Tumorigenesis Of Endometrial Cancer Research Articles

Abstract 1430: Activation of WNT pathway in endometrial cancer stromal fibroblasts

Abstract The dynamic interactions between tumor cells and their corresponding microenvironment play an important role in carcinogenesis. Fibroblasts are a dominant feature within a tumor stroma and have undergone a “reprogramming” to become cancer-activated fibroblasts (CAFs). In our study we established primary cell cultures of fibroblasts from matched pairs of normal human endometrium and endometrial cancer tissues and analyzed the differential expressions of mRNA and microRNA. We found that the WNT pathway was activated in CAFs and confirmed these results via Topflash luciferase reporter assays. Wingless-type (WNT) proteins are a highly conserved family of secreted glycoproteins that have been implicated in the carcinogenesis of many cancers. We demonstrated that one of the reasons for this WNT pathway activation was the methylation-dependent silencing of the secreted frizzled-related protein 4 (SFRP4), an antagonist to the WNT signaling pathway. An additional reason for WNT pathway activation was found in the microRNA analysis. These experiments showed downregulation of miR-148a, which is a predicted regulator of the founder member of the WNT family, WNT1. We observed that CAFs have increased WNT1 protein expression in three of the five endometrial cancer CAFs. We confirmed that miR-148a directly targets WNT1 by cloning the WNT1 3'UTR into a luciferase reporter construct and showed that co-transfection with miR-148a results in a decrease of luciferase activity. When mutations to the miR-148a binding sites were introduced into the same luciferase reporter construct, the downregulation of luciferase activity by miR-148a was prevented. We conclude that the observed activation of the WNT pathway in endometrial cancer CAFs may be regulated by the miR-148a and contribute to the progression of the endometrial cancer tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1430.

Proteomics Reveals Protein Profile Changes in Cyclooxygenase-2 Inhibitor-Treated Endometrial Cancer Cells

To examine effects of an inhibitor of cyclooxygenase (COX)-2, NS-398, on the proliferation, apoptosis and invasion characteristics of endometrial cancer cell RL95-2. (1) Western blotting was carried out to determine COX-2 protein expression in RL95-2 cells and normal endometrium specimens. (2) The effect of NS-398 treatment on the cell proliferation, apoptosis, and invasion was assessed by methyl thiazolyl tetrazolium assay, flow cytometry, and matrigel invasion assay, respectively. (3) Finally, the proteomic analysis was used to find out proteins that are differentially expressed because of NS-398 treatment. (1) COX-2 protein in RL95-2 cell line was significantly higher than that in normal endometrium. (2) NS-398 had significant growth inhibition effects on RL95-2 cells in a dose- and time-dependent manner. (3) NS-398 increased the proportion of cells in G1 and decreased the proportion of cells in the G2 phase in RL95-2 cells. (4) NS-398 could restrain endometrial cancer cells invasion. (5) The proteomic analysis revealed several proteins that are differentially expressed because of NS-398 treatment; the down-regulated proteins identified are hnRNP K, alpha enolase, Hsp70, tropomyosin, and protein disulfide isomerase, the up-regulated protein is phosphatidylethanolamine binding protein. The expression of COX-2 plays an important role in tumorigenesis of endometrial cancer. NS-398 can inhibit the ability of RL95-2 cell proliferation, viability, and invasion. In this study, the well-resolved reproducible 2-DE maps of NS-398 treated and control RL95-2 cells were established, and the significantly different expressed proteins are preliminary identified.

