Metastasis of cervical cancer indicated by elevation of serum CA125 produced by mediastinal lymph nodes: a case report.

BACKGROUND: In patient assessment for recurrence of neoplasia, a biomarker that shows an elevated serum value before the first treatment is a candidate for follow-up examination. The biomarker squamous cell carcinoma antigen is usually utilized for follow-up of squamous cell cancer of the cervix. CASE PRESENTATION: We herein report a 30-year-old Japanese woman of postoperative metastasis of cervical squamous cell cancer to the mediastinal and supraclavicular lymph nodes as indicated by an elevated serum cancer antigen 125 concentration and not by the squamous cell carcinoma antigen value. After chemoradiotherapy and chemotherapy, the serum cancer antigen 125 concentration decreased to a normal value. Squamous cell carcinoma antigen was found to be distributed in both the squamous cell cancer tissue of the cervix and the supraclavicular lymph node metastatic tissue. By contrast, cancer antigen 125 was distributed in the supraclavicular lymph node metastatic tissue but not in the original squamous cell cancer tissue of the cervix. CONCLUSION: In this case, metastasis of cervical cancer to the mediastinal and supraclavicular lymph nodes was shown by the biomarker cancer antigen 125, which was not present in the original neoplasia.

Protein Complex of Fibrinogen Gamma Chain and Complement Factor H in Ovarian Cancer Patient Plasma.

BACKGROUND: In the plasma of an advanced cancer patient, fibrinogen is sometimes increased with possible effects on red blood cells (RBCs). MATERIALS AND METHODS: The plasma fraction deteriorating osmotic resistance of RBCs was separated from a patient's plasma with advanced ovarian cancer by phenyl-sepharose column chromatography and analyzed with gel filtration chromatography. RESULTS: In the plasma fraction, we found a protein reactive against whole fibrinogen with a molecular weight higher than that of intact fibrinogen from a healthy volunteer. The-high molecular weight protein was immunoractive to an antibody against fibrinogen gamma chain but not to an antibody against alpha or beta chain. Complement factor H, identified by N-terminal sequencing of a 150-kDa protein separated from the protein, was also eluted from anti-fibrinogen gamma immunoaffinity column. CONCLUSION: Fibrinogen gamma chain and complement factor H were found to be bound as a protein complex in the plasma of a patient with advanced ovarian cancer.

Human Papillomavirus E6 Knockdown Restores Adenovirus Mediated-estrogen Response Element Linked p53 Gene Transfer in HeLa Cells.

The p53 gene is inactivated by the human papillomavirus (HPV) E6 protein in the majority of cervical cancers. Treatment of HeLa S3 cells with siRNA for HPV E6 permitted adenovirus-mediated transduction of a p53 gene linked to an upstream estrogen response element (ERE). Our previous study in non-siRNA treated HHUA cells, which are derived from an endometrial cancer and express estrogen receptor ß, showed enhancing effects of an upstream ERE on adenovirus-mediated p53 gene transduction. In HeLa S3 cells treated with siRNA for HPV E6, adenovirus-mediated transduction was enhanced by an upstream ERE linked to a p53 gene carrying a proline variant at codon 72, but not for a p53 gene with arginine variant at codon 72. Expression levels of p53 mRNA and Coxsackie/adenovirus receptor (CAR) mRNA after adenovirus-mediated transfer of an ERE-linked p53 gene (proline variant at codon 72) were higher compared with those after non-ERE-linked p53 gene transfer in siRNA-treated HeLa S3 cells. Western blot analysis showed lower ß-tubulin levels and comparatively higher p53/ß-tubulin or CAR /ß-tubulin ratios in siRNA-treated HeLa S3 cells after adenovirus-mediated ERE-linked p53 gene (proline variant at codon 72) transfer compared with those in non-siRNA-treated cells. Apoptosis, as measured by annexin V binding, was higher after adenovirus-mediated ERE-linked p53 gene (proline variant at codon 72) transfer compared with that after non-ERE-linked p53 gene transfer in siRNA-treated cells.

