Low levels of cathepsin D are associated with a poor prognosis in endometrial cancer.
(9/18479)
Total cytosolic cathepsin D (Cat D) levels were estimated by an immunoradiometric assay in a series of 156 consecutive patients with surgical stages I-III primary endometrial adenocarcinoma. Simultaneously, the tissue content of both oestrogen (ER) and progesterone (PR) receptors, and p185HER-2/neu, DNA content (ploidy), and the fraction of S-phase cells (S-phase) were also estimated. Tumoral Cat D content ranged from 0 to 243 pmol mg(-1) protein (median 44 pmol mg(-1) protein) and was not associated with any of the established clinicopathological and biological prognostic variables, with the exception of a weak positive correlation with the tumoral p185HER-2/neu levels. Univariable analysis performed on a subset of 97 patients, followed for a minimum of 2 years or until death, showed that patient age at diagnosis, high histological grade, advanced surgical stage, vascular invasion, positive peritoneal cytology, low levels of Cat D, negative ER and PR status, aneuploidy, and high S-phase were predictive of the presence of persistent or recurrent disease. However, multivariable analysis revealed that only histological grade, surgical stage, Cat D and PR were significantly associated with the patient's outcome. From these findings, we conclude that Cat D is an independent prognostic factor in endometrial adenocarcinoma, its low levels being associated with a worse clinical outcome. (+info)
Differential expression of Hsp27 in normal oesophagus, Barrett's metaplasia and oesophageal adenocarcinomas.
(10/18479)
The protein expression patterns of normal, metaplastic and malignant oesophageal tissues were analysed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to identify changes associated with Barrett's metaplasia and transformation to oesophageal adenocarcinoma. Heat-shock protein 27 (Hsp27), a small heat-shock protein which is protective against cytotoxic stresses, was abundant in normal oesophagus. However, Hsp27 expression was markedly lower in Barrett's metaplasia and oesophageal adenocarcinomas. This was confirmed by immunohistochemical analysis. Hsp27 protein was most highly expressed in the upper layers of squamous epithelium and exhibited a pattern of expression that corresponded with the degree of squamous maturation. Northern and Southern analysis demonstrated Hsp27 to be regulated at the level of mRNA transcription or abundance. Normal oesophageal tissues were examined for gender differences in Hsp27 expression. Women expressed fourfold higher levels of Hsp27 mRNA, however, this difference was not appreciable in protein expression. Hsp27 protein was inducible by heat shock in Barrett's adenocarcinoma cell lines and an immortalized oesophageal epithelial cell line (HET-1A), but not by oestradiol. These results demonstrate abundant constitutive expression of the stress-response protein Hsp27 in the normal oesophagus, and suggest that low-level expression in Barrett's metaplasia may be one factor which may influence susceptibility to oesophageal adenocarcinoma development. (+info)
Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors.
(11/18479)
Three different membrane-type matrix metalloproteinases (MT1-, MT2-, and MT3-MMPs) are known to activate in vitro the zymogen of MMP-2 (pro-MMP-2, progelatinase A), which is one of the key MMPs in invasion and metastasis of various cancers. In the present study, we have examined production and activation of pro-MMP-2, expression of MT1-, MT2-, and MT3-MMPs and their correlation with pro-MMP-2 activation, and localization of MMP-2, MT1-MMP, and MT2-MMP in human astrocytic tumors. The sandwich enzyme immunoassay demonstrates that the production levels of pro-MMP-2 in the anaplastic astrocytomas and glioblastomas are significantly higher than that in the low-grade astrocytomas (P<0.05 and P<0.01, respectively), metastatic brain tumors (P<0.05), or normal brains (P<0.01). Gelatin zymography indicates that the pro-MMP-2 activation ratio is significantly higher in the glioblastomas than in other astrocytic tumors (P<0.01), metastatic brain tumors (P<0.01), and normal brains (P<0.01). The quantitative reverse transcription polymerase chain reaction analyses demonstrate that MT1-MMP and MT2-MMP are expressed predominantly in glioblastoma tissues (17/17 and 12/17 cases, respectively), and their expression levels increase significantly as tumor grade increases. MT3-MMP is detectable in both astrocytic tumor and normal brain tissues, but the mean expression level is approximately 50-fold lower compared with that of MT1-MMP and MT2-MMP in the glioblastomas. The activation ratio of pro-MMP-2 correlates directly with the expression levels of MT1-MMP and MT2-MMP but not MT3-MMP. In situ hybridization indicates that neoplastic astrocytes express MT1-MMP and MT2-MMP in the glioblastoma tissues (5/5 cases and 5/5 cases, respectively). Immunohistochemically, MT1-MMP and MT2-MMP are localized to the neoplastic astrocytes in glioblastoma samples (17/17 cases and 12/17 cases, respectively), which are also positive for MMP-2. In situ zymography shows gelatinolytic activity in the glioblastoma tissues but not in the normal brain tissues. These results suggest that both MT1-MMP and MT2-MMP play a key role in the activation of pro-MMP-2 in the human malignant astrocytic tumors and that the gelatinolytic activity is involved in the astrocytic tumor invasion. (+info)
Enhanced tumor growth and invasiveness in vivo by a carboxyl-terminal fragment of alpha1-proteinase inhibitor generated by matrix metalloproteinases: a possible modulatory role in natural killer cytotoxicity.
