Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among multiple genetic pathways involved in endometrial cancer (EC), the mutator pathway is characterized by defective mismatch repair (MMR) causing microsatellite instability (MSI+). Inactivation of MMR genes allows elevation of mutation rates in key target genes involved in important cellular pathways, providing a selective growth advantage. Our aim was to investigate apoptotic and growth regulatory target genes in young endometrioid adenocarcinoma patients and their association with stepwise neoplastic progression through distinct stages of hyperplasia and cancer. Screening of 184 ECs revealed 38 microsatellite high (MSI-H), 10 microsatellite low (MSI-L) and 136 microsatellite stable (MSS) tumors. We observed somatic frameshift mutations in the coding region repeats of the target genes in 12/38 MSI-H tumors (T) and in 3/8 of available associated hyperplasias (HY). Mutations were detected in FAS (T=1, HY=1), BAX (T=6, HY=1), CASP5 (T=2) and IGFIIR (T=3, HY=1) genes. None of the MSI-L or MSS tumors showed alterations in these coding repeats. Increased mutation frequency in apoptotic and growth regulatory genes demonstrated a significant relationship with advancing tumor grade (p=0.02) by Fisher's exact test. Furthermore, a significant trend was found by Bartholomew's test (P<0.05) for the apoptotic pathway and close to significant (p approximately 0.06) for the overall mutation status for both pathways combined. Our results suggest that genes implicated in apoptosis may serve as targets in the progression of MSI+ EC in young patients.
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PMID:Apoptotic and growth regulatory genes as mutational targets in mismatch repair deficient endometrioid adenocarcinomas of young patients. 1501 Aug 97

Cathepsin D is a lysosomal acid proteinase which is involved in the malignant progression of breast cancer and other gynecological tumors. Clinical investigations have shown that in breast cancer patients cathepsin D overexpression was significantly correlated with a shorter free-time disease and overall survival, whereas in patients with ovarian or endometrial cancer this phenomenon was associated with tumor aggressiveness and a degree of chemoresistance to various antitumor drugs such as anthracyclines, cis-platinum and vinca alkaloids. Therefore, a lot of research has been undertaken to evaluate the role and the prognostic value of cathepsin D also in other solid neoplasms. However, conflicting results have been generated from these studies. The discrepancies in these results may, in part, be explained with the different methodological approaches used in order to determine the levels of expression of the enzyme in tumor tissues and body fluids. Further investigations using well-standardized techniques may better define the clinical significance of cathepsin D expression in solid tumors. Nevertheless, evidence emerging from these studied indicates that this proteinase seems to facilitate early phases of tumor progression such as cell proliferation and local dissemination. These findings support the concept that cathepsin D may be a useful marker for identifying patients with highly malignant tumor phenotypes who may need more aggressive clinical treatment; this enzyme may also be considered as a potential target for a novel therapeutic approach in the treatment of solid neoplasms.
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PMID:Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications. 1516 27

This is the first report in the English literature of a composite endometrial tumor composed of papillary serous carcinoma and small cell carcinoma. A 79-year-old woman underwent total abdominal hysterectomy and left salpingo-oophorectomy due to endometrial carcinoma. Grossly, the uterus was enlarged with an irregular and nodular serosal surface, thickened myometrium, and irregular endometrium. Microscopic examination revealed an endometrial carcinoma composed of papillary serous carcinoma and small cell carcinoma. There was a differential immunoreactivity between the two components: the cells of the papillary serous carcinoma were positive for cytokeratin, CA-125, CEA, and HER-2/Neu, whereas these markers were negative in the small cell carcinoma. Various neuroendocrine markers were positive in the small cell carcinoma and negative in the papillary serous carcinoma. Fluorescence in situ hybridization analysis using 4, 8, and 10 centromeric probes revealed hyperploidy (6-8 signals) in the small cell carcinoma cells. Most of the serous carcinoma cells were euploid, with scattered trisomies and tetrasomies of these chromosomes. The patient died of progressive disease 5 months after surgery. We suggest that the small cell carcinoma may have arisen from the endometrial papillary serous carcinoma undergoing tumor progression with neuroendocrine differentiation.
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PMID:An unusual composite endometrial tumor combining papillary serous carcinoma and small cell carcinoma. 1525 20

