Cyclin E mRNA overexpression in epithelial ovarian cancers: inverse correlation with p53 protein accumulation.

OBJECTIVE: We investigated the relationship between cyclin E mRNA overexpression and p53 protein accumulation in epithelial ovarian cancers. METHODS: mRNA was isolated and cDNA was prepared from 36 epithelial ovarian tumors (three adenomas, three low malignant potential tumors, and 30 carcinomas), and six normal ovaries. The cyclin E mRNA expression levels relative to an internal control, beta-tubulin, were determined by semiquantitative polymerase chain reaction (PCR). Cyclin E and p53 protein expression in ovarian cancer tissues were examined by immunohistochemistry using the same series of samples. Fisher exact test of significance and an unpaired t test were used for statistical analysis. RESULTS: Considerable levels of cyclin E mRNA were detected in all normal ovaries and ovarian tumor samples examined by semiquantitative PCR amplification. mRNA levels of cyclin E were significantly higher in nine of 30 (30%) ovarian cancers compared with those in normal ovaries. The immunohistochemical expression of cyclin E protein was confirmed in the nuclei of tumor cells in 13 of 30 (43%) ovarian cancers. p53 protein accumulation was detected in 12 of 30 (40%) ovarian cancers examined. There was a significant inverse correlation between cyclin E mRNA overexpression and p53 protein accumulation (P <.01, Fisher exact test). CONCLUSIONS: Cyclin E mRNA overexpression frequently occurs in ovarian cancers without p53 protein accumulation. Cyclin E might have an important effect on the development of a limited number of ovarian cancers.

Underexpression of cyclin-dependent kinase inhibitor p27 is associated with poor prognosis in serous ovarian carcinomas.

Reduced expression of a cyclin-dependent kinase inhibitor, p27, has been reported to be associated with poor prognosis in several human cancers. The aim of this study was to investigate the potential role of p27 in ovarian cancer development and progression. Immunohistochemical expression of p27 was determined using 117 epithelial ovarian tumor tissues and 8 normal ovaries. p27 mRNA expression was examined by semi-quantitative PCR amplification using 26 ovarian cancer samples. Nuclear staining of p27 was commonly observed in the normal ovarian surface epithelium and the epithelial cells of germinal inclusion cysts. Positive p27 staining rates were significantly higher in serous adenomas (p=0.006) and in serous LMP tumors (p=0.013) than that in serous carcinomas (Fisher's exact test). In serous ovarian cancers, positive p27 staining rate was significantly higher in early stage (stage1/2) than that in advanced stage (stage 3/4) diseases (p=0.030, Fisher's exact test). Log-rank testing showed that negative p27 expression significantly correlates with poor survival in serous ovarian cancer patients (p=0.041). Considerable levels of p27 mRNA were detected in all ovarian cancer samples examined. These results suggest that the underexpression of p27 caused by post-translational mechanism may contribute to the development and progression and result in poor prognosis of serous ovarian cancers.

Increased expression of protease M in ovarian tumors.

Proteases are known to play important roles in tumor invasion and metastasis. Protease M, which was originally identified by Anisowicz and colleagues in 1996, is a new member of the serine protease family. We also identified the protease M transcript in a differential PCR screen of ovarian tumors and have investigated its expression in 44 ovarian tumors (12 low malignant potential tumors, 32 carcinomas) and 10 normal ovaries using quantitative PCR. The PCR product was labeled with (32)P and a phosphoimager was used to determine the relative expression of the protease M gene compared to internal control beta-tubulin. mRNA expression levels of protease M were significantly elevated in 9 of 12 low malignant potential tumors and 30 of 32 carcinomas. Northern blot hybridization showed that the 1.7-kb protease M transcript was abundant in carcinoma but not detected in normal ovary. Immunohistochemical staining of normal ovary and ovarian tumor tissue sections with antibodies generated to protease M derived peptides corroborated the semi-quantitative PCR and Northern analysis data. Our results suggest that protease M is frequently overexpressed in ovarian tumors and may therefore contribute to the invasive nature or growth capacity of ovarian carcinomas.

Ovarian tumor cells express a transmembrane serine protease: a potential candidate for early diagnosis and therapeutic intervention.

Proteases have been implicated in the extracellular modulation required for tumor growth and invasion. In an effort to categorize those proteases contributing to ovarian carcinoma progression, we have utilized redundant primers to conserved amino acid (AA) domains surrounding the catalytic triad of His, Asp and Ser to amplify serine proteases that are differentially expressed in carcinomas. Using this method, we have identified and cloned a serine protease named TADG-15 (tumor-associated differentially expressed gene 15) that is overexpressed in ovarian tumors. TADG-15 is a transmembrane multidomain serine protease which includes ligand binding domains and a serine protease in the extracellular space.