(12/18479)
Matrix metalloproteinases (MMPs) are believed to contribute to the complex process of cancer progression. They also exhibit an alpha1-proteinase inhibitor (alphaPI)-degrading activity generating a carboxyl-terminal fragment of approximately 5 kd (alphaPI-C). This study reports that overexpression of alphaPI-C in S2-020, a cloned subline derived from the human pancreas adenocarcinoma cell line SUIT-2, potentiates the growth capability of the cells in nude mice. After stable transfection of a vector containing a chimeric cDNA encoding a signal peptide sequence of tissue inhibitor of metalloproteinase-1 followed by cDNA for alphaPI-C into S2-020 cells, three clones that stably secrete alphaPI-C were obtained. The ectopic expression of alphaPI-C did not alter in vitro cellular growth. However, subcutaneous injection of the alphaPI-C-secreting clones resulted in tumors that were 1.5 to 3-fold larger than those of control clones with an increased tendency to invasiveness and lymph node metastasis. These effects could be a result of modulation of natural killer (NK) cell-mediated control of tumor growth in nude mice, as the growth advantage of alphaPI-C-secreting clones was not observed in NK-depleted mice, and alphaPI-C-secreting clones showed decreased NK sensitivity in vitro. In addition, production of alphaPI and generation of the cleaved form of alphaPI by MMP were observed in various human tumor cell lines and in a highly metastatic subline of SUIT-2 in vitro. These results provide experimental evidence that the alphaPI-degrading activity of MMPs may play a role in tumor progression not only via the inactivation of alphaPI but also via the generation of alphaPI-C. (+info)
Adenosquamous carcinoma of the endometrium.
(13/18479)
An adenosquamous carcinoma of the endometrium is one which contains both malignant glandular and malignant squamous components; such tumours are considered rare in Britain but are thought to account for nearly one-third of all endometrial neoplasms in the United States. A survey of 675 cases of endometrial cancer seen during the period 1956-75 showed that the incidence of adenosquamous carcinoma was 5%, an incidence that remained static during this 20-year period. The principal difficulties encountered in the diagnosis of these neoplasms are in identifying the squamous component as such and in differentiating it from benign metaplastic squamous epithelium. The prognosis for patients with an endometrial adenosquamous carcinoma is very much worse than for women with a pure adenocarcinoma, and because these neoplasms are often wrongly identified it is possible that the currently accepted prognoses for both pure adenocarcinoma and adenoacanthoma of the endometrium may have to be revised. There appears to be a true variation in the incidence of this neoplasm between Britain and the United States. (+info)
Detection of occult lymph node metastases in esophageal cancer by minimally invasive staging combined with molecular diagnostic techniques.
