αv‐Integrin isoform expression in primary human tumors and brain metastases

To determine whether metastasis to brain is associated with altered expression patterns of integrins, we investigated the expression of αvβ3, αvβ5, αvβ6 and αvβ8 integrins in primary malignancies and metastases to brain of breast, lung and renal carcinomas and in malignant melanoma. Inhibitors of αv integrins are currently in clinical trials for glioblastoma. The role of integrins in the process of brain metastasis from other human tumors is unknown. Immunohistochemistry with novel integrin subtype specific rabbit monoclonal antibodies was performed on tissue microarrays of archival material of surgical biopsies taken from primary tumors and brain metastases. Integrin αvβ3 expression was increased in brain metastases compared to primary tumors of breast adenocarcinoma, non‐small cell lung cancer, renal clear cell cancer and malignant cutaneous melanoma (all p < 0.01). Similarly, integrin αvβ8 expression was increased in brain metastases compared to primary tumors of breast cancer (p < 0.0001), lung cancer (p < 0.01) and renal cancer (p < 0.0001), with a similar trend in metastatic melanoma. Integrin αvβ5 was expressed in most primary tumors (98% breast cancer; 67% lung cancer; 90% renal cancer; 89% melanoma) and showed a stronger expression in brain metastases compared to primary tumors from lung cancer and melanoma (p < 0.05). Also integrin αvβ6 expression was increased in brain metastases compared to primary breast cancer (p < 0.001). Conclusions: The stronger αv‐integrin expression in brain metastases, especially of αvβ3 and αvβ8 integrins, suggests that certain αv integrin are involved in the process of brain metastasis. αv Integrins may be therapeutic targets for patients with metastatic cancer in brain.     

Treatment strategy for metastatic brain tumors from renal cell carcinoma: selection of gamma knife surgery or craniotomy for control of growth and peritumoral edema

We retrospectively studied the efficacy of gamma knife surgery (GKS) for metastatic brain tumors from renal cell carcinoma (RCC). To evaluate the efficacy of GKS for control of peritumoral edema, we retrospectively studied 280 consecutive metastatic brain tumors (100 from lung cancers, 100 from breast cancers, and 80 from RCC) associated with peritumoral edema. In addition, this study included 11 patients with metastatic brain tumors from RCC who underwent direct surgery. The tumor growth control rate of GKS was 84.3%. The extent of edema of RCC metastases was significantly larger than those from lung and breast cancer. Primary site (renal or not renal) and delivered marginal dose (25 Gy or more) were significantly correlated with control of peritumoral edema. All tumors treated by direct surgery were more than 2 cm in maximum diameter. Peritumoral edema at surgery was extensive but disappeared within 1–3 months, and neurological symptoms also improved in many cases. Total removal of brain metastases from RCC was easy with little bleeding in most cases. Our results suggest that GKS is effective for growth control of metastatic brain tumors from RCC. Higher marginal dose such as 25 Gy or more is desirable to obtain peritumoral edema control, so GKS is not suitable for control of symptomatic peritumoral edema associated with relatively large tumors. Tumor removal of RCC metastases is relatively easy and rapidly reduces peritumoral edema. Treatment strategy for metastatic brain tumors from RCC depends on tumor size, number of tumors, and presence of symptomatic peritumoral edema.     

Loss of FHIT expression in breast cancer is correlated with poor prognostic markers.