Expression of the protease inhibitor antileukoprotease and the serine protease stratum corneum chymotryptic enzyme (SCCE) is coordinated in ovarian tumors.

We have previously reported that the stratum corneum chymotryptic enzyme (SCCE) is overexpressed in ovarian cancers and that SCCE has potential as a useful marker and/or a therapeutic target for ovarian carcinoma. Antileukoprotease (ALP) has been shown to be a specific inhibitor of SCCE. The objective of this study was to investigate the potential cotranscription and overexpression of ALP in carcinoma of the ovary. The expression of ALP transcript was evaluated by Northern blot hybridization and by semiquantitative polymerase chain reaction (PCR) technique. The presence of the ALP protein in ovarian tumor cells was evaluated by immunohistochemistry. Northern blot hybridization showed that the ALP transcript was abundant in ovarian carcinomas but was not detected in the normal ovary. Semi-quantitative PCR examination revealed that the mRNA level of ALP was significantly elevated in low-malignant-potential tumors and in ovarian carcinomas compared with that in normal ovaries (P < 0.01). There was significant positive correlation between SCCE and ALP mRNA overexpression status in ovarian tumor cases (P < 0.01). Immunohistochemical expression of ALP protein was observed in ovarian tumor cells, whereas little or no staining was observed in normal ovarian surface epithelium. Like SCCE, ALP is highly overexpressed in ovarian tumor cells, which begs the question of whether it remains an effective inhibitor of SCCE or whether it is discordant in time or space and is ineffective as an inhibitor of the SCCE enzyme.

Overexpression of testisin, a serine protease expressed by testicular germ cells, in epithelial ovarian tumor cells.

OBJECTIVE: In a continued effort to identify and characterize secreted proteases that are overexpressed in ovarian carcinomas, we discovered the testisin protease as such a candidate. When this discovery was originally made, no data existed in the literature or in the GenBank database that identified such a gene. Our main objective was to determine whether this gene was overexpressed exclusively in ovarian tumor tissues compared with normal ovary and whether it was expressed in any other normal tissues. METHODS: mRNA was isolated and cDNA was prepared from 34 ovarian tumors (four adenomas, three low malignant potential tumors, and 27 carcinomas) and seven normal ovaries. The testisin mRNA expression level relative to internal control, beta-tubulin, was determined by Northern blot analysis and semiquantitative polymerase chain reaction (PCR). RESULTS: Northern blot hybridization showed that the testisin transcript was abundant in ovarian carcinoma but was not detected in normal ovary. On examination of Northern blots from normal fetal and adult tissues, only adult testis showed abundant transcripts of testisin. Semiquantitative PCR examination showed that the testisin mRNA levels in ovarian tumors of low malignant potential and in ovarian carcinomas were significantly higher than in normal ovaries (P <.01). Testisin mRNA level in ovarian carcinomas was also significantly higher than in ovarian adenomas (P <.05). Testisin overexpression rates in advanced stage (stage 2 or 3) diseases were significantly higher than that in early stage diseases (stage 1) in ovarian carcinoma samples (P <.05). CONCLUSIONS: The induction of the testisin transcript might contribute to the development, progression, and invasive or metastatic capacity of ovarian carcinomas.

Ovarian tumor cells express a novel multi-domain cell surface serine protease.

Serine proteases serve many functions in normal biological processes. These functions are often usurped by cancer cells to allow progression of tumors by increasing the growth and metastatic potential of the neoplasia. Here, we have used a polymerase chain reaction (PCR)-based strategy to clone Tumor Associated Differentially-expressed Gene-12 (TADG-12), a new serine protease from ovarian carcinoma. This technique also revealed a variant splicing form of TADG-12 that could lead to a truncated protein product. Semi-quantitative PCR showed that TADG-12 is overexpressed in 41 of 55 ovarian cancer specimens relative to normal expression, and the variant form, TADG-12V is found at increased levels in 8 of 22 carcinomas examined. Northern blot revealed three transcripts, the largest of which is approximately 2.4 kb. An ovarian tumor cDNA library was screened, and the entire cDNA of TADG-12 has been identified. This sequence encodes a putative protein of 454 amino acids which includes a potential transmembrane domain, an LDL receptor-like domain, a scavenger receptor cysteine-rich domain, and a serine protease domain. These features imply that TADG-12 will be at the cell surface, and it may be useful as a molecular target for therapy or a diagnostic marker.