(14/18479)
BACKGROUND AND OBJECTIVES: Lymph node metastases are the most important prognostic factor in patients with esophageal cancer. Histologic examination misses micrometastases in up to 20% of lymph nodes evaluated. In addition, non-invasive imaging modalities are not sensitive enough to detect small lymph nodes metastases. The objective of this study was to investigate the use of reverse transcriptase-polymerase chain reaction (RT-PCR) of messenger RNA (mRNA) for carcinoembryonic antigen (CEA) to increase the detection of micrometastases in lymph nodes from patients with esophageal cancer. METHODS: RT-PCR of CEA mRNA was performed in lymph nodes from patients with malignant and benign esophageal disease. Each specimen was examined histopathologically and by RT-PCR and the results were compared. RESULTS: Metastases were present in 29 of 60 (48%) lymph nodes sample by minimally invasive staging from 13 patients with esophageal cancer when examined histopathologically. RT-PCR identified nodal metastases in 46 of these 60 (77%) samples. RT-PCR detected CEA mRNA in all 29 histologically positive samples and in 17 histologically negative lymph nodes. All lymph nodes from patients with benign disease (n = 15) were negative both histopathologically and by RT-PCR. The stage of two patients was reclassified based on the RT-PCR results, which identified lymph node spread undetected histopathologically. Both of these patients developed recurrent disease after resection of the primary tumor. CONCLUSIONS: RT-PCR is more sensitive than histologic examination in the detection of lymph node metastases in esophageal cancer and can lead to diagnosis of a more advanced stage in some patients. The combination of minimally invasive surgical techniques in combination with new molecular diagnostic techniques may improve our ability to stage cancer patients. (+info)
T helper cell type 1-associated and cytotoxic T lymphocyte-mediated tumor immunity is impaired in interleukin 4-deficient mice.
(15/18479)
It is widely accepted that cellular immune responses are induced by CD4(+) T helper 1 (Th1) cells secreting interleukin (IL)-2 and interferon (IFN)-gamma. Tumor immunity is often mediated by cytotoxic T lymphocytes (CTLs) whose activation is supported by Th1 cytokines. Since IL-4 directs Th2 development and has been shown to inhibit Th1-dominated responses, we assumed that IL-4-deficient (IL-4(-/-)) mice would develop vigorous CTL-mediated tumor immunity compared with IL-4-competent (IL-4(+/+)) mice. Surprisingly, IL-4(-/-) mice were severely impaired to develop tumor immunity to both a mammary adenocarcinoma line and a colon carcinoma line. The lack of tumor immunity in IL-4(-/-) mice was associated with reduced IFN-gamma production, diminished levels of tumor-reactive serum IgG2a, and undetectable CTL activity, indicating a defective Th1 response in the absence of endogenous IL-4. Anti-IL-4 monoclonal antibody blocked tumor immunity in IL-4(+/+) mice when administered at the time of immunization but not at the time of challenge. Additionally, tumor immunity could be induced in IL-4(-/-) mice, if IL-4 was provided by gene-modified cells together with immunizing tumor cells. These results demonstrate that tumor immunity requires IL-4 in the priming phase for the generation of effector cells rather than for their maintenance and exclude secondary, developmental defects in the "knockout" strain. Together, our results demonstrate a novel and previously unanticipated role of IL-4 for the generation of Th1-associated, CTL-mediated tumor immunity. (+info)
Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer.
(16/18479)
BACKGROUND: Tamoxifen and the citrus flavonoid tangeretin exhibit similar inhibitory effects on the growth and invasive properties of human mammary cancer cells in vitro; furthermore, the two agents have displayed additive effects in vitro. In this study, we examined whether tangeretin would enhance tamoxifen's therapeutic benefit in vivo. METHODS: Female nude mice (n = 80) were inoculated subcutaneously with human MCF-7/6 mammary adenocarcinoma cells. Groups of 20 mice were treated orally by adding the following substances to their drinking water: tamoxifen (3 x 10(-5) M), tangeretin (1 x 10(-4) M), tamoxifen plus tangeretin (3 x 10(-5) M plus 1 x 10(-4) M), or solvent. RESULTS AND CONCLUSIONS: Oral treatment of mice with tamoxifen resulted in a statistically significant inhibition of tumor growth compared with solvent treatment (two-sided P = .001). Treatment with tangeretin did not inhibit tumor growth, and addition of this compound to drinking water with tamoxifen completely neutralized tamoxifen's inhibitory effect. The median survival time of tumor-bearing mice treated with tamoxifen plus tangeretin was reduced in comparison with that of mice treated with tamoxifen alone (14 versus 56 weeks; two-sided P = .002). Tangeretin (1 x 10(-6) M or higher) inhibited the cytolytic effect of murine natural killer cells on MCF-7/6 cells in vitro, which may explain why tamoxifen-induced inhibition of tumor growth in mice is abolished when tangeretin is present in drinking water. IMPLICATIONS: We describe an in vivo model to study potential interference of dietary compounds, such as flavonoids, with tamoxifen, which could lead to reduced efficacy of adjuvant therapy. In our study, the tumor growth-inhibiting effect of oral tamoxifen was reversed upon addition of tangeretin to the diet. Our data argue against excessive consumption of tangeretin-added products and supplements by patients with mammary cancer during tamoxifen treatment. (+info)