This study evaluated the clinical significance of endometrial cells in Papanicolaou test (Pap test). A retrospective study was performed from the cytological database of Seoul National University Hospital. The results of Pap tests of women aged 40 years or older between January 1998 and December 2007 were sorted. Medical records were reviewed to identify the presence of endometrial cells from cytology, and cytologic and histologic follow-ups were performed to determine the clinical significance of the lesions. Among 75,673 Pap cases, 832 cases presenting normal endometrial cells (nEMCs) were included in this study. Their follow-up data are as follows: 800 with nEMCs, 5 with atypical EMCs (aEMCs), and 27 with endometrial cancer cells (EMCCs) on cytologic and histologic follow-ups. Significant endometrial or cervical diseases were found in 0.5%, 40%, and 100% of the cases on the following-up the pathologic examination of the women with nEMCs, aEMCs, and EMCCs, respectively. Unlike aEMCs and EMCCs, nEMCs on Pap tests did not increase the risk of developing endometrial hyperplasia or endometrial cancer in women aged 40 years or older. There is no clinical benefit to perform routine endometrial work-up in women with nEMCs, as recommended in the 2001 Bethesda System. However, symptomatic women with nEMCs on Pap test should perform endometrial work-up regardless of menopausal status.
E-cadherin complexes with the actin cytoskeleton via cytoplasmic catenins and maintains the functional characteristics and integrity of the epithelia in normal epithelial tissues. Lost expression of E-cadherin disrupts this complex resulting in loss of cell polarity, epithelial denudation and increased epithelial permeability in a variety of tissues. Decreased expression of E-cadherin has also been observed in invasive and metastatic human tumors. In this study, we investigated the effect of E-cadherin loss in prostatic epithelium using newly developed genetically engineered mouse models. Deletion of E-cadherin in prostatic luminal epithelial cells with modified probasin promoter driven Cre (PB-Cre4) induced the development of mouse prostatic intraepithelial neoplasia (PIN). An increase in levels of cytoplasmic and nuclear β-catenin appeared in E-cadherin deleted atypical cells within PIN lesions. Using various experimental approaches, we further demonstrated that the knockdown of E-cadherin expression elevated free cytoplasmic and nuclear β-catenin and enhanced androgen-induced transcription and cell growth. Intriguingly, pathological changes representing prostatic epithelial cell denudation and increased apoptosis accompanied the above PIN lesions. The essential role of E-cadherin in maintaining prostatic epithelial integrity and organization was further demonstrated using organoid culture approaches. To directly assess the role of loss of E-cadherin in prostate tumor progression, we generated a new mouse model with bigenic Cdh1 and Pten deletion in prostate epithelium. Early onset, aggressive tumor phenotypes presented in the compound mice. Strikingly, goblet cell metaplasia was observed, intermixed within prostatic tumor lesions of the compound mice. This study provides multiple lines of novel evidence demonstrating a comprehensive role of E-cadherin in maintaining epithelial integrity during the course of prostate oncogenic transformation, tumor initiation and progression.