Cadherins are a superfamily of adhesion molecules that mediate Ca++ -dependent cell-cell adhesion necessary for normal morphogenesis and maintenance of tissue integrity. A classical cadherin molecule, such as E-cadherin, is a glycoprotein made up of three parts: an extracellular portion composed of five identical domains, a transmembrane portion composed of a single domain and a cytoplasmic portion composed of two domains. The cytoplasmic portion is anchored by means of cytoplasmic catenins to the cytoskeleton. The three amino acids sequence, histidine, alanine and valine (HAV motif) located at the most external domain of the extracellular portion, plays a key role in homophilic recognition between two cadherin molecules and cell-cell adhesion. Loss of cell-cell adhesion may be a prerequisite for malignant transformation and the invasive behavior of malignant tumors. Research of cadherin in malignancies has attracted much attention since cadherins may be proven to be reliable markers of biological behavior and prognosis The studies on cadherin in malignancies of the female genital tract have shown the following results: 1) in malignant transformation of the ovarian surface epithelium (OSE) and in epithelial ovarian carcinoma confined to the ovary (Stage I) there is a switch from N-cadherin expression to E-cadherin expression; 2) In advanced-stage epithelial ovarian carcinoma (Stages II-IV) the results are at odds: some investigators have shown a loss of E-cadherin expression most often because of hypermethylation of the promoter region of the gene, while others have demonstrated an increase in E-cadherin expression; 3) In endometrial carcinoma, E-cadherin expression is decreasing and P-cadherin expression is increasing with worsening of histologic type and differentiation, increased penetration into the myometrium, spread beyond the uterus and involvement of pelvic lymph nodes; 4) In squamous cell carcinoma of the uterine cervix E-cadherin expression is decreasing with tumor progression and in adenocarcinoma of the uterine cervix P-cadherin expression is increasing with tumor progression. It is hoped that the development of drugs that amend cell-cell adhesion will improve the prognosis of patients in whom tumor progression is associated with decrease or loss of cadherin expression.
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PMID:[Cadherins in malignancies of the female genital tract]. 1588 10

We tested the hypothesis that PTEN inactivation may stratify cancer progression risk among putative endometrial hyperplasias, classified prognostically by means of the morphometric D score (DS). The DS, calculated from 3 morphometric variables measured in routine hematoxylin-eosin-stained endometrial biopsy slides, is the most sensitive and specific method of endometrial cancer risk prediction currently available. Clinical outcomes of 103 women with endometrial hyperplasia on biopsy were tallied according to the DS. Seven (7/103; 7%) patients with carcinoma during follow-up were all distributed within the high-risk prognostic group (ie, DS <1 = endometrial intraepithelial neoplasia [EIN]) (7/21; 33% progression). None of the 82 cases with a DS higher than 1 progressed. All cases that progressed were PTEN null, indicating that this genotype is capable of further stratifying cancer progression risk in hyperplasias irrespective of histological categorization. However, only 16% of the PTEN-null cases progressed. When PTEN expression pattern was combined with EIN, the prognostic power was greatly increased (specificity from 63% for PTEN and 85% for EIN to 93% when combined; positive predictive value from 16% and 33% to 50%). We conclude that loss of PTEN expression is the first biomarker in EIN that increases the accuracy of the prognostic DS to predict cancer progression risk. Unless endometrial hyperplasias are stratified by histological morphometric D-Score, PTEN has a low positive predictive value.
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PMID:Lack of PTEN expression in endometrial intraepithelial neoplasia is correlated with cancer progression. 1594 23

Perlecan is a major heparan sulfate proteoglycan (HPSG) of the basement membrane (BM) and binds to various cytokines and growth factors via its heparan sulfate glycosaminoglycan (HS-GAG) chains. The aim of this study was to investigate BM HS-GAG expression in endometrial cancers. We investigated the expression of BM HS-GAG by immunohistochemistry in 109 endometrial cancers and analyzed correlations with various clinicopathological features. The HS-GAG expression index was significantly lower in cases of advanced stage, high-grade, deep myometrial invasion, positive peritoneal cytology, lymph vascular space invasion and lymph node metastasis. There was no association between HS-GAG expression status and patient outcome. Decreased HS-GAG expression of BM is associated with tumor progression, but is not be a useful prognostic factor in patients presenting with endometrial cancer.
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PMID:Loss of basement membrane heparan sulfate expression is associated with tumor progression in endometrial cancer. 1612 88

Cyclooxygenase-2 (COX-2) plays a critical role not only in maintenance of the endometrium during the menstrual cycle, but also in the progression of endometrial cancer. The role of COX-2 in tumor growth and development is complex and multifaceted. This review presents evidence for the expression of COX-2 being linked to angiogenesis, tumor cell apoptosis, tumor cell growth, metastasis and local immunosuppression in cancer progression. It also outlines the clinicopathological and prognostic significance of COX-2 in endometrial cancer.
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PMID:Multiple roles of cyclooxygenase-2 in endometrial cancer. 1630 26