OBJECTIVE: The fragile histidine triad (FHIT) gene is a putative tumor suppressor gene that is thought to be involved in the carcinogenesis of breast cancer. Loss of FHIT expression has been observed in up to 72% of breast cancers and has been associated with increased p53, a high proliferation index, and increased tumor size and grade. However, loss of FHIT expression has not been investigated in association with apoptosis and cyclooxygenase-2 (COX-2) expression in breast cancer. Furthermore, expression of FHIT in primary breast tumors and their metastatic axillary lymph nodes has also not been previously described. The purpose of this study was to evaluate the expression of FHIT, COX-2, bcl-2, and p53 in primary breast tumor tissue; correlate their expression with known clinical and pathologic markers; and in cases when tissue was available, evaluate the expression of FHIT and COX-2 in the corresponding metastatic axillary lymph node in the same patient. METHODS: Primary breast tumor specimens from 80 patients were examined for the presence of FHIT, COX-2, bcl-2, and p53 expression by immunohistochemistry using standard methods. When tissue was available, the expression of FHIT and COX-2 was also evaluated in the corresponding metastatic axillary lymph node specimen. RESULTS: FHIT expression in primary breast tumors was 56%. There was a significant correlation between FHIT expression in primary breast tumor and bcl-2 expression (P = 0.017). We also observed a significant inverse correlation between FHIT expression in primary breast tumor tissue and p53 expression (P = 0.023) in lymph node-negative cases. A significant inverse correlation between FHIT expression in the primary tumor and Ki-67 (P = 0.009) was also observed in lymph node-negative cases. FHIT expression in primary tumors correlated with FHIT expression in the metastatic lymph node (52.5%; P = 0.001). FHIT expression in primary tumors did not correlate with COX-2 expression. CONCLUSION: Our results suggest that loss of FHIT expression in breast cancer is associated with poor prognostic features. Furthermore, loss of FHIT expression is also seen in metastatic axillary lymph node. The prognostic and predictive value of these findings needs to be further evaluated in larger trials with longer follow-up.     

Cyclooxygenase-2 expression is not associated with clinical outcome in synovial sarcoma

Several studies have identified cyclooxygenase-2 (COX-2) expression in a variety of sarcomas, including rhabdomyosarcoma, osteosarcoma and chondrosarcoma. Although overexpression of COX-2 has been associated with poor prognosis and decreased survival in chondrosarcoma and osteosarcoma, no relationship between COX-2 expression and patient outcome has been demonstrated in rhabdomyosarcoma or adult soft tissue sarcomas. Little is known concerning the expression of COX-2 in synovial sarcoma. Therefore, the aim of this study was to examine the expression of COX-2 in synovial sarcoma and if shown, to identify any association with tumor stage and oncologic outcome. Paraffin-embedded specimens from 27 patients with synovial sarcoma who were treated with surgical resection or biopsy were obtained. Specimens were evaluated for the degree of COX-2 expression after immunohistochemical staining. Specimens were assigned an immunoreactivity score (IS) based on the percent positivity of the specimen. A retrospective chart analysis was performed to determine the clinical stage at presentation, incidence of local recurrence, presence of metastatic disease and overall survival. Statistical analysis was then performed to determine whether there was a significant relationship between IS and stage at presentation or patient outcomes. COX-2 expression was detected in 18 of 27 (66.67%) of the pathological specimens. There was a statistically significant relationship between COX-2 expression and patient clinical stage at presentation; however, we were unable to identify a significant relationship between IS and patient survival. We also found no significant relationship between IS and development of metastases or local recurrence. COX-2 was expressed to some degree in 67% of the tumor specimens. There was a significant relationship between IS and patient stage at presentation, but no significant relationship between COX-2 expression and clinical outcome could be identified. The fact that these tumors do express COX-2, however, suggests the potential for an additional target for more effective therapy.     

环加氧酶-2 通过调控EMT促进乳腺癌MDA-MB-231 细胞的迁移和侵袭

[摘要] 目的：探讨环加氧酶-2（COX-2）在乳腺癌转移中的作用及其可能的机制。方法：收集从2015 年10 月至2018 年4 月在云南省肿瘤医院接受乳腺切除术的患者中获得的原发乳腺癌组织和脑转移乳腺癌组织临床病理样本共45 例,其中原发30 例、脑转移15 例。采用qPCR检测COX-2 在原位乳腺癌和脑转移乳腺癌组织中的表达。将COX-2 过表达重组病毒（LV6-COX2）或敲减COX-2 重组病毒（LV3-COX2 shRNA1、LV3-COX2 shRNA2）感染人乳腺癌MDA-MB-231 细胞并获得稳转细胞株后,CCK-8法检测COX-2 表达对MDA-MB-231 细胞增殖的影响,划痕实验和Transwell 法检测对MDA-MB-231 细胞迁移和侵袭的影响。qPCR和WB实验分析各组细胞中COX-2 mRNA和蛋白的表达水平,qPCR检测COX-2 表达对MDA-MB-231 细胞内EMT相关基因表达的影响。结果：COX-2 表达水平在脑转移乳腺癌患者组织中显著高于原位乳腺癌组织（P<0.01）;并且与乳腺癌患者肿瘤TMN分期有关。成功构建稳定过表达/敲减COX-2 的MDA-MB-231 细胞株。过表达COX-2 促进MDA-MB-231 细胞的迁移和侵袭（均P<0.01）,同时显著提高MMP2、MMP1、N-cadherin 和vimentin 的表达（均P<0.01）,但对细胞增殖无明显影响;而沉默COX-2 则有相反的作用,且可促进细胞增殖（P<0.05）。结论：COX-2 在脑转移乳腺癌组织中高表达,其可能通过调控EMT过程促进乳腺癌MDA-MB-231 细胞的迁移和侵袭。     

Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer

Cyclooxygenase-2 (Cox-2) expression can induce mammary tumorigenesis in transgenic mice, and selective Cox-2 inhibitors are both chemopreventive and chemotherapeutic in rat models of breast cancer. We analyzed the expression of Cox-2 protein by immunohistochemistry in tissue array specimens of 1576 invasive breast cancers. Moderate to strong (elevated) expression of Cox-2 protein was observed in 37.4% of the tumors, and it was associated with unfavorable distant disease-free survival (P < 0.0001). Elevated Cox-2 expression was associated with a large tumor size, a high histological grade, a negative hormone receptor status, a high proliferation rate (identified by Ki-67), high p53 expression, and the presence of HER-2 oncogene amplification (P < 0.0001 for all comparisons), along with axillary node metastases and a ductal type of histology (P = 0.0001 and P = 0.0017, respectively). Interestingly, association with the unfavorable outcome was especially apparent in the subgroups defined by estrogen receptor positivity, low p53 expression, and no HER-2 amplification (P < 0.0001 for all comparisons). These results indicate that elevated Cox-2 expression is more common in breast cancers with poor prognostic characteristics and is associated with an unfavorable outcome. The present findings support efforts to initiate clinical trials on the efficacy of Cox-2 inhibitors in adjuvant treatment of breast cancer.     

Immunohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors.

PURPOSE:Prostanoids are important mediators of pulmonary vaso- and bronchotone regulation and strongly influence inflammatory reactivity. The product of cyclooxygenase (Cox), prostaglandin H(2), is further metabolized via downstream enzymes into the different effective metabolites. The specific cellular equipment with certain downstream enzymes crucially determines the cellular reactivity by generation of functionally different prostanoid metabolites. EXPERIMENTAL DESIGN: To elucidate the role of arachidonic acid metabolism via the cyclooxygenase pathway in different human lung tumors, expression of cyclooxygenase isoenzymes (Cox-1 and Cox-2) and downstream enzymes of prostanoid metabolism was investigated in human non-small cell lung cancer and normal human lung tissue by immunohistochemical techniques. RESULTS: In comparison to strong Cox-1 reactivity in airways and endothelial cells of normal lung specimens, only 4 of 15 adenocarcinomas showed infrequent Cox-1 expression. All lung cancer specimens displayed an increased Cox-2 immunostaining pattern with strong reactivity in adenocarcinomas and lower reactivity in squamous cell carcinomas. Adenocarcinomas and squamous cell carcinomas were also positive for thromboxane A(2) synthase, prostaglandin D(2) synthase, and prostaglandin E(2) synthase, but not for prostacyclin synthase. Endothelial cells of vessels found within or near the tumor show extensive immunostaining of Cox-2 and thromboxane A(2) synthase, whereas endothelial cells of normal lung specimens, in contrast, expressed Cox-1 and prostacyclin synthase. CONCLUSIONS: We conclude that non-small cell lung cancer shows a specific Cox-/downstream-enzyme expression pattern, which is specifically altered in lung tumor cells and tumor supplying vessels in contrast to normal lung tissue. This may have major impact on tumor progression and tumor-associated inflammation via an altered prostanoid metabolism with consecutive tumor-associated blood flow distribution.     