Association of copper transporter expression with platinum resistance in epithelial ovarian cancer.

BACKGROUND: Copper transporters (CTR) also regulate the cellular transport of platinum drugs, but their role in platinum resistance of ovarian cancer has not been elucidated. MATERIALS AND METHODS: CTR expression in ovarian cancer tissues resected from patients treated by platinum-based chemotherapy was evaluated immunohistochemically. CTR2 expression in ovarian cancer cells was inhibited by bathocuproine disulfonate, and the changes in cisplatin sensitivity were examined. RESULTS: CTR2 expression was increased in chemoresistant patients, but not significantly. However, the CTR2/CTR1 ratio was significantly increased in chemoresistant patients. Cases with positive CTR2 expression or positive CTR2/CTR1 ratio had poor prognoses. When the CTR2 expression in ovarian cancer cells was suppressed, sensitivity to cisplatin was significantly increased. CONCLUSION: These data suggest that CTR2 contributes to platinum resistance in ovarian cancer. The CTR2/CTR1 ratio is a useful marker for platinum sensitivity and a potential prognostic factor in patients with ovarian cancer.

An upstream estrogen response element linked to exogenous p53 tumor suppressor gene expression differentiates effects of the codon 72 polymorphism.

The objective of this study was to assess the effects of an upstream estrogen response element (ERE) on exogenous p53 tumor suppressor gene with a codon 72 polymorphism about which there have been controversial reports in relation to cancer risk. The p53 gene (bases 166-1143 from start codon) with the codon 72 polymorphism, inserted into the pIRES-hrGFP II plasmid with or without upstream ERE, were transfected into HHUA endometrial cancer cells expressing the estrogen receptor. The ERE-linked p53 gene with the proline variant at codon 72 showed lower transfection rates than the gene without ERE or with the arginine variant at codon 72. p21 expression was significantly higher in HHUA cells transfected with the proline variant gene than in those transfected with the arginine variant gene. We consider that the presence of an upstream ERE promotes the transcriptional effects of the exogenous p53 gene with the proline variant, which strengthens the expression of p21, and results in lower transfection rates through cell cycle inhibition.

Claudin-4: a potential therapeutic target in chemotherapy-resistant ovarian cancer.

BACKGROUND: Claudin-4, a component of the tight junction, plays an important role in tumorigenesis and metastasis of ovarian cancer, but its role in platinum resistance has not been elucidated. MATERIALS AND METHODS: Claudin-4 expression in ovarian cancer cells was inhibited and the changes in cisplatin sensitivity were examined. Fluorescence-labeled cisplatin was used to examine whether inhibition of claudin-4 changed the cellular accumulation of cisplatin. Claudin-4 expression in ovarian cancer tissue resected from the patients surgically was evaluated immunohistochemically. RESULTS: Suppression of claudin-4 resulted in a significant increase of cisplatin sensitivity and cellular accumulation of fluorescence-labeled cisplatin. Claudin-4 expression was significantly greater in ovarian cancer tissue from chemoresistant patients compared to chemosensitive patients. The overall survival was significantly shorter for claudin-4-positive than claudin-4-negative cases. CONCLUSION: These data suggest that claudin-4 contributes to platinum resistance in ovarian cancer and may be a potential target in the treatment of platinum-resistant tumors.

Extragastrointestinal stromal tumor originating from the vulva.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They have gain-of-function mutations of the c-kit receptor tyrosine kinase gene and have been suggested to originate from the interstitial cells of Cajal. A small percentage of GISTs form extragastrointestinal masses. We report a rare case of a GIST originating from the vulva. A 55-year-old woman presented with a vulvar tumor. The tumor was initially diagnosed as a leiomyosarcoma following the first resection. Following a second recurrence the patient was administered chemotherapy. A third recurrence occurred and the patient underwent a third resection. Histology revealed that a bundle of fibrous tumor cells had invaded the connected tissue and muscular coat, and some spindle-shaped and blunt-ended nuclei were detected. Furthermore, immunohistochemical evaluation revealed that the tumor cells exhibited strong and diffuse staining for c-kit and CD34. The recurrent tumor was diagnosed as a GIST and a reevaluation of the original specimens also revealed a GIST. The patient was treated with imatinib, and is currently healthy with no evidence of recurrence at 20 months after the last surgery.