Abstract Background: Aurora kinases (AK) constitute one family of seine/threonine kinases, whose activity is essential for mitotic progression. Expression of aurora kinase is greatest in G2-M phase, and their function includes spindle formation, centrosome maturation, chromosomal segregation, and cytokinesis. Over-expression of AK is related to aneuploidy and carcinogenesis. Herein, we investigated the in vitro and in vivo anticancer acvitivity of a novel AK inhibitor, VX-680 in gastric cancer. Methods: AK protein expression and kinase activity were screened in gastric cancer cell lines using immunoblot and in vitro kinase assay, respectively. The anti-proliferative activity of VX-680 was measured using MTT assay. The changes of cell cycle by the treatment of VX-680 were analyzed by flow cytometry. YCC-16 cell line selected for tumor xenograft models. In vivo activity validation using mouse xenograft models and extract protein or tissue slide from each tumors. Results: AK protein expression and its kinase activity were variable among cell lines. VX-680 showed anti-proliferative effect in vitro on a wide range of gastric cancer cell lines, and calculating the IC50 value, it was distributed from 0.04uM to 19.87uM. It was correlated with kinase activity, not with protein expression of AK. VX-680 induced the reduction of phosphor-histone H3 and the cell cycle defects that accumulated >4N DNA. In vivo experiment, confirmed that AKI had an effect on tumor inhibition. Solid tumor formed with YCC-16 cell lines and VX-680 was injected twice a day for 5 days with a dose of 50mg/kg. Estimating the tumor volume for 21 days after VX-680 injection, the difference in tumor volume between the control and the treated mice were statistically significant. Kinase activity and phospho-histone H3 in VX-680 treated tumor was reduced in drug treatment samples compared to the control samples. Conclusion: We demonstrated that VX-680 has anti-cancer activity in gastric cancer. Kinase activity of AK might be a predictor for sensitivity of VX-680. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C77.
Abstract ADAM (A Disintegrin and Metalloproteinase)-9 is a cell-surface membrane glycoprotein, which enables diverse roles in a wide range of cellular process. Over-expression of ADAM-9 has been reported in several cancers but its biological role remained to be clarified in gastric cancer. Herein, we investigated the possible involvement of ADAM-9 related to invasion and metastasis in gastric cancer. We also evaluated its possibility as a therapeutic target for anti-metastasis treatment. We examined transcription and expression pattern of ADAM-9 in 24 gastric cancer cell lines. ADAM-9 protease activity was measured using fluoregenic ADAM-9 substrate (R&D systems). We conducted trans-well assay coated with matrigel to associate ADAM-9 expression with invasion activity. A specific anti-ADAM-9 monoclonal antibody (RAV-18, Macrogenics, Inc.) was used to evaluate its anti-invasion property. And then, to evaluate the ADAM-9 protease activity in vivo, MKN-28, one of high ADAM-9 cell lines, was subcutaneously inoculated in flank of mice. The IP of mice were injected with or without RAV-18. The protein expression and protease activity of ADAM-9 was various by each cell line. The protease activities were moderately correlated with the protein expressions (mature form) (R2 = 0.49). ADAM-9 protease activity was decreased dose-dependently on RAV-18 treatment, being remarkable in the cells of high ADAM-9 expression (SNU-638, YCC-1, MKN-74 and MKN-28) compared with low expressing cells (YCC-6, YCC-7 and HS-746T). Baseline level of invasiveness was poorly correlated with ADAM-9 expression, but in high ADAM-9 cells, the administration of RAV-18 significantly suppressed invasiveness, while not in low ADAM-9 cells. Exposure to hypoxia (1% O2, 5% CO2, 37°C) up-regulated protease activity and invasiveness in low ADAM-9 cells, and these were suppressed dose-dependently by the treatment of RAV-18. RAV-18 inhibited ERK phosphorylation in high ADAM-9 cells, which suggests that that ADAM-9-related invasiveness depends on its protease activity and it is, at least partially, via MAPK pathway. In vivo, the tumor volume of mice of RAV-18 treated group (n=7) was smaller than control group (n=7). As in vitro results, EGFR and Erk phosphorylation were reduced in RAV-18 treated group than control group. This study shows that ADAM-9 is upregulated in gastric cancer, and that ADAM-9 might be a plausible target for therapeutic inhibition of invasion/metastatic process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C43.
Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. Whereas up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional Met transgenic mouse strain, H11Met/+:PB-Cre4, to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred H11Met/+/PtenLoxP/LoxP:PBCre4 compound mice, in which transgenic Met expression and deletion of the tumor suppressor gene Pten occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with PtenLoxP/LoxP:PB-Cre4 mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from H11Met/+/PtenLoxP/LoxP:PB-Cre4 compound mice compared with those from PtenLoxP/LoxP:PB-Cre4 littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both Met transgene expression and Pten deletion compared with Pten-null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors.
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