Use of the monoclonal antibody MOC-31 as an immunomarker for detecting metastatic adenocarcinoma in effusion cytology

BACKGROUND:

MOC‐31 is an established immunologic marker with which to detect adenocarcinomas. The objective of the current study was to evaluate the use of MOC‐31 in the diagnosis of metastatic adenocarcinoma in effusion specimens.

METHODS:

The authors evaluated cytologic specimens of effusions/washings in which MOC‐31 immunostaining was performed on unstained cell block sections or Papanicolaou‐stained cytospin preparations. Membranous staining with or without cytoplasmic staining was considered to be positive. The immunostaining results were correlated with the cytologic diagnoses and clinical follow‐up data.

RESULTS:

A total of 215 effusions and washings were identified (cell blocks in 162 cases, cytospin preparations in 53 cases, and both in 2 cases in which MOC‐31 immunostaining was performed). A total of 94 (44%) of the 215 cases were found to be positive for malignancy, including 87 metastatic adenocarcinomas. Specimens were positive for MOC‐31 in 76 (87%; 55 cell blocks and 21 cytospin preparations) of 87 cases of metastatic adenocarcinoma. Eleven cases of metastatic adenocarcinoma were found to be negative for MOC‐31 (4 cases from lung tumors, 2 from stomach tumors, 2 from colon tumors, 2 from breast tumors, and 1 from a renal tumor). Minimal and/or focal cytoplasmic staining for MOC‐31 was noted in 13% of cases of reactive mesothelial cells/mesothelioma. The sensitivity of MOC‐31 for metastatic adenocarcinoma was 89%, the specificity was 100%, the negative predictive value was 92%, and the positive predictive value was 100%.

CONCLUSIONS:

MOC‐31 alone was found to be highly sensitive for distinguishing reactive mesothelial cells/mesothelioma from metastatic adenocarcinoma in effusion specimens. Interpreting membranous MOC‐31 staining as positive can help prevent confusion between reactive mesothelial cells/mesothelioma and metastatic adenocarcinoma. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society     

Systemic treatments for brain metastases from breast cancer,non-small cell lung cancer,melanoma and renal cell carcinoma: An overview of the literature

The frequency of metastatic brain tumors has increased over recent years; the primary tumors most involved are breast cancer, lung cancer, melanoma and renal cell carcinoma. While radiation therapy and surgery remain the mainstay treatment in selected patients, new molecular drugs have been developed for brain metastases. Studies so far report interesting results.     

Clinical and cell line specific expression profiles of a human gene identified in experimental central nervous system metastases

Some cancers, particularly malignant melanomas and carcinomas of the breast and lung, metastasize to the central nervous system (CNS) in advanced stages. In order to develop into clinically manifest metastases, hematogenously disseminated tumor cells must respond to trophic factors within the CNS microenvironment. We have previously identified a nuclearfactor, com1, expressed in human breast carcinoma cells upon formation of experimental metastatic tumors in the CNS. In the present study distinct com1 mRNA expression was detected in cerebral metastases from patients with lung carcinomas, whereas the expression level was generally much lower in glioblastomas (primary brain tumors). In tissue specimens from normal brain and lung, as well as in glioma and lung carcinoma cell lines, com1 expression was barely detectable. One potential mechanism involved in the induction of com1 expression was indicated in the metastatic MCF7/LCC2 breast carcinoma cells. Significant increases in the level of com1 mRNA were observed upon activation of receptor tyrosine kinase signaling, which is known to operate during metastatic tumor cell proliferation within the CNS. The observations in this study strengthen the assumption that com1 may be involved in the tumor cell response to regulatory signals upon metastasis formation.     

