferentiated invading nests. Observations showed that an increased number of gamma2-positive cells correlated significantly with a shorter life expectancy under invading epithelia (log-rank test p<0.05), not when a count was performed under normal or dysplastic epithelia of the same patient. The number of gamma2-positive cells also correlated with the histopathological pattern of invasion. Our results show that gamma2 may be a reliable prognostic tool for oral squamous cell carcinomas.     

Cyclooxygenase-2 expression correlates with diminished survival in invasive breast cancer treated with mastectomy and radiotherapy

PURPOSE: To evaluate the relationship between cyclooxygenase-2 (COX-2) expression and pathologic features and outcome in invasive breast cancer. METHODS AND MATERIALS: Formalin-fixed, paraffin-embedded tumor specimens from 23 women with invasive breast cancer were stained for COX-2 expression. All women underwent mastectomy and locoregional radiotherapy. The distribution (percentage of positive staining cells) and intensity of COX-2 expression within the tumor cells were compared with clinical factors, including stage, grade, lymph node involvement, and outcome. RESULTS: For invasive breast cancer, the distribution and intensity of COX-2 tumor expression correlated significantly with diminished overall survival. The 5-year overall survival rate was 100% for patients with <75% of breast cancer cells expressing COX-2 compared with 49% for patients with > or =75% (p = 0.044). The 5-year overall survival rate was 100% for patients with COX-2 intensity <80 compared with 60% for patients with COX-2 intensity > or =80 (p = 0.018). The percentage and intensity of COX-2 expression also correlated significantly with disease-free survival. The percentage of cells expressing COX-2 was significantly greater in women <40 years old than in women > or =40 years old (81% vs. 59%, respectively, p = 0.04). CONCLUSION: Both the distribution and the intensity of COX-2 expression correlated significantly with disease-free and overall survival in patients with invasive breast cancer. Younger patients with invasive breast cancer may have a greater percentage of COX-2 expression in their tumors.     

Immunohistochemical analysis of cyclooxygenase-2 expression in premalignant and malignant esophageal glandular and squamous lesions in Cixian,China

Increased cyclooxygenase-2 (COX-2) expression has been observed in both squamous cell carcinoma (SCC) and adenocarcinoma (AC) in Western countries, and COX-2 inhibitors have been considered as potential chemopreventive agents for esophageal cancers. Since chemoprevention often targets the premalignant lesions in high-risk population, it is worthwhile to study COX-2 expression in a spectrum of premalignant and malignant lesions obtained from the high-risk populations. In this study, biopsy samples were taken from 240 subjects identified by screening of the high-risk population in Cixian, China, including 27 normal, 29 with squamous hyperplasia, 84 with dysplasia (31 low grade and 53 high grade), 30 with carcinoma in situ, and 70 with invasive carcinoma (60 SCC and 10 AC). For comparison, tissue samples were also collected from He Lon Jiang Province, a low-risk population in China, including 10 patients with invasive SCC, 20 patients with AC, and 17 patients with Barrett's esophagus. The COX-2 protein expression was examined by immunohistochemistry. Using 10% staining as a threshold, 9 of 10 (90%) invasive SCC from low-risk population were COX-2 positive. However, no positive COX-2 staining was seen on normal, hyperplastic, dysplastic, and in situ squamous lesions from the high-risk population, and only 4 of 60 (6%) invasive SCC exhibited positive COX-2 staining. For glandular lesions, 6 of 10 (60%) AC from high-risk area and 15 of 20 (75%) from low-risk area showed positive COX-2 staining, and 12 of 17 (70%) premalignant Barrett's esophagus were also positive. Our findings show that COX-2 expression various in squamous lesions from high- and low-risk areas, but not in glandular lesions. Additional studies are needed to fully explore the mechanisms that are associated with the different COX-2 immunohistochemical staining patterns in esophageal squamous lesions from low- and high-risk populations.     

Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy

Purpose: The purpose of this study was to examine the relationship between overall survival and prognostic factors in carcinoma of the cervix treated with radiation therapy. A clinicopathologic study was performed on 24 patients.

Methods and Materials: Formalin-fixed, paraffin-embedded tumor biopsies were stained for Cyclooxygenase-2 (COX-2), Topoisomerase I, Topoisomerase II, and p53. Clinical factors such as stage, grade, tumor size, pre- and post-treatment hemoglobin level, and radiotherapy dose were also evaluated.

