Cytokeratin 5-Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer.
OBJECTIVE
Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)(+) breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5(+) cell populations to cisplatin therapy.


METHODS
Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC(50) (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5(+) cells pretreatment and posttreatment was determined. Proliferation of CK5(+) versus CK5(-) cell populations was determined using 5-bromo-2'-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5(+) versus CK5(-) cells was measured using immunohistochemical staining for cleaved caspase-3.


RESULTS
Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5(+) specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5(+) tumors were also ER(+)). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER(+) epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5(+) compared with CK5(-) cells were slower proliferating. The prevalence of CK5(+) cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5(+) ovarian cancer cells compared with CK5(-) ovarian cancer cells were more resistant to cisplatin-induced apoptosis.


CONCLUSIONS
Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.
*Departments of Obstetrics and Gynecology and †Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO; and ‡Texas Oncology, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX.
Bradley R
BR
Corr
Jessica
J
Finlay-Schultz
Rachel B
RB
Rosen
Lubna
L
Qamar
Miriam D
MD
Post
Kian
K
Behbakht
Monique A
MA
Spillman
Carol A
CA
Sartorius
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053555:Keratin-5 / Q000032:analysis*; D009375:Neoplasms, Glandular and Epithelial / Q000737:chemistry* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000473:pathology; D011960:Receptors, Estrogen / Q000032:analysis; D046888:Tissue Array Analysis
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D053555:Keratin-5; D011960:Receptors, Estrogen; D002945:Cisplatin