Quantitative analysis of aromatase, sulfatase and 17beta-HSD(1) mRNA expression in soft tissue metastases of breast cancer

Expression of the estrogen-synthesizing genes aromatase, steroid sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type1 (17beta-HSD(1)) has been shown to be up-regulated in primary breast cancer tissue but their expression status in metastatic tumor tissue has yet to be determined. The mRNA expression levels of the three estrogen-synthesizing genes as well as of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and cyclooxygenase (COX)-2, all of which have been reported to up-regulate the estrogen-synthesizing genes, were determined by means of a real-time PCR assay in 100 primary breast cancer tissues and 15 soft tissue metastases. In addition, PCR-gel electrophoresis was used to determine the proportion (%) of promoter (l.4, l.3, Pll and l.7) usage of aromatase. Aromatase and STS mRNA levels were significantly (P=0.04 and P=0.03, respectively) higher in soft tissue metastases than in primary tumors, while 17beta-HSD(1) mRNA levels tended (P=0.09) to be higher. The proportions of the promoter usages were very similar for primary tumors and soft tissue metastases, and the mRNA levels of TNF-alpha, IL-6 and COX-2 were not significantly different. Levels of aromatase, STS and 17beta-HSD(1) mRNA are up-regulated in soft tissue metastases compared to those in primary tumors, suggesting that intra-tumoral estrogen synthesis may play a significant role in the growth stimulation of tumor cells in soft tissue metastases as in primary tumors. TNF-alpha, IL-6 and COX-2, on the other hand, are unlikely to be implicated in this up-regulation.     

Therapy of hematogenous melanoma brain metastases with endostatin.

PURPOSE: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases. EXPERIMENTAL DESIGN: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed. RESULTS: In vitro secretion of endostatin by 2.5 x 10(5) cells within 24 hours was 0.12 +/- 0.03 ng, 4.35 +/- 0.4, and 1.18 +/- 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was <20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 +/- 2.6 versus 13.3 +/- 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 x 10(5) wild-type cells killed the mice within 24 +/- 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals. CONCLUSION: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.     

HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process

BACKGROUND: The objective of this study was to determine whether HER2 expression levels in breast carcinomas were modified by chemotherapy or during the metastatic process. METHODS: HER2 expression was analyzed on sequential tissue specimens taken from the primary tumor before patients received preoperative chemotherapy (CT) and from post-CT residual breast tumor or at a metastatic site. The first group of patients included 59 women who presented with T2-T4,N1-N2 breast carcinoma and were treated by preoperative anthracycline-based CT and then underwent surgery. The second group included 44 patients with metastatic breast carcinoma localized to the lung (27 patients) or to the liver (17 patients). HER2 status was determined by immunohistochemistry using an anti-p185(HER/neu) monoclonal antibody and was classified as overexpressed or not overexpressed. RESULTS: Among the patients who received preoperative CT, HER2 overexpression was observed in 15 of 59 patients (25%). A complete pathologic response was observed in 2 of these 15 patients. HER2 still was overexpressed in 11 of 13 remaining residual tumors and was no longer detectable in 2 tumors. In addition, the 29 tumors with no HER2 overexpression before CT remained negative after treatment. In patients with metastatic breast carcinoma, HER2 was overexpressed in 11 of 44 primary tumors (25%). In 9 of these 11 tumors, HER2 overexpression was maintained in the metastases (9 pulmonary metastases and 4 hepatic metastases). In two patients who had low levels of HER2 overexpression in their primary tumors, no staining was observed in the secondary tumor (one pulmonary tumor and one liver tumor). There were no tumors in which the overexpression of HER2 was found only in the metastasis. CONCLUSIONS: The current study showed that, in most patients, HER2 overexpression was unchanged after CT and in metastatic sites. No HER2 negative primary tumors became HER2 positive after patients received CT or during the metastatic process. In a few patients, a diminution in the level of HER2 expression was observed after CT or in secondary tumors. This may have been due to a transitory state of altered tumor cells or to the selection of HER2 negative tumor cells clones.     

Allelic deletions on chromosome-17 and mutations in the p53 gene in tumors metastatic to brain

Metastasis associated with tumor progression denotes more aggressive tumor behavior, more malignant histology, and worsening patient prognosis. Brain is one of the common sites to which solid tumors metastasize. Since mutations in the tumor suppressor gene p53 are associated with tumor progression to malignancy in various cancers, we examined the molecular genetic profile of the p53 gene and also analyzed allelic losses of various genes on the short arm of chromosome 17 (17p) in 10 metastatic brain tumors (4 breast, 3 renal, 1 lung, 1 esophageal, and 1 squamous cell carcinoma) and in two of the primary tumors (I breast, 1 renal) corresponding to two of the 10 metastases. Six of the 10 metastatic tumors (4/4 breast, 1/1 esophageal and 1/1 squamous cell carcinoma) contained allelic loss and/or mutations of the p53 gene. The p53 gene profile was identical in both of the primary tumors and their corresponding metastases that were examined. If borne out by a larger series of analysis on tumors, especially from breast, as well as from other organs, detection of chromosome 17/p53 alterations may be of substantial clinical significance in predicting the metastatic potential of primary tumors.     