Differential expression of matrix metalloprotease-7 in each component of uterine carcinosarcoma.

The aim of this study was to investigate the expression of matrix metalloprotease-7 (MMP-7) in each component of uterine carcinosarcoma. Surgical specimens of primary tumors of uterine carcinosarcomas were obtained from 13 patients. The carcinomatous component consisted of adenocarcinoma with or without squamous differentiation. The sarcomatous component consisted of spindle cell sarcoma, chondrosarcoma and rhabdomyosarcoma, either alone or in combination. The immunohistochemical expression of MMP-7 protein was examined using the avidin-biotin peroxidase complex technique employing the anti-MMP-7 monoclonal antibody. Expression of MMP-7 protein was detected in 9 (69.2%) of 13 adenocarcinoma components, while no staining was observed in any of the sarcomatous components examined. There was a statistically significant difference of the positive rate for MMP-7 between epithelial components and sarcomatous components of uterine carcinosarcoma (p<0.01). In some cases, MMP-7 was abundantly expressed at the invasive front of adenocarcinomas. It is concluded that MMP-7 protein is differentially expressed between the carcinomatous component and the sarcomatous component of uterine carcinosarcoma. Each component of carcinosarcoma may have its own potential for invasion and metastasis. MMP-7 may contribute to the invasive nature or growth capacity of the carcinomatous component of uterine carcinosarcoma, while it may not have a relation to that of the sarcomatous components.

Induction of matrix metalloprotease-7 is common in mucinous ovarian tumors including early stage disease.

Matrix metalloproteases are known to play an important role in tumor invasion by mediating degradation of the extracellular matrix. In this study, we have investigated the immunohistochemical expression of matrix metalloprotease -7 (MMP-7) in 44 mucinous ovarian tumors (9 adenomas, 13 low malignant potential tumors, 22 adenocarcinomas) and 6 normal ovaries. Positive staining of MMP-7 is observed in all mucinous ovarian tumors, whereas little or no staining was observed in surface epithelium as well as the epithelial cells of germinal inclusion cyst of the normal ovary. Positive immunostaining of MMP-7 is also observed in the secreted mucin in the tumor glands, which suggests the secretion of the MMP-7 protein from tumor cells. mRNA expression of MMP-7 was confirmed using RT-PCR. The MMP-7 gene was amplified in parallel with an internal control gene beta-tubulin using a thermal cycler. mRNA expression levels of MMP-7 were significantly elevated in mucinous tumor samples compared with that in normal ovaries. Our results suggest that MMP-7 is frequently overexpressed in mucinous ovarian tumors and secreted with the mucin which is produced from the tumor cells. MMP-7 may therefore contribute to mucinous ovarian tumor development or enhanced growth capacity of mucinous ovarian tumors. MMP-7 may also serve as a target for therapeutic intervention in the down regulation of tumor progression.

The stratum corneum chymotryptic enzyme that mediates shedding and desquamation of skin cells is highly overexpressed in ovarian tumor cells.

BACKGROUND: Proteases play essential roles in the process of tumor invasion and metastasis. The serine protease stratum corneum chymotryptic enzyme (SCCE) has been purified from human stratum corneum and is known to contribute to the cell shedding process by catalyzing the degradation of intercellular cohesive structures at the skin surface. The presence of SCCE on the surface of tumor cells suggests it also may contribute to the process of tumor cell shedding, resulting in early metastasis of carcinoma. METHODS: Gene expression of SCCE was investigated in 44 ovarian tumors (12 low malignant potential tumors and 32 carcinomas) and 10 normal ovaries by quantitative polymerase chain reaction (PCR). The PCR product was labeled with (32)P and a phosphoimager was used to determine the relative expression of SCCE compared with an internal control Beta-tubulin. mRNA transcripts were studied by Northern blot hybridization and protein expression and localization was examined by Western blot analysis and immunohistochemistry. RESULTS: mRNA expression levels of SCCE were elevated significantly in 66.7% of 12 low malignant potential tumors and 78.1% of 32 carcinomas. Furthermore, SCCE protein was abundant in tumor cells and tumor cell lines that overexpressed the mRNA transcript. CONCLUSIONS: The results of the current study suggest that SCCE frequently is overexpressed in ovarian tumors and therefore may contribute to tumor cell growth, tumor spread, and the metastatic potential of ovarian tumor cells.