Multiple organ failure of tumor-bearing rabbits in cancer cachexia is caused by apoptosis of normal organ cells.

In cancer-bearing animals, we previously demonstrated that skeletal muscle apoptosis may be involved in muscle wasting and that Bax may play a role in skeletal muscle cell apoptosis at an early stage. In this study, we investigated the occurrence of apoptosis in the liver, kidney, spleen, lung and heart during cancer cachexia as well as the associations between apoptosis and the expression levels of Bcl-2, Bcl-xL and Bax proteins. We also examined the relationship between normal organ apoptosis in cancer cachexia and multiple organ failure. We further studied the changes in body weight, lean body mass (LBM), apoptotic index (AI), DNA laddering pattern and expression levels of Bax, Bcl-2 and Bcl-xL in the liver, kidney, spleen, lung and heart in VX2 carcinoma-bearing rabbits. In the early stage of tumor bearing (20 days after implantation), the LBM was significantly reduced by 19.06+/-1.02% in the tumor-bearing group compared to an increase of 1.66+/-0.83% in the control group. The apoptotic indices of the liver, kidney, lung and spleen in the tumor-bearing group increased by 14.2+/-1.8%, 34.4+/-2.0%, 66.7+/-6.0% and 24.8+/-3.8%, respectively and were significantly higher than the corresponding indices in the control group. DNA laddering patterns characteristic of DNA fragmentation were visible on day 50 in the liver, kidney, spleen and lung in the tumor-bearing group. The expression of Bax increased in the tumor-bearing group and coincided with the occurrence of apoptosis. However, no significant changes were noted in the expression levels of Bcl-2 and Bcl-xL. These findings suggest the possibility that normal organ cell apoptosis related to Bax not only causes body weight loss but also multiple organ failure in cancer cachexia.

S1-1 nuclear domains: characterization and dynamics as a function of transcriptional activity.

BACKGROUND INFORMATION: The RNA-binding protein S1-1, also called RBM10 (RNA-binding motif 10), is a paralogue of putative tumour suppressor RBM5 and has been correlated with cancer proliferation and apoptosis. In the present study, we have investigated the cell biology of S1-1. RESULTS: In the extranucleolar nucleoplasm, S1-1 occurred in hundreds of punctate and irregular domains. Some 10-40 of these domains were larger than 0.5 mum and prominent for S1-1 immunostaining. These domains (S1-1 nuclear bodies) were commonly present in tissue cells and in cultured cells. When cellular transcription was globally reduced by heat shock, serum starvation, culture at high cell densities or inhibition with RNA polymerase II inhibitors, small S1-1 domains (S1-1 granules), with weak immunostaining signals, reduced in number, whereas S1-1 nuclear bodies became prominent and increased in size. These altered S1-1 domains were returned to initial states when the cells were placed under normal conditions. Similar to paraspeckles, S1-1 nuclear bodies occurred closely adjacent to nuclear speckles or IGCs (interchromatin granule clusters), as determined by immunoelectron microscopy. However, the S1-1 nuclear bodies did not correspond to paraspeckles or IGAZs (interchromatin-granule-associated zones), but coincided with TIDRs (transcription-inactivation-dependent RNA domains), which we had characterized previously at the RNA level. The enlarged S1-1 nuclear bodies/TIDRs accumulated the S1-1 protein and microinjected primary and spliced mRNAs, presumably for later elevation of gene expression. In addition, electron microscopy revealed that S1-1 was also present on perichromatin fibrils, suggesting the structure of S1-1 granules seen at higher resolution. CONCLUSIONS: S1-1 constitutes hundreds of nuclear domains, which dynamically change their structures in a reversible manner. Upon globally reducing RNA polymerase II transcription, S1-1 nuclear bodies enlarge and decrease in number. They are novel domains different from paraspeckles or IGAZs, despite their similar occurrence adjacent to nuclear speckles. We discuss S1-1 granules in terms of their association with gene expression. In addition, this is the first report of a TIDR-localized protein.

