Evidence for cancer stem cells in human endometrial carcinoma.
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 10(6)-1 x 10(4) cells) generated tumors in 8 of 9 samples with morphologies similar to the parent tumors. These tumors recapitulated cytokeratin, vimentin, estrogen receptor-alpha, 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.
Departments of Obstetrics and Gynaecology and Anatomical Pathology, Centre for Women's Health Research, Monash Institute of Medical Research and Monash University, Clayton, Victoria, Australia.
Sonya A
SA
Hubbard
Anne M
AM
Friel
Beena
B
Kumar
Ling
L
Zhang
Bo R
BR
Rueda
Caroline E
CE
Gargett
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D003114:Colony-Forming Units Assay; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000302:isolation & purification; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D012334:RNA, Neoplasm