Edi-3, a new independent prognostic factor in ovarian cancer

10585 Background: Recently, we have identified for the first time a new putative phosphodiesterase named edi-3 that correlates with tumorigenesis in endometrial cancer. In the present study we analyzed the prognostic relevance of edi-3 in ovarian cancer. Methods: Edi-3 mRNA expression was measured by quantitative RT-PCR (TaqMan) in 62 patients with primary ovarian cancer. All patients signed informed consent, approved by the Clinical Review Board and Ethics Committee of the Medical University Berlin, Charité, Germany. The tumor specimens were collected according to the Tumor Bank Ovarian Cancer standard operating procedures. A validated systematic intraoperative documentation tool was used for the detailed documentation of all surgical procedures. Using the multivariate proportional hazard model we analyzed whether edi-3 predicts survival independent from FIGO-stage, grading, postoperative residual disease and histological type. Results: Edi-3 expression is associated with survival in the univariate Cox model (hazards ratio [HR]: 1.488, 95% confidence interval [CI]: 1.131 - 1.959, P=0.005). Interestingly, edi-3 was also predictive in the multivariate proportional hazard model adjusted for the conventional clinical factors (HR: 1.521, CI: 1.107 - 2.090, P=0.010). Conclusions: Edi-3 is a new independent prognostic factor in primary ovarian cancer with HR=1.5 (P=0.010). Its function, a possible role in inositol phosphate metabolism, will be further explored in a multi-instutional setting. No significant financial relationships to disclose.

Lymphotoxin-α polymorphisms and the risk of endometrial cancer in Japanese subjects

To test the association of endometrial cancer with the lymphotoxin-alpha (LTalpha) C804A and A252G polymorphisms, a hospital-based incident case-control study was performed in Japanese subjects. The cases comprised 110 endometrial cancer patients, and the controls were 220 age-matched cancer-free females. The LTalpha C804A and A252G polymorphisms were in complete linkage disequilibrium. We performed conditional logistic regression analysis adjusted for age, which revealed that the LTalpha 252AG and 804CA variant genotypes were associated with a significantly reduced risk of endometrial cancer (OR=0.51, 95% CI=0.31-0.86, P=0.011). Being homozygous of the LTalpha 252G and 804A alleles was not associated with the risk of endometrial cancer. However, the presence of at least one variant LTalpha allele was associated with a significantly lower risk of endometrial cancer (OR=0.54, 95% CI=0.33-0.87, P=0.012). After adjusting for potential confounders (body mass index, age at menarche, parity, hypertension, diabetes mellitus, family history of endometrial cancer, hormone replacement therapy, smoking status, and alcohol consumption), the risk of endometrial cancer was significantly lower both in carriers of one variant allele and in carriers of either one or two of the variant alleles (OR=0.47, 95% CI=0.26-0.85, P=0.017; OR=0.50, 95% CI=0.28-0.89, P=0.019; respectively). The results suggest that these LTalpha polymorphisms play an important role in the tumorigenesis of endometrial cancer.

Immunohistochemical Expression of Thymidine Phosphorylase in Human Endometrial Cancer

Objective.To investigate correlations between the expression of thymidine phosphorylase (TP) by endometrial cancer cells and the density of microvessels within the tumor, the clinicopathologic features, and the prognosis.Methods.We examined tumor specimens obtained from 46 patients with endometrial cancer (9 FIGO stage IA, 16 stage IB, 8 stage IC, 1 stage IIA, 6 stage IIB, and 6 stage IIIC). The cellular expression of TP and the intratumoral density of microvessels were determined by immunohistochemistry using monoclonal antibodies to TP and factor VIII-related antigen, respectively. We investigated the relationship between the cellular expression of TP and the following factors: clinicopathologic features (menopausal status, histologic type, tumor size, histologic grade, myometrial invasion, cervical invasion, and metastasis), the microvessel count, and the disease-free survival period.Results.Of the 46 tumors, 19 (41%) were TP-positive. The microvessel count was significantly higher in TP-positive tumors than in TP-negative tumors (P= 0.01, Mann–WhitneyUtest). There was no significant correlation between TP expression and clinicopathologic features, and there was no significant difference in the disease-free survival period between patients with TP-positive tumors and patients with TP-negative tumors.Conclusion.TP expression was not correlated with clinicopathologic features or prognosis, but was associated with an increased density of microvessels in endometrial cancer. These findings suggest that TP may play an important role in angiogenesis and may be involved in the tumorigenesis of endometrial cancer.