Estradiol-17beta regulates vascular endothelial growth factor and Bcl-2 expression in HHUA cells.

HHUA, a rare endometrial cancer cell line expressing the estrogen receptor (ER), was adopted to investigate the expression of vascular endothelial growth factor (VEGF), erythropoietin (Epo), Bcl-2 and p53 under the administration of estradiol-17beta (E2). Based on quantitative real-time reverse transcription polymerase chain reaction assays, both VEGF and Bcl-2 mRNA levels decreased in a dose-dependent manner, although VEGF levels were increased in a time-dependent manner; no significant change was found for Epo and p53. An immunocytochemical study also showed the suppressed expression of VEGF and Bcl-2 under E2 induction. Both ERalpha and ERbeta mRNAs were detected in HHUA cells with ERbeta expression being predominantly higher than that of ERalpha, which is the converse of the pattern seen in normal endometria. The present study shows the E2-downregulated expression of VEGF and Bcl-2, and reveals a disrupted balance of ERalpha and ERbeta expression, which should be taken into consideration to understand the particularity of E2-regulated gene expression in HHUA cells.

Vascular endothelial growth factor, matrix metalloproteinases, and cyclooxygenase-2 influence prognosis of uterine cervical cancer in young women.

Recent changes in the lifestyle of young women have led to an increase in the rate of uterine cervical cancer. We investigated the clinicopathological characteristics of uterine cervical cancer in young women, and examined the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Tumor samples from 439 patients with uterine cervical cancer, who were initially treated at Osaka City University Medical School Hospital, Japan between 1995 and 2004, were stained immunohistochemically. The patients were classified into two groups according to age at onset: group Y included women aged < or =35 years, and group O included women aged > or =36 years. Group Y had more cases of squamous cell carcinoma, while group O had more advanced cases (P<0.05). Advanced cases (beyond stage Ib2) had a significantly worse prognosis in group Y than in group O (P<0.05). There were no differences between the two groups in the expressions of VEGF, MMP-2 and COX-2. However, in advanced cases (beyond stage Ib2), the expression of VEGF, MMP-2 and COX-2 was significantly greater in group Y than in group O (P<0.05). The above findings suggest that the expression of VEGF, MMPs and COX-2 is related to a worse prognosis for advanced uterine cervical cancer in young women.

Dandelion T-1 extract up-regulates reproductive hormone receptor expression in mice.

Reproductive hormones exert their actions via receptors in diverse tissues. In this study, we examined the expression of estrogen receptors (ERalpha and ERbeta), progesterone receptor (PR), and follicle-stimulating hormone receptor (FSHR) in the adipose tissue and reproductive organs of mice following oral treatment with Dandelion T-1 extract (DT-1E) for 6 weeks. Quantitative assays by real-time reverse transcription polymerase chain reaction showed enhanced expression of ERalpha and ERbeta mRNA in the adipose tissue of mice fed a diet containing DT-1E compared with the control group fed a plain diet. Furthermore, following gonadotropin injection, higher mRNA expression of ERalpha, ERbeta and PR in the uterus and FSHR in the ovary was found in the DT-1E group compared with the control group. An immunohistochemical study also showed increased levels of the above-mentioned receptors in the DT-1E group. The present study shows that oral intake of DT-1E up-regulates ERalpha, ERbeta, PR and FSHR expression in mice, suggesting the potential application of DT-1E for the clinical treatment of reproductive hormone-related disturbances.