The interaction between epithelial tumor cells and their surrounding stroma is important in tumor progression and metastasis. This is accomplished through a number of transmembrane receptors that interact with stromal extracellular matrix molecules. One of these receptors, CD44, binds to extracellular matrix component hyaluronic acid (HA). The purpose of this study was to evaluate the significance of HA, CD44s, and CD44v6 in benign, hyperplastic, atypical, and malignant endometrial epithelia. Archival paraffin-embedded cell blocks from proliferative endometrium (n = 11), secretory endometrium (n = 12), simple hyperplasia (n = 13), complex hyperplasia without atypia (n = 9), complex hyperplasia with atypia (n = 17), and adenocarcinoma (n = 21) were stained for HA, CD44s, and CD44v6. HA was detected throughout the normal menstrual cycle but was more intense during the secretory phase. Only during the secretory phase was CD44s expressed in the stromal cells in 11 cases (92%), whereas CD44v6 was detected in glandular epithelium in 9 (75%). CD44s was expressed in the glandular epithelium in 2 (15%) cases of simple hyperplasia, 4 (44%) of complex hyperplasia without atypia, 14 (82%) of complex hyperplasia with atypia, and in 16 (76%) of adenocarcinoma. CD44v6 was expressed in the glandular epithelium in 1 (11%) case of complex hyperplasia without atypia, 17 (100%) cases of complex hyperplasia with atypia, and in 18 (86%) cases of adenocarcinoma, but in none of the cases of simple hyperplasia. The endometrial stromal cells expressed CD44v6 in 1 (8%) case of simple hyperplasia, 6 (67%) of complex hyperplasia without atypia, 8 (47%) of complex hyperplasia with atypia, and in 3 (14%) of adenocarcinoma. We concluded that in the normal menstrual cycle, the timing of peak staining of HA and CD44s in the stroma and the up-regulation of CD44v6 in secretory glands are coincident with the period in which the endometrium is most receptive to embryo implantation. HA is more abundant in the stroma adjacent to the tumor, suggesting that interactions between tumor cells and stromal HA promote tumorigenesis. With progression from hyperplasia and with increasing atypia to adenocarcinoma, levels of stromal HA, glandular CD44v6, and glandular and stromal CD44s all increase. Thus, HA and CD44 are both involved in the development and progression of endometrial cancer.
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PMID:Expression of hyaluronic acid and its receptors, CD44s and CD44v6, in normal, hyperplastic, and neoplastic endometrium. 1630 59

Homeobox genes encode transcription factors that control cell differentiation and play essential roles in developmental patterning. Increasing evidence indicates that many homeobox genes are aberrantly expressed in cancers, and that their deregulation significantly contributes to tumor progression. The homeobox gene HOXA10 controls uterine organogenesis during embryonic development and functional endometrial differentiation in the adult. We investigated whether HOXA10 expression is deregulated in endometrial carcinomas, and how counteracting this aberrant expression modifies tumor behavior. We found that down-regulation of HOXA10 expression in endometrial carcinomas strongly correlates with increased tumor grade and is associated with methylation of the HOXA10 promoter. Enforced expression of HOXA10 in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice. The inhibitory effect of HOXA10 on invasive behavior was attributable at least in part to the ability of HOXA10 to induce expression of the epithelial cell adhesion molecule E-cadherin by down-regulating expression of Snail, a repressor of E-cadherin gene transcription. These findings reveal a novel role for HOXA10 deregulation in the progression of endometrial carcinoma by promoting epithelial-mesenchymal transition.
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PMID:Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial-mesenchymal transition. 1642 22

Early presentation of endometrial cancer permits effective management with excellent clinical outcome. The addition of hysteroscopy to dilatation and curettage (D&C) in the evaluation of postmenopausal bleeding adds little to the detection of malignancy. Imaging studies such as computed tomography, magnetic resonance imaging, and positron-emission tomography may be of use in determining the presence of extrauterine disease in patients medically unfit for surgical staging. However, these studies are not sufficiently sensitive to replace surgical staging and have little role in routine preoperative evaluation. Clinical staging alone is clearly inadequate, as 23% of preoperative clinical stage I/II patients are upstaged with comprehensive surgical staging. Preoperative tumor grade from D&C or office biopsy may be inaccurate and lead to an underestimate of tumor progression if used to determine which patients should be surgically staged. Clinical estimation of depth of invasion, with or without frozen section, is inaccurate and may lead to underestimation of disease status when surgical staging is not performed. The practice of resecting only clinically suspicious nodes should be discouraged as it is no substitute for comprehensive surgical staging. Comprehensive surgical staging provides proper guidance for postoperative adjuvant therapy, avoiding needless radiation in 85% of clinical stage I/II patients. Finally, resection of occult metastasis with surgical staging may improve survival.
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PMID:Surgical staging in endometrial cancer. 1657 93


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