Results: Median follow-up was 75 months for living patients. The only immunohistochemical or clinical factor that was associated with improved survival was decreased COX-2 distribution staining. High COX-2 distribution staining was associated with decreased overall survival (p = 0.021) and decreased disease-free survival (p = 0.015) by log-rank comparison of Kaplan-Meier survival curves. The 5-year overall survival rates for tumors with low vs. high COX-2 distribution values were 75% and 35%, respectively. COX-2 staining intensity was found to correlate positively with tumor size (p = 0.022).

Conclusion: These findings indicate that increased expression of COX-2 portends a diminished survival in patients with invasive carcinoma of the cervix treated with radiotherapy. Because COX-2 is an early-response gene involved in angiogenesis and inducible by different stimuli, these data may indicate opportunity to intervene with specific inhibitors of COX-2 in carcinoma of the cervix.     

富含半胱氨酸的酸性分泌蛋白在喉癌和下咽癌间质组织中表达及功能

目的:通过研究富含半胱氨酸的酸性分泌蛋白(SPARC)在喉癌及下咽癌的蛋白表达与相关功能,探讨SPARC对头颈鳞癌发展所起的作用。方法:免疫组织化学染色检测SPARC在51例肿瘤组织中的表达,观察外源性SPARC对体外细胞系生长及迁移的影响。结果:免疫组化染色显示SPARC在46.3%（19/41）喉癌及60.0%（6/10）下咽癌的间质组织表达下调,外源性SPARC抑制头颈鳞癌细胞株的增殖及迁移。结论:肿瘤间质SPARC表达下调促进了喉癌及下咽癌细胞的增殖。     

Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas

PURPOSE: Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debate exists about the premalignant potential of hamartomas. Also, treatment options other than surveillance are not available. Therefore, molecular alterations in hamartomas and PJS carcinomas were studied. The objective was (a) to evaluate expression of cyclooxygenase (COX)-2 as target for chemopreventive treatment and (b) to define the neoplastic potential of hamartomas at the molecular level. Experimental Design: Paraffin-embedded samples of 24 PJS hamartomas, including 2 hamartomas with dysplastic changes, and 11 PJS carcinomas were available. Slides were stained with antibodies against COX-2, beta-catenin, cyclin D1, p21(waf1/cip1), Ki-67, and p53. DNA was studied for loss of heterozygosity (LOH) at 19p (STK11), 5q (APC), and 17p (TP53); mutations in beta-catenin, APC, and K-RAS; and microsatellite instability. RESULTS: Moderate or strong epithelial COX-2 was present in 25% of hamartomas, including two hamartomas with dysplastic changes, and 64% of carcinomas. Several hamartomas showed focal nuclear beta-catenin (18%) and cyclin D1 overexpression (29%), both unrelated to dysplasia at histological examination. Disturbed topographical expression of Ki-67 in relation to p21(waf1/cip1) was focally present in 27% of hamartomas, including those with dysplastic changes. Most carcinomas showed nuclear beta-catenin (71%), cyclin D1 overexpression (71%), and aberrant Ki-67 staining (100%). There was LOH at 19p in 32% of hamartomas and 82% of carcinomas. p53 staining was present in four (36%) carcinomas, one of which showed LOH at 17p. No beta-catenin mutations were found. APC mutations were present in two carcinomas, but LOH at 5q was not found. Two carcinomas had K-RAS mutations, and one carcinoma had microsatellite instability. CONCLUSIONS: The presence of COX-2 expression in PJS carcinomas and dysplastic hamartomas provides a rationale for chemoprevention with nonsteroidal anti-inflammatory drugs or COX-2 inhibitors. Focal immunohistochemical changes, which may indicate a premalignant potential, were present in some nondysplastic PJS hamartomas. Molecular changes in carcinomas and dysplastic hamartomas in PJS are distinct from the usual adenoma-carcinoma sequence.     