Cloning of tumor-associated differentially expressed gene-14, a novel serine protease overexpressed by ovarian carcinoma.

The family of enzymes known as serine proteases supports many biological functions for cancer cells, including activation of growth and angiogenic factors and activation of other proteases for invasion and metastasis. In addition, many of these serine proteases are secreted by cells into the extracellular space to serve these functions. Therefore, serine proteases are excellent candidate tumor markers. To examine serine proteases expressed by ovarian carcinoma, we designed degenerate PCR primers corresponding to the conserved regions of these genes and used them in reverse transcriptase-PCR experiments with normal and tumor cDNA as a template. The PCR products were subcloned and sequenced, and one of these clones was found to encode a novel serine protease, named tumor-associated differentially expressed gene-14 (TADG14). Northern blot analysis indicated that the mRNA for TADG14 is 1.4 kb long and that it is highly overexpressed in ovarian carcinoma compared with normal ovary. The entire cDNA has been obtained, and based on sequence homology, it encodes a 260-amino acid serine protease. Semiquantitative PCR indicates that TADG14 is overexpressed in 24 of 40 tumors studied. Northern blot data confirm this overexpression, and immunohistochemical staining suggests that this protein is secreted. As such, the TADG14 protease may be useful as a diagnostic tool or as a molecular target for therapy.

Cyclin D1 overexpression and p53 mutation status in epithelial ovarian cancer.

OBJECTIVE: To examine the cyclin D1 mRNA expression level in ovarian tumor samples as compared with normal ovaries and to determine the relationship between cyclin D1 overexpression and p53 mutation status in ovarian tumors. METHODS: mRNA was isolated and cDNA was prepared from 27 epithelial ovarian tumors (3 tumors of low malignant potential (LMP) and 24 cancers) and 6 normal ovaries. The cyclin D1 sequences were amplified by using a thermal cycler in parallel with the beta-tubulin gene as an internal control. The cyclin D1 mRNA expression level relative to beta-tubulin was determined by 32P phosphoimager analysis. To confirm the overexpression of the cyclin D1 protein in ovarian tumor cells, immunostaining was performed. The p53 gene mutation status was examined by direct cDNA sequencing. RESULTS: mRNA levels of cyclin D1 were significantly higher in 21 (78%) of the 27 ovarian tumors than in normal ovaries. Cyclin D1 overexpression was detected in ovarian LMP tumors as well as in ovarian cancer cases. Positive immunostaining of cyclin D1 protein was observed in 10 of 18 (56%) ovarian tumors examined. p53 mutations were found in 11 (61%) of 18 ovarian tumors. Of 11 ovarian tumor cases with p53 mutations, 5 showed overexpression of cyclin D1. All 7 ovarian tumor cases without p53 mutations showed significant cyclin D1 mRNA overexpression. CONCLUSION: Cyclin D1 overexpression seems to be an early genetic event in ovarian tumor development. Although p53 may be one of the proteins whose function regulates the expression of G1 cyclins, ovarian tumors with no p53 mutation consistently showed cyclin D1 overexpression. Cyclin D1 overexpression may play an important role in the tumorigenesis of epithelial ovarian tumors.

Ultrastructural interactions in the microvasculature of human endometrial adenocarcinoma.

OBJECTIVES: Our purpose was to study the ultrastructural morphology of the microvasculature of human endometrial adenocarcinoma and to determine the effect of this malignancy on cell-to-cell communication between the components of the microvasculature and with the other tissue compartments of human endometrium. Methods. Multiple cases of human endometrial adenocarcinoma were studied and graded by light microscopy. Six cases of Grade I and six cases of Grade II were selected. Two blocks per case were studied ultrastructurally. RESULTS: In contrast to our expectation that the ultrastructure of tumor vessels would suggest a great deal of proliferation and new vessel formation, we found that tumor vessels displayed a high degree of cellular differentiation, in the form of numerous and varied cell-to-cell contacts, and large amounts of protein production. CONCLUSIONS: The morphology of the microvasculature of endometrial adenocarcinoma suggests an active rather than passive role in tumor vessels.

The matrix metalloprotease pump-1 (MMP-7, Matrilysin): A candidate marker/target for ovarian cancer detection and treatment.