Expression of glucose transporters in epithelial ovarian carcinoma: correlation with clinical characteristics and tumor angiogenesis.

We immunohistochemically examined the expression of the glucose transporters (GLUT)1, GLUT3 and GLUT4, in 154 tumor samples of epithelial ovarian carcinoma. In addition, we investigated the correlations between the expression of GLUTs and the vascular endothelial growth factor (VEGF), and microvessel count and clinical parameters. The rates of expression of GLUT1, GLUT3 and GLUT4 were 98.7%, 92.8% and 84.4%, respectively. GLUT1 and GLUT4 were both strongly expressed in serous adenocarcinoma, but weakly expressed in clear cell adenocarcinoma. The expressions of GLUT1 and GLUT4 correlated with the clinical disease stage. The expressions of GLUT1, GLUT3 and GLUT4 correlated positively with VEGF expression. The expression status for GLUT1, GLUT3, GLUT4 and VEGF did not represent a prognostic factor. These findings suggest that characteristic differences in the patterns of glucose uptake can exist according to the histological type and that GLUT1, GLUT3 and GLUT4 could be related to tumor angiogenesis in epithelial ovarian carcinoma.

In vitro effect of dehydroepiandrosterone sulfate on steroid receptors, aromatase, cyclooxygenase-2 expression, and steroid hormone production in preovulatory human granulosa cells.

OBJECTIVE: To examine the effect of a low concentration of DHEAS on the expression of the androgen receptor, estrogen receptor alpha and beta, progesterone receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2 in human preovulatory granulosa cells, and to measure their production of steroid hormones (estrone, estradiol, progesterone, androstenedione, and testosterone). DESIGN: Analysis of cultured primary human preovulatory granulosa cells by real-time reverse-transcriptase polymerase chain reaction and assays of hormone production. SETTING: Osaka City University Postgraduate School of Medicine. INTERVENTION(S): Preovulatory granulosa cells were collected from follicular fluid obtained from patients undergoing transvaginal oocyte retrieval with ultrasound guidance. The cells were cultured in the absence or presence of a low concentration of DHEAS. Real-time reverse-transcriptase polymerase chain reaction was performed to quantify the RNA expression of the investigated genes, and steroid hormone (estrone, estradiol, progesterone, androstenedione, and testosterone) levels were measured in the culture medium. MAIN OUTCOME MEASURE(S): Changes in [1] the levels of mRNAs encoding androgen receptor, estrogen receptor alpha, estrogen receptor beta, progesterone receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2; and [2] the levels of steroid hormones (estrone, estradiol, progesterone, androstenedione, and testosterone) in the culture medium. RESULT(S): Treatment of granulosa cells with 20 ng/mL DHEAS increased the expression of androgen receptor, aromatase, 3-beta-hydroxysteroid dehydrogenase, and cyclooxygenase-2, reduced the expression of estrogen receptor beta, and increased estrone and estradiol levels, but had no effect on progesterone, androstenedione, or testosterone levels. CONCLUSION(S): DHEAS may be an essential trigger of ovulation.

Insulin-lowering agents inhibit synthesis of testosterone in ovaries of DHEA-induced PCOS rats.

BACKGROUND: Insulin-lowering agents are reported to be useful in treating polycystic ovary syndrome (PCOS) anovulation. It has been suggested that lower insulin levels secondarily affect ovarian tissue, although the direct mechanism of action has not yet been verified. Here we investigated if these agents directly affect the ovary. METHODS: Thirty female Wister rats were studied. Six control rats were injected subcutaneously with 0.2 ml sesame oil, while 24 rats used as PCOS models were injected subcutaneously with dehydroepiandrosterone (DHEA) and divided into four groups. Six rats were injected with only DHEA, while the remaining 18 rats received metformin, pioglitazone or troglitazone. The ovaries were immunohistochemically stained with anti- testosterone and anti-17beta-HSD antibodies, and then evaluated for morphological changes. RESULTS: In the DHEA administration group, the number of atretic follicles significantly increased compared to that of control rats. The insulin-lowering agents did not improve the multicystic appearance. Serum testosterone concentrations significantly increased with DHEA administration, but the increase was inhibited by oral administration of insulin-lowering agents. Testosterone deposits in ovarian tissue were also reduced by feeding rats insulin-lowering agents. CONCLUSION: Insulin-lowering agents affected ovarian tissue by inhibiting testosterone biosynthesis in vivo.