细胞周期调控因子与下咽癌生物学行为相关性初步研究

目的：探讨细胞周期调控因子与下咽癌临床生物学行为之间的关系。方法：取下咽鳞状细胞癌手术标本53例，癌旁正常粘膜标本11例，应用免疫组化SP法检测P27^Kipl、Cyelin D1、CDK4在下咽癌组织及正常粘膜中的表达。结果：P27^Kipl、CyclinD1、CDK4均为弥漫性细胞核表达。P27^Kipl。在下咽癌中的表达低于正常粘膜．且表达与N分级明显相关（P〈0．05）；CyclinD1在下咽癌中的表达高于正常粘膜，且表达与T分级明显正相关（P〈0．05）：CDK4在下咽癌中的表达高于正常粘膜，且表达与T分级、N分级明显正相关（P〈0．01、P〈0．05）P27^Kipl与CyclinD1．P27^Kipl与CDK4在下咽癌组织中多呈反向表达，CyclinD1与CDK4多呈同向表达。结论：CyclinD1、CDK4与P27^Kipl在下咽癌发病机制中共同作用．对预后有一定的参考价值。     

Cyclooxygenase-2 Expression in Cervical Squamous Cell Carcinoma: the Significance of Expression in Neoplastic Cells within the Lymphovascular Space

Background: Cyclooxygenase-2 (COX-2) activity is related to the development and progression of cervicalcancer. Previous studies have shown that COX-2 expression in early stage (stage IB-IIA) cervical squamous cellcarcinoma is associated with lymph node metastasis in tumors with lymphovascular space invasion (LVSI), andthat COX-2 expression may facilitate lymph node metastasis after LVSI occurs. In this study, we evaluatedwhether COX-2 expression of neoplastic cells within lymphovascular spaces (tumor emboli) would provideadditional prognostic information. Methods: Immunohistochemical stained slides for COX-2 on 150 cases ofstage IB-IIA cervical squamous cell carcinoma with LVSI were evaluated for expression of COX-2 in tumoremboli. Results were correlated with overall COX-2 expression of tumor and clinicopathologic features usingstatistical analysis. Results: Expression of COX-2 was detected in 49.3% of cases. Expression of COX-2 intumor emboli (LV-COX-2 expression) was identified in 61 cases (40.7%). LV-COX-2 expression was associatedwith high LVSI count (p<0.001) and had a marginal association with tumor COX-2 expression (p=0.050) andlymph node metastasis (p=0.063). In tumors showing high LVSI count, LV-COX-2 expression was an independentpredictor for lymph node metastasis (p=0.038, 95% CI=1.030-2.725) whereas tumor COX-2 expression (p=0.550)was not. Conclusion: Evaluation of COX-2 expression in tumor emboli may provide additional prognostic valuefor lymph node metastasis in cervical squamous cell carcinomas with a high LVSI count.     

Expression of SGLT-1 in preneoplastic and neoplastic lesions of the head and neck

Tumors show an increased glucose uptake that is mediated by glucose transport proteins. We have analyzed the expression of the sodium-dependent glucose co-transporters SGLT-1 and-2 in short-term cultures of squamous cell carcinomas of the head and neck (HNSCC) by RT-PCR. Distribution of the SGLT-1 protein in HNSCC tissues was investigated by immunohistochemistry. While we observed in 17/36 HNSCC short-term cultures the SGLT-1 mRNA, we found no SGLT-2 expression. SGLT-1 mRNA expression occurred preferentially in cultures originating from moderately and well differentiated HNSCC. In tumor tissues a heterogeneous SGLT-1 staining restricted to differentiated tumor cells was seen in 27/30 HNSCC analyzed. In normal mucosa SGLT-1 staining was also confined to differentiated compartments and lacked in dysplastic areas. Our data indicate a differentiation-dependent expression of SGLT-1 in HNSCC. This is important knowledge for the planning of glucose-targeting therapies and suggest SGLT-1 as a differentiation marker in head and neck tissues.     

The cyclooxygenase 2-selective inhibitor NS398 inhibits proliferation of oral carcinoma cell lines by mechanisms dependent and independent of reduced prostaglandin E2 synthesis.