Matrix metalloproteases are known to play an important role in tumor invasion by mediating degradation of extracellular matrix. In this study, we have investigated the expression of the matrix metalloprotease pump-1 gene (also referred to as MMP-7, Matrilysin) in 44 ovarian tumors (12 low malignant potential tumors, 32 carcinomas) and 10 normal ovaries using quantitative PCR. The PCR product was labelled with 32P and a phosphoimager was used to determine the relative expression of pump-1 compared to an internal control beta-tubulin. mRNA expression levels of pump-1 were significantly elevated in 9 of 12 low malignant potential tumors and 26 of 32 carcinomas. Northern blot hybridization showed that the 1. 1-kb pump-1 transcript was abundant in carcinoma but seldom expressed in normal adult tissues including normal ovary. Immunohistochemical localization of the pump-1 protein confirms its expression by ovarian tumor cells. Our results suggest that pump-1 is frequently overexpressed in ovarian tumors and may contribute to its invasive nature or growth capacity, therefore pump-1 may serve as a useful marker for early detection of disease and/or a target for therapeutic intervention in downregulation of tumor progression.

Expression of the farnesyltransferase beta-subunit gene in human ovarian carcinoma: correlation to K-ras mutation.

The ras signaling protein requires a posttranslational modification to localize it to the inner surface of plasma membrane. In this state it can behave as a signal transduction mediator. Farnesyltransferase plays an important role in this posttranslational processing of ras by attaching a farnesyl group to the cysteine of the ras C-terminal tetrapeptide. In this study, we investigated the relationship of K-ras expression and mutation with farnesyltransferase beta-subunit expression in 20 ovarian tumors (17 carcinomas and 3 low malignant potential tumors) and 4 normal ovaries. The expression level of mRNA was determined by using quantitative PCR and mutation analysis was performed by direct cDNA sequencing. K-ras mutations were found in 1 of 3 low malignant potential tumors and in 4 of 17 carcinoma cases. K-ras mRNA overexpression was found in 1 of 3 low malignant potential tumors (one with mutated ras) and in only 1 of 17 carcinoma cases. Farnesyltransferase beta-subunit mRNA overexpression was found in 2 of 3 low malignant potential tumors and in 7 of 17 carcinoma cases. Interestingly, all K-ras mutation cases showed farnesyltransferase beta-subunit overexpression. These findings suggest that there may be a direct relationship between K-ras (ras dysfunction) mutation and expression of farnesyltransferase beta-subunit gene.

Hepsin, a cell surface serine protease identified in hepatoma cells, is overexpressed in ovarian cancer.

Extracellular proteases mediate the digestion of neighboring extracellular matrix components in initial tumor growth, allow shedding or desquamation of tumor cells into the surrounding environment, provide the basis for invasion of basement membranes in target metastatic organs, and are required for release and activation of many growth and angiogenic factors. We identified overexpression of the serine protease hepsin gene in ovarian carcinomas and investigated the expression of this gene in 44 ovarian tumors (12 low malignant potential tumors and 32 carcinomas) and 10 normal ovaries. Quantitative PCR was used to determine the relative expression of hepsin compared to that of beta-tubulin. The mRNA expression levels of hepsin were significantly elevated in 7 of 12 low malignant potential tumors and in 27 of 32 carcinomas. On Northern blot analysis, the hepsin transcript was abundant in carcinoma but was almost never expressed in normal adult tissue, including normal ovary. Our results suggest that hepsin is frequently overexpressed in ovarian tumors and therefore may be a candidate protease in the invasive process and growth capacity of ovarian tumor cells.

p16 overexpression: a potential early indicator of transformation in ovarian carcinoma.

OBJECTIVE: The recently cloned gene p16 (MST1) has been identified as a putative tumor suppressor gene that binds to CDK4 and CDK6 (cyclin-dependent kinases), preventing their interaction with cyclin D1 and thereby preventing cell cycle progression at the G1 stage. In addition, the p16 gene has been shown to have a high frequency of mutation in some tumor cell lines; however, it has also been shown that a much lower frequency of mutation occurs in primary tumors. This study investigated the mRNA expression level and mutation status of the p16 gene in ovarian tumors. METHODS: We performed quantitative polymerase chain reaction and direct cDNA sequencing analysis. To confirm the p16 protein level in ovarian tumors, Western blotting and immunohistochemical staining were performed. Expression levels of mRNA for the p16 gene relative to the beta-tubulin gene were examined in 32 ovarian tumors (24 carcinomas, six low malignant potential tumors, and two benign tumors) and six normal ovaries. RESULTS: The mRNA expression level of p16 was significantly elevated in 28 ovarian tumors (22 carcinomas, five low malignant potential tumors, and one benign tumor) compared with that of normal ovaries. Western blotting analysis and immunohistochemical staining confirmed elevated p16 protein levels in ovarian tumor samples. Among 32 ovarian tumors, cDNA sequencing of the p16 gene showed no p16 mutation resulting in a coding error, although one silent mutation and three polymorphisms were found. CONCLUSIONS: Although p16 is seldom mutated in ovarian tumors, the overexpression of p16 in most ovarian tumor cases indicates a dysfunction in the regulatory complex for G1 arrest. Therefore, overexpression of p16 may be an important early event in the neoplastic transformation of the ovarian epithelium.

