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.
Highlights
It 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
We searched for genes distinguishing early and late endometrioid carcinoma (EEC) according to a statistical pipeline we used [21,22]
Here we reveal distinct epithelial stem cell traits and gene expression patterns in late EECs and some of these genes hold the potential of being novel drug targets
Summary
It 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. Glioblastomas possess characters and gene expression patterns of local neural stem cells (NSCs) [5], and artificially introducing cancer-associated mutations into stem or lineage-restricted precursor cells can turn them into cancer initiating cells and all mice received mutations developed medulloblastomas [6,7]. Another example that the adult stem cell represents the cell of origin of cancer has recently been made in chronic myeloid leukemia (CML): by restricting BCR-ABLp210 expression to mouse Sca1(+) hematopoietic stem cells, it is sufficient to induce CML formation that recapitulates the human disease [8]. These evidences support the idea that mutations of stem cells may initiate the carcinogenic process of certain, not necessary all, tumors
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