Correlation of Bcl-2 and p53 expression in primary breast tumors and corresponding metastatic lymph nodes

BACKGROUND: The p53 tumor suppressor gene product participated in G1 cell cycle arrest or cell death. Loss of function was associated with poor outcome in patients with breast carcinoma. bcl-2 prevented apoptosis induced by c-myc or growth factor deprivation. High bcl-2 expression in breast tumor tissue specimens appears to be associated with favorable prognostic factors. However, Bcl-2 and p53 expression in primary tumor tissue specimens versus metastatic lymph node specimens in breast carcinoma has not been studied. The current study compared Bcl-2 and p53 expression in primary breast carcinoma tissue specimens with Bcl-2 and p53 expression in axillary lymph node specimens. METHODS: Primary breast tumor and corresponding axillary metastatic lymph node tissue specimens were obtained from 60 patients with breast carcinoma. They were evaluated for the presence of Bcl-2 and p53 expression by immunohistochemistry using standard methods. RESULTS: Bcl-2 expression in primary tumor tissue specimens (53%) was correlated with Bcl-2 expression in metastatic lymph node specimens (50 %; Pearson correlation = 0.656). p53 expression in primary tumor specimens (72%) was correlated with p53 expression in metastatic lymph node specimens (60 %; Pearson correlation = 0.800). A significant inverse correlation also was found between p53 and Bcl-2 expression in primary breast tumor tissue specimens (Pearson correlation = -0.310). CONCLUSIONS: The current study suggested that Bcl-2 and p53 expression in axillary metastatic lymph node specimens is correlated with Bcl-2 and p53 expression in the primary tumor tissue specimens. The prognostic and predictive value of Bcl-2 and p53 expression in axillary lymph node metastasis in patients with breast carcinoma needs to be further evaluated in larger trials with longer follow-up.     

Genomic analysis identifies unique signatures predictive of brain,lung, and liver relapse

The ability to predict metastatic potential could be of great clinical importance, however, it is uncertain if predicting metastasis to specific vital organs is feasible. As a first step in evaluating metastatic predictions, we analyzed multiple primary tumors and metastasis pairs and determined that >90% of 298 gene expression signatures were found to be similarly expressed between matched pairs of tumors and metastases; therefore, primary tumors may be a good predictor of metastatic propensity. Next, using a dataset of >1,000 human breast tumor gene expression microarrays we determined that HER2-enriched subtype tumors aggressively spread to the liver, while basal-like and claudin-low subtypes colonize the brain and lung. Correspondingly, brain and lung metastasis signatures, along with embryonic stem cell, tumor initiating cell, and hypoxia signatures, were also strongly expressed in the basal-like and claudin-low tumors. Interestingly, low “Differentiation Scores,” or high expression of the aforementioned signatures, further predicted for brain and lung metastases. In total, these data identify that depending upon the organ of relapse, a combination of gene expression signatures most accurately predicts metastatic behavior.     

Expression of cyclooxygenase-2 in benign naevi and during human cutaneous melanoma progression

Cyclooxygenase-2 (COX-2) is an enzyme that plays an important role in the production of prostaglandins. Numerous studies have demonstrated increased levels of COX-2 in human cancers of different types. It is thought that COX-2 may be involved in the development and progression of malignant tumours. However, data on the changes in COX-2 expression during the development and progression of human melanoma are relatively limited. Moreover, the results reported by different groups disagree to a large extent. The aim of this work was to evaluate whether COX-2 protein might be considered a potential molecular marker of melanoma progression. The expression of COX-2 was determined immunohistochemically in formalin-fixed, paraffin-embedded specimens of 64 human melanocytic skin tumours (17 naevi, 36 primary cutaneous melanomas and 11 lymph node melanoma metastases, with six pairs of primary and metastatic lesions obtained from the same patients). It was found that the expression level of COX-2 was dependent on both the stage and histopathological type of the melanoma. Collectively, our data indicate that changes in the expression level of COX-2 are correlated with the development and progression of human melanoma, and imply that the COX-2 protein may be considered a potential prognostic and predictive marker in malignant melanoma.     

Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer.

PURPOSE: Recent studies have shown that cyclooxygenase (Cox)-2 may be involved in colorectal carcinogenesis. We aimed to determine whether Cox-2 expression in itself can predict outcome of colorectal cancer patient after surgery. In addition, the expression of Cox-1 was also evaluated. EXPERIMENTAL DESIGN: Tissue samples of primary and secondary tumors from 288 patients undergoing surgical resections for colorectal adenocarcinoma were immunohistochemically examined for Cox-2 and Cox-1 expressions. The specimens were graded based on the intensity and extent of staining; then, the correlations between Cox-2 and Cox-1 expressions with clinicopathologic parameters and survival time were analyzed. RESULTS: Expression of Cox-2 was positive in 70.8% of primary tumor, 92.0% of lymph node metastases, 100.0% of hepatic metastases, and was significantly associated with tumor size, depth of invasion, lymph node metastasis, vessels invasion, stage and recurrence. In contrast, Cox-1 was positive in 42.7% of primary tumor, 84.0% of lymph node metastases, 37.5% hepatic metastases, and was associated with only tumor size. Patients with Cox-2-positive tumors had a significant shorter survival time than those with negative tumors did (P = 0.0006 by log-rank test); and, in a multivariate analysis, Cox-2 was an independent prognostic factor (P = 0.0103; relative risk 4.114; 95% confidence interval, 1.397-12.120). Cox-1 status had no statistically effect on patient survival time. CONCLUSIONS: Elevated Cox-2 expression, but not that of Cox-1, was significantly associated with reduced survival and recognized as an independent prognostic factor in our cohort of colorectal cancer patients.     

Cyclooxygenase-2 in oligodendroglial neoplasms

BACKGROUND: Although increased expression of cyclooxygenase-2 (COX-2) has been described in association with a variety of neoplasms, including tumors of astrocytic derivation, limited data are available on COX-2 expression in oligodendrogliomas. METHODS: The current study retrospectively reviewed 53 oligodendrogliomas and 7 oligodendroglioma-predominant oligoastrocytomas (mixed gliomas) for COX-2 expression and MIB-1 proliferative index (by immunohistochemistry) and for chromosome 1p status (by fluorescence in situ hybridization). RESULTS: Patients included 35 males and 25 females, with a mean age of 41 years (range, 12-73 years) at the time of surgery. Forty-four tumor specimens were classified as World Health Organization (WHO) Grade II neoplasms and 16 as WHO Grade III tumors. MIB-1 labeling indices (marker of cell proliferation) ranged from 0 to 22.3 (mean 4.5). Twenty-eight tumor specimens demonstrated allelic loss on chromosome 1p. Positive staining was observed in 17 tumor specimens with COX-2 antibody. COX-2-positive tumor specimens were also evaluated with CD68 (macrophage/microglial cell marker) by coimmunolabeling to confirm that the observed COX-2 immunostaining was not due to immunoreactive macrophages or microglial cells. COX-2 expression, lack of allelic loss at chromosome 1p, and high proliferation indices were associated with decreased survival (P = 0.002, P = 0.009, and P = 0.015, respectively). No correlation with outcome was found with patient gender, age at diagnosis, or histologic grade. CONCLUSIONS: Chromosome 1p, COX-2 immunoreactivity, and MIB-1 labeling indices correlated with outcome and were associated with decreased survival. There was not a one-to-one correspondence between COX-2 immunoreactivity and lack of allelic loss at chromosome 1p. Tumors with expression of COX-2 by immunohistochemistry may, in theory, benefit from treatment with therapeutic agents that inhibit COX-2.