CA125 phosphorylation is associated with its secretion from the WISH human amnion cell line.

Evidence is presented suggesting that CA125 is a serine and/or threonine phosphoprotein and that its secretion from the human amnion WISH cell line is closely linked to its phosphorylation. It is also indicated that regulation of CA125 secretion requires protein(s) tyrosine phosphorylation. WISH cells treated with a tyrosine phosphatase inhibitor, vanadate/ H2O2, resulted in increased levels of CA125 secretion. Exposure of vanadate-treated cells to epidermal growth factor further enhanced this secretory activity. Immunohistochemistry of vanadate-treated cells resulted in a substantial increase in not only cytoplasmic tyrosine phosphoproteins but also in membrane-associated CA125 when stained with the PY20 anti-phosphotyrosine and M11 anti-CA125 monoclonal antibodies, respectively. M11 immunoprecipitation of CA125 from cells labelled with [32P]-orthophosphate was analyzed by SDS-PAGE and autoradiography. Immunoprecipitates from cell lysates demonstrated that a phosphoprotein of > 200 kD was isolated and immunoreacted with both the OC125 and M11 anti-CA125 monoclonal antibodies by Western blotting. CA125 immunoprecipitated from vanadate-treated cells showed a marked increase in cell-associated CA125 phosphorylation. Although CA125 could be immunoprecipitated from WISH cell media incubated with [32P]-orthophosphate in the presence or absence of vanadate as detected by Western blotting, autoradiographic analysis of the Western blots revealed no [32P]-labelled CA125 co-migrating with the 200-kD plus molecule detected by M11. When the PY20 anti-phosphotyrosine monoclonal antibody was used as the probe, no tyrosine-phosphorylated CA125 was detected in cell lysates.

Gestational trophoblastic disease: a spectrum of radiologic diagnosis.

Gestational trophoblastic disease (GTD) encompasses a broad spectrum of conditions that includes hydatidiform mole, invasive mole, and choriocarcinoma. Although ultrasound (US) is the examination of choice for initial diagnosis, plain radiography, angiography, computed tomography (CT), and magnetic resonance (MR) imaging all play a role in determining the presence of GTD and the extent of its complications. US shows molar gestations as alternating cystic and solid tissue that fills the entire uterus. CT and MR imaging are useful in detecting myometrial invasion, parametrial extension, and metastasis. Because each imaging technique offers a unique perspective highlighting different aspects of GTD, it is important to understand the pathophysiology and natural history of the disease. Such knowledge in turn leads to a greater understanding of the spectrum of findings seen on various kinds of radiologic images and enables the radiologist to play an important role in directing patient work-up by recognizing the implications of various findings and guiding management decisions.

The nuclear channel system in endometrial adenocarcinoma exposed to medroxyprogesterone acetate.

The nuclear channel system (NCS), giant mitochondria and subnuclear glycogen form a triad of ultrastructural features observed in normal human endometrial epithelium in response to progestational steroids. Both the giant mitochondria and subnuclear glycogen have been described in endometrial adenocarcinoma, but the NCS has not. This article reports the development of the NCS in adenocarcinoma treated with medroxyprogesterone acetate. Previous studies suggest that the NCS in normal tissue is a response to the acyl group in the 17-beta position of the D-ring of some progestational steroids, such as medroxyprogesterone acetate. Medroxyprogesterone acetate was administered to 12 postmenopausal women with endometrial adenocarcinoma. Hysterectomies were performed 8 to 20 days after treatment. Pretreatment specimens were also obtained on 8 of the 12 patients. Using standard electron microscopy procedures, light microscopy on plastic semithin sections was first used to confirm the presence of tumor. Thin sections of malignant endometrium were prepared and evaluated ultrastructurally for progestational alterations. Abnormal giant mitochondria and subnuclear glycogen were found both before and after treatment. The third element of the triad, the NCS, was not observed in any of the available pretreatment biopsies, but was seen in three of the treated specimens. Thus it appears that the NCS is a response to the given progesterone therapy.