Models representing type I and type II human endometrial cancers: Ishikawa H and Hec50co cells

Albitar, Lina; Pickett, Gavin; Morgan, Marilee; Davies, Suzy; Leslie, Kimberly K.

doi:10.1016/j.ygyno.2007.02.033

Cited by 54 publications

(81 citation statements)

References 26 publications

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“…The cells can form a serous phenotype in mice and are a good model of type II endometrial cancers. 24 We tested three shRNAs designed to knock down ZEB1. In preliminary studies using real-time RT-PCR, one of the three, shRNAmir G10, reduced ZEB1 RNA levels by approximately 47% (Figure 6a).…”

Section: Zeb1 In Endometrial Cancermentioning

confidence: 99%

ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease

et al. 2008

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Zinc-finger E-box-binding homeobox 1 (ZEB1) is a transcription factor containing two clusters of Kruppel-type zinc-fingers, by which it binds E-box-like sequences on target DNAs. A role for ZEB1 in tumor progression, specifically, epithelial to mesenchymal transitions, has recently been revealed. ZEB1 acts as a master repressor of E-cadherin and other epithelial markers. We previously demonstrated that ZEB1 is confined to the stromal compartment in normal endometrium and low-grade endometrial cancers. Here, we quantify ZEB1 protein expression in endometrial samples from 88 patients and confirm that it is expressed at significantly higher levels in the tumor-associated stroma of low-grade endometrioid adenocarcinomas (type I endometrial cancers) compared to hyperplastic or normal endometrium. In addition, as we previously reported, ZEB1 is aberrantly expressed in the epithelial-derived tumor cells of highly aggressive endometrial cancers, such as FIGO grade 3 endometrioid adenocarcinomas, uterine serous carcinomas, and malignant mixed Mü llerian tumors (classified as type II endometrial cancers). We now demonstrate, in both human endometrial cancer specimens and cell lines, that when ZEB1 is inappropriately expressed in epithelial-derived tumor cells, E-cadherin expression is repressed, and that this inverse relationship correlates with increased migratory and invasive potential. Forced expression of ZEB1 in the nonmigratory, low-grade, relatively differentiated Ishikawa cell line renders them migratory. Conversely, reduction of ZEB1 in a highly migratory and aggressive type II cell line, Hec50co, results in reduced migratory capacity. Thus, ZEB1 may be a biomarker of aggressive endometrial cancers at high risk of recurrence. It may help identify women who would most benefit from chemotherapy. Furthermore, if expression of ZEB1 in type II endometrial cancers could be reversed, it might be exploited as therapy for these highly aggressive tumors.

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Section: Zeb1 In Endometrial Cancermentioning

confidence: 99%

ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease

et al. 2008

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“…An endometrial cancer cell line, Hec50co (CO) cell, was reported to have a papillary serous morphology in vivo and with a p53 null mutation (15,16). We have shown that AMF and PTX have a synergistic effect on CO cell growth in in vitro and in vivo (12).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, AMF can protect mouse red blood cells and white blood cells from side effects of PTX (12). However, these studies were conducted with an endometrial cancer cell line, Hec50co cells, which contain a TP53 null mutation (15). Additionally, previous in vivo studies were conducted in xenografts created from Hec50co cells.…”

Section: Discussionmentioning

confidence: 99%

“…While these studies did suggest that AMF enhances paclitaxel's therapeutic effect in cancer cells, it was not clear if their synergistic effect was dependent upon the cell line we used or related to the subtype of endometrial cancer and TP53 status. In order to investigate the underlying mechanism for the synergy between AMF and PTX, we created a p53 protein knockdown cell from Ishikawa H cell, which represents type I endometrial cancer and is believed to have a functional p53 protein (14,15).…”

Section: Discussionmentioning

confidence: 99%

“…Ishikawa-H cell (H) has been used in previous studies (13)(14)(15). They are maintained in DMEM with 10% FBS in 95% O 2 and 5% CO 2 at 37˚C.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent

Luo

Wu²,

Elmaoued³

et al. 2010

Int J Oncol

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Abstract. Endometrial cancer (ECa) is the fourth most common malignancy in women. Currently, there is no effective therapy for advanced and recurrent cancer. Among the pooroutcome endometrial cancers, there is a high frequency of TP53 mutations. We have previously reported that amifostine has a direct anti-cancer effect and has a significant synergistic effect with paclitaxel when used in endometrial cancer cell and xenograft models. In this report, using a cell line with knock-down p53 expression through siRNA, we found that amifostine enhancement of paclitaxel's anticancer effect is p53 status-dependent. Amifostine promotes entry into the G2-M phase through regulation of cyclin-dependent kinase-1 activity in cells with dysfunctional p53, thereby enhancing cancer cell sensitivity to paclitaxel. The synergistic effect between amifostine and paclitaxel was further confirmed in vivo using xenografts created with primary patient tumor tissue. Sensitivity to the therapeutic effect of paclitaxel in combination with amifostine was dependent upon the status of p53. A tumor with a nonsense TP53 mutation showed increased therapeutic response to paclitaxel and amifostine as measured by tumor weight compared to a tumor with wildtype TP53. Our study provides a rationale for a clinical trial of combined paclitaxel and amifostine in endometrial cancer patients whose tumors harbor TP53 mutations.

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Protein kinase C alpha‐dependent signaling mediates endometrial cancer cell growth and tumorigenesis

Haughian

Reno

Thorne

et al. 2009

Intl Journal of Cancer

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Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCa, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCa protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCa knockdown increased levels of the cyclin-dependent kinase (CDK) inhibitors p21 Cip1/WAF1 (p21) and p27 Kip1 (p27). Despite the absence of functional phosphatase and tensin homolog (PTEN) protein in Ishikawa cells, PKCa knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3b (GSK-3b). PKCa knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting that PKCa regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCa expression, with foci of elevated PKCa staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCa signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK-dependent proliferative pathways. Thus, targeting PKCa may provide novel therapeutic options in endometrial tumors. ' 2009 UICC

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Models representing type I and type II human endometrial cancers: Ishikawa H and Hec50co cells

Cited by 54 publications

References 26 publications

ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease

ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease

Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent

Protein kinase C alpha‐dependent signaling mediates endometrial cancer cell growth and tumorigenesis

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