This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-4808v1 69/21/8241    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hubbard, S. A. Articles by Gargett, C. E. PubMed PubMed Citation Articles by Hubbard, S. A. Articles by Gargett, C. E.

Evidence for Cancer Stem Cells in Human Endometrial Carcinoma

¹ Centre for Women's Health Research, Monash Institute of Medical Research and Monash University Departments of Obstetrics and Gynaecology and ² Anatomical Pathology, Monash Medical Centre, Clayton, Victoria, Australia and ³ Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, Massachusetts

Requests for reprints: Caroline E. Gargett, Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: 61-3-9594-5392; Fax: 61-3-9594-6389; E-mail: Caroline.Gargett{at}med.monash.edu.au.

Emerging evidence indicates that the highly regenerative human endometrium harbors rare populations of epithelial progenitor cells. In tumors of other regenerative epithelial tissues, rare cancer stem cells (CSC) have been identified that may have originated from normal epithelial stem/progenitor cells. We hypothesized that CSC are responsible for epithelial neoplasia associated with endometrial carcinoma, the most common gynecologic malignancy in women. Stem cell characteristics of single cells isolated from endometrial carcinoma tissues from women ages 62 ± 11.8 years (n = 34) were assessed. Twenty-five of 28 endometrial carcinoma samples contained a small population of clonogenic cells [0.24% (0-1.84%)], with no significant difference in cloning efficiency between the three grades of endometrial carcinoma or between endometrial carcinoma and normal endometrial epithelial samples. Isolated endometrial carcinoma cells transplanted under the kidney capsule of immunocompromised mice in serial dilution (2 x 10⁶-1 x 10⁴ cells) generated tumors in 8 of 9 samples with morphologies similar to the parent tumors. These tumors recapitulated cytokeratin, vimentin, estrogen receptor-, and progesterone receptor expression of the parent tumor, indicating that tumor-initiating cells likely differentiated into cells comprising the endometrial carcinoma tissue. Individual clones underwent serial clonal subculture 2.5 to 4 times, with a trend of increasing number of subclonings with increasing tumor grade, indicating increasing self-renewal with greater malignancy. Clonally derived endometrial carcinoma cells also expressed the self-renewal genes BMI-1, NANOG, and SOX-2. Isolated cells from primary tumors were serially transplanted 3 to 5 times in nonobese diabetic/severe combined immunodeficient mice, showing self-renewal in vivo. This evidence of cells with clonogenic, self-renewing, differentiating, and tumorigenic properties suggests that a CSC population may be responsible for production of endometrial carcinoma tumor cells. [Cancer Res 2009;69(21):8241–8]

Key Words: Endometrial cancer • Cancer stem cells • Tumor-initiating cells • Human