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinase in uterine endometrial carcinoma and a correlation between expression of matrix metalloproteinase-7 and prognosis.

Matrix metalloproteinases (MMPs) are associated with invasion and metastasis of several human malignant tumors, in particular MMP-7, which is mainly produced by the cancer cell itself. We examined the expression of MMP-2, 7 and 9, and tissue inhibitors of metalloproteinase (TIMP)-1 and 2 in uterine endometrial carcinoma, and compared the expression with clinicopathological characteristics in uterine endometrial carcinoma (UEC). A group of 256 patients with UEC received surgery at the Osaka City University Medical School Hospital, and 196 tumor samples were immunohistochemically stained to examine the expression of MMP-2, 7 and 9, and TIMP-1 and 2. Additionally, the invasion ability of cell stain established from UEC was examined using an in vitro invasion assay. The expression of MMP-2, 7 and 9, and TIMP-1 and 2 was observed in the cytoplasm, and the expression of MMP-2 and 7, and TIMP-1 and 2 was observed in stromal cells around the tumor cells. The expression of MMP-7 was significantly stronger in higher-grade than lower-grade tumors (P<0.05). The invasion assay showed that the invasion of cells derived from UECs was significantly inhibited by TIMP-1 and 2. The disease-free interval was significantly shorter when MMP-7 expression was intense. This increased expression of MMP-7 in high grade UECs may be associated with tumor invasion and metastasis, and MMP-7 could serve as a prognostic maker in UEC.

Expression of apoptosis-related proteins in advanced uterine cervical cancer after balloon-occluded arterial infusion chemotherapy as an indicator of the efficiency of this therapy.

We previously reported satisfactory therapeutic results of cisplatin-based cyclic balloon-occluded arterial infusion chemotherapy (BOAI) as neoadjuvant chemotherapy, which enabled treatment by hysterectomy in patients with advanced cervical cancer. We also reported expression of apoptosis among these patients and determined that the bax gene is related to this apoptosis. In the present study, we investigated the relationship between the effectiveness of BOAI therapy and expression of apoptosis regulatory genes and proteins in these cases. The subjects were 27 women with advanced cervical cancer classified as FIGO (International Federation of Gynecology and Obstetrics) stage III or higher who were admitted to the Department of Gynecology, Osaka City University Medical School Hospital between 2000 and 2003. All patients were treated by BOAI, and expression of cancer cell apoptosis was examined by the TUNEL method, expression of bax, bcl-2 and bcl-xL proteins were examined by immunohistochemistry, and expression of bax, bcl-2 and bcl-xL mRNA was examined by quantitative RT-PCR before and 3 days after BOAI. The effectiveness of BOAI therapy was thus determined. The 20 patients in whom BOAI was effective showed significantly higher expression of the bax protein and gene after BOAI, and cancer cell apoptosis was accelerated. On the other hand, the 7 patients in whom BOAI was ineffective showed significantly higher expression of the bcl-xL protein and gene after BOAI. These results suggest that bax/bcl-xL expression can be used as an indicator of the effectiveness of BOAI therapy.

Association of HPV infection with prognosis after neoadjuvant chemotherapy in advanced uterine cervical cancer.

