A genetically defined model for human ovarian cancer.
Disruptions of the p53, retinoblastoma (Rb), and RAS signaling pathways and activation of human telomerase reverse transcriptase (hTERT) are common in human ovarian cancer; however, their precise role in ovarian cancer development is not clear. We thus introduced the catalytic subunit of hTERT, the SV40 early genomic region, and the oncogenic alleles of human HRAS or KRAS into human ovarian surface epithelial cells and examined the phenotype and gene expression profile of those cells. Disruption of p53 and Rb pathway by SV40 early genomic region and hTERT immortalized but did not transform the cells. Introduction of HRAS(V12) or KRAS(V12) into the immortalized cells, however, allowed them to form s.c. tumors after injection into immunocompromised mice. Peritoneal injection of the transformed cells produced undifferentiated carcinoma or malignant mixed Mullerian tumor and developed ascites; the tumor cells are focally positive for CA125 and mesothelin. Gene expression profile analysis of transformed cells revealed elevated expression of several cytokines, including interleukin (IL)-1beta, IL-6, and IL-8, that are up-regulated by the nuclear factor-kappaB pathway, which is known to contribute to the tumor growth of naturally ovarian cancer cells. Incubation with antibodies to IL-1beta or IL-8 led to apoptosis in the ras-transformed cells and ovarian cancer cells but not in immortalized cells that had not been transformed. Thus, the transformed human ovarian surface epithelial cells recapitulated many features of natural ovarian cancer including a subtype of ovarian cancer histology, formation of ascites, CA125 expression, and nuclear factor-kappaB-mediated cytokine activation. These cells provide a novel model system to study human ovarian cancer.
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jliu@mdanderson.org
Jinsong
J
Liu
Gong
G
Yang
Jennifer A
JA
Thompson-Lanza
Armand
A
Glassman
Kimberly
K
Hayes
Andrea
A
Patterson
Rebecca T
RT
Marquez
Nelly
N
Auersperg
Yinhua
Y
Yu
William C
WC
Hahn
Gordon B
GB
Mills
Robert C
RC
Bast
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras; D006801:Humans; D000090204:Mesothelin; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000235:genetics; D019098:Telomerase / Q000235:genetics
D000952:Antigens, Polyomavirus Transforming; D016207:Cytokines; D004268:DNA-Binding Proteins; C000715528:Msln protein, mouse; D016328:NF-kappa B; D019098:Telomerase; D000090204:Mesothelin