Increased epithelial stem cell traits in advanced endometrial endometrioid carcinoma

Abstract

BackgroundIt has been recognized cancer cells acquire characters reminiscent of those of normal stem cells, and the degree of stem cell gene expression correlates with patient prognosis. Lgr5(+) or CD133(+) epithelial stem cells (EpiSCs) have recently been identified and these cells are susceptible to neoplastic transformation. It is unclear, however, whether genes enriched in EpiSCs also contribute in tumor malignancy. Endometrial endometrioid carcinoma (EEC) is a dominant type of the endometrial cancers and is still among the most common female cancers. Clinically endometrial carcinoma is classified into 4 FIGO stages by the degree of tumor invasion and metastasis, and the survival rate is low in patients with higher stages of tumors. Identifying genes shared between advanced tumors and stem cells will not only unmask the mechanisms of tumor malignancy but also provide novel therapeutic targets.ResultsTo identify EpiSC genes in late (stages III-IV) EECs, a molecular signature distinguishing early (stages I-II) and late EECs was first identified to delineate late EECs at the genomics level. ERBB2 and CCR1 were genes activated in late EECs, while APBA2 (MINT2) and CDK inhibitor p16 tumor suppressors in early EECs. MAPK pathway was significantly up in late EECs, indicating drugs targeting this canonical pathway might be useful for treating advanced EECs. A six-gene mini-signature was further identified to differentiate early from advanced EECs in both the training and testing datasets. Advanced, invasive EECs possessed a clear EpiSC gene expression pattern, explaining partly why these tumors are more malignant.ConclusionsOur work provides new insights into the pathogenesis of EECs and reveals a previously unknown link between adult stem cells and the histopathological traits of EECs. Shared EpiSC genes in late EECs may contribute to the stem cell-like phenotypes shown by advanced tumors and hold the potential of being candidate therapeutic targets and novel prognosis biomarkers.

EGFR isoforms and gene regulation in human endometrial cancer cells

“…Also at 12 h of gefitinib treatment, APBA2 and RSP2, previously found to be highly expressed in endometrial carcinomas [36] and prostate cancer [37], respectively, were inhibited. However, by 24 h treatment (Additional File 10, Figure S9), Hec50co cells demonstrated a transcriptional response that may be compensatory to the anti-proliferative effects of gefitinib in that some genes associated with malignant transformation and tumor progression were induced.…”

Integrated genomics has identified a new AT/RT-like yet INI1-positive brain tumor subtype among primary pediatric embryonal tumors

“…It is clear that cancer cells possess traits that are reminiscent of those ascribed to normal stem cells and that the degree of stem cell gene expression correlates with patient prognosis. Histologically poorly differentiated tumors or late-stage tumors show preferential overexpression of genes that are normally enriched in ES cells (ESCs) or in somatic stem cells, which may partly explain why these tumors are more malignant [ 22 , 23 ]. We hypothesized that the distinct clinical survival trends of different PEBTs might be reflected by their gene expression traits.…”

Clinical translation for endometrial cancer stem cells hypothesis

“…The stem cell genes expression was correlated with tumor prognosis in endometrial cancer. Advanced endometrioid tumors had a positive association with epithelial stem cells (EpiSCs) genes [62] Some of the stemness genes included in this signature were ADAM17 (A Disintegrin and A Metalloproteinase 17), CAP1 (adenylate cyclase-associated protein 1), PDCD10 (CCM3), PSEN1 (presenilin 1) and SENP2 (SUMO-specific protease 2) [62].…”

“…Chang et al studied a signature of EpiSC genes and found a total of 26 genes overexpressed in advanced endometrioid tumors [62]. The CD133+ cells were isolated from endometrial tumors by flow cytometry, representing an average of 18.1 % (1.3 to 61.6 %) [79] The staining of CD133/1 antibody was diffuse and the epithelial tumor cells expressed Tn-MUC1 glycoform.…”