Whether the human papillomavirus (HPV) status of the tumor affects the sensitivity to neoadjuvant chemotherapy, and the prognosis in advanced uterine cervical cancer (FIGO stage III or higher) remains unknown. We examined the HPV status of 43 patients who had received CDDP therapy by balloon-occluded arterial infusion (BOAI), as neoadjuvant chemotherapy for advanced uterine cervical cancer (squamous cell carcinoma) stage III or higher. DNA was extracted from formalin-fixed, paraffin-embedded tumor samples obtained by punch biopsy before the neoadjuvant chemotherapy. The detection of HPV and its typing were analyzed by a polymerase chain reaction (PCR)-based assay using consensus primers for the L1 consensus regions. HPV DNA was detected in all 43 patients (100%): 29 cases with HPV 16 (67.4%), 5 cases with HPV 33 (11.6%), 4 cases with HPV 31 (9.3%), 3 cases with HPV 35 (7.0%), 1 case with HPV 18 (2.3%) and 1 case with HPV 58 (2.3%). The HPV types were divided into 3 groups, HPV 16, HPV 33 and other HPV types (HPV 18, 31, 35, 58), and comparisons and examinations were performed among the 3 groups. Although the rates of tumor reduction and operation accomplishment after 3 courses of BOAI showed no significant differences among the 3 groups, there were significant differences in the survival rates. The survival rate of advanced uterine cervical cancer patients with HPV 33 infection was the highest, followed by that of patients with HPV 16 infection. The survival rates of patients with the other types of HPV infection were the worst among the 3 groups and significantly lower than those of patients with HPV 16 or HPV 33 infection. The differences in the curative effect after BOAI may depend on the different characters of the HPV types.

Expression and distribution of cyclooxygenase-2 in human ovary during follicular development.

Prostaglandins play important roles for oocyte maturation and follicular rupture. Cyclooxygenase-2 (COX-2), an inducible isoform of a prostaglandin metabolic enzyme, is essential for the timed production of prostaglandins in the ovary. The aim of the present study is to examine expression and distribution of COX-2 in human ovarian follicles at each of the maturation stages. Immunohistochemical staining shows that COX-2 is expressed in the granulosa cell layer of secondary and developing follicles, but is not detected in primary and Graafian follicles. Western blotting analysis revealed the existence of COX-2 in periovulatory follicular fluid at a mean concentration of 5.6 +/- 0.6 ng/ml. COX-2 might begin to be produced at the secondary follicle stage, and once a follicle reaches the Graafian follicle stage, the production of this enzyme is stopped. After exposure to luteinizing hormone (LH) surge, follicles might resume production of COX-2, and this is secreted into the follicular fluid.

Expression of survivin and matrix metalloproteinases in adenocarcinoma and squamous cell carcinoma of the uterine cervix.

Cervical cancer can be classified into two histological types: squamous cell carcinoma (SCA) and adenocarcinoma (ACA). Reportedly ACA has poorer prognoses, metastasizes more easily to lymph nodes, and is more resistant to radiotherapy than SCA. To clarify the cause of characteristic differences between these histological types, we examined the expressions of apoptosis inhibiting and tumor-invasion related factors in both histological types. We reviewed the 34 cases of cervical cancer (17 ACA, 17 SCA) that had surgery as their initial treatment at Osaka City University Medical School Hospital between 1996 and 2001. The differences of survivin, and matrix metalloproteinase (MMP-2, and MMP-7) expressions between both histological types were immunohistochemically assayed, and the correlation between the expression of each protein and clinicopathological characteristics was analyzed. Survivin was expressed significantly stronger in ACA cases (p=0.035). The number of patients who expressed MMP-2 and MMP-7 simultaneously was significantly higher in SCA cases (p=0.039). MMP-2 and MMP-7 had tendencies to be expressed stronger in SCA (p=0.057 and p=0.084, respectively). These results suggest that the differences of the expression of survivin (an apoptosis inhibiting factor), MMP-2, and MMP-7 (tumor-invasion related factors) between ACA and SCA were causes of the characteristic differences between the two histological types.