Increased epithelial stem cell traits in advanced endometrial endometrioid carcinoma.
BACKGROUND
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. 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.


RESULTS
To 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.


CONCLUSIONS
Our 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.
Chang
Shing-Jyh
SJ
Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu, Taiwan. justine3@ms8.hinet.net
Wang
Tao-Yeuan
TY
Tsai
Chan-Yen
CY
Hu
Tzu-Fang
TF
Chang
Margaret Dah-Tsyr
MD
Wang
Hsei-Wei
HW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics; D018269:Carcinoma, Endometrioid / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D019295:Computational Biology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D054389:Receptors, CCR1 / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
D015820:Cadherins; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009419:Nerve Tissue Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D054389:Receptors, CCR1; C491636:APBA2 protein, human; C515300:CCR1 protein, human; C508053:ERBB2 protein, human