PURPOSE: We investigated the potential of cyclooxygenase (COX)-2 as anappropriate chemopreventive and/or therapeutic target for oral cancer. EXPERIMENTAL DESIGN: Immunohistochemical analysis of COX-2 expression was carried out on 37 oral squamous cell carcinomas (OSCCs) and 23 normal oral epithelium samples. We investigated whether the COX-2-selective inhibitor NS398 induced growth inhibition in four human OSCC cell lines and whether this was COX-2 dependent. RESULTS: COX-2 staining was more intense in the carcinomas compared with normal epithelium (P < 0.001). Early-stage tumors (stages I and II) had significantly higher epithelial COX-2 staining than late-stage tumors (stages III and IV; P = 0.034), and overexpression of COX-2 was detected in hyperplastic and dysplastic epithelium. Treatment of OSCC cells with NS398 for 72 h at concentrations of 50 micro M and above resulted in growth inhibition accompanied by a reversible G(0)-G(1) arrest, but no apoptosis or terminal differentiation. However, a concentration of 10 micro M was sufficient to abolish secreted prostaglandin E(2) (PGE(2)) production. Over a longer treatment time, lower concentrations of NS398 were growth inhibitory. Growth inhibition of the OSCC cell line H357 was detected after treatment with 5 micro M NS398 as well as 100 micro M NS398 for 6-12 days. In cultures treated with 5 micro M NS398, but not in those treated with 100 micro M NS398, restoration of PGE(2) to control levels abrogated growth inhibition. CONCLUSIONS: NS398 inhibits the growth of OSCC cells by mechanisms that are dependent and independent of suppression of PGE(2) synthesis. Molecular targeting of COX-2, PGE(2) synthase, or PGE(2) receptors may be useful as a chemopreventive or therapeutic strategy for oral cancer.     

COX-2 correlates with F-box protein, Skp2 expression and prognosis in human gastric carcinoma

The expression of cyclooxygenase (COX)-2 is induced by growth factors, tumor promoters and cytokines, and is correlated with carcinogenesis, tumor progression and inhibition of apoptosis. To clarify the pathological significance of COX-2, we examined the effect of a selective COX-2 inhibitor, NS398, on two human gastric carcinoma cell lines, MKN-45 and KATO-III, and the expression of Skp2, P27/Kip1 and COX-2 protein in human gastric carcinomas. NS398 inhibited cell growth in a time- and dose-dependent manner and exerted cell cycle arrest in the G0/G1 phase without induction of apoptosis in MKN-45, but had no effect in KATO-III. In MKN-45, NS398 induced up-regulation of P27/Kip1 and down-regulation of COX-2, cyclin D1 and Skp2. Immunohistochemistry using 63 surgically resected gastric carcinomas disclosed that COX-2 expression was correlated with Skp2 expression and that P27/Kip1 expression was inversely correlated with COX-2 and Skp2 expression. High levels of COX-2 or Skp2 were significantly correlated with poor survival (P=0.02 and P=0.004). Our results suggested that: a) NS398 induced inhibition of cell proliferation through cell cycle arrest and suppressed the expression of Skp2 in COX-2-expressing gastric carcinoma cells, and b) COX-2 contributes to the expression of Skp2 and poor survival in human gastric carcinomas.     

Cyclooxygenase-2 expression is related to prognosis in patients with esophageal squamous cell carcinoma

Aim

Esophageal carcinoma is one of the most aggressive malignancies. Many studies have examined various biological factors associated with the malignant potential of esophageal carcinoma. Cyclooxygenase (COX)-2 is overexpressed in various types of human malignancies, including esophageal carcinomas. Although some groups have described COX-2 expression in esophageal adenocarcinoma, few studies have reported COX-2 expression in esophageal squamous cell carcinoma (ESCC).

Methods

We immunohistochemically investigated relationships between COX-2 overexpression in surgical specimens of primary tumors in 228 patients with ESCC. Relationships between COX-2 expression and clinicopathological factors, including prognosis, were analyzed. COX-2 expressions were classified into 4 criteria: Score 0, no staining; Score 1, <10% staining; Score 2, 10–90% staining; and Score 3, >90% staining.

Results

Scores of COX-2 immunoreactivity in 228 patients were as follows: Score 0, 21 of 228; Score 1, 71of 228; Score 2, 117 of 228; and Score 3, 19 of 228, respectively. COX-2 expression was significantly correlated with depth of invasion and tumor stage (p = 0.03 and p = 0.04, respectively). The 5-year survival rate of patients decreased significantly with increased expression of COX-2 (p = 0.005). Multivariate regression analysis indicated COX-2 expression as an independent prognostic factor for ESCC.

Conclusions

COX-2 overexpression was significantly correlated with depth of invasion, tumor stage and survival in ESCC. Evaluation of COX-2 expression should be useful for determining tumor properties, including prognosis, in patients with ESCC.