Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2012-06, Vol.11 (11), p.2107-2113
• Main Authors: Shan, Weiwei, Mercado-Uribe, Imelda, Zhang, Jing, Rosen, Daniel, Zhang, Shiwu, Wei, Jianjun, Liu, Jinsong
• Format: Article
• Language: English
• Subjects: Adenocarcinoma, Mucinous - genetics; Adenocarcinoma, Mucinous - metabolism; Adenocarcinoma, Mucinous - pathology; Animals; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - metabolism; Binding; Biology; Bioscience; Calcium; Cancer; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma, Ovarian Epithelial; Cell; Cell Line, Transformed; Cell Transformation, Neoplastic; Cycle; Epithelial Cells - cytology; Epithelial Cells - metabolism; fallopian tube epithelial cells; Fallopian Tubes - cytology; Female; Humans; Immunohistochemistry; Keratins - metabolism; Landes; Mice; Mice, Nude; mucinous adenocarcinoma; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; oncogene; Organogenesis; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Paired Box Transcription Factors - metabolism; PAX8 Transcription Factor; Proteins; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; retrovirus; Telomerase - genetics; Telomerase - metabolism; transformation
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.20544

Recent studies have suggested that some ovarian and pelvic serous carcinomas could originate from the fimbriated end of the distal fallopian tube. To test this hypothesis, we immortalized a normal human fallopian tube epithelial (FTE) cell line by using retrovirus-mediated overexpression of the early region of the SV40 T/t antigens and the human telomerase reverse transcriptase subunit (hTERT). These immortalized FTEs were then transformed by ectopic expression of oncogenic human HRAS V12 . Tumorigenicity of the immortalized and/or transformed cells was subsequently tested by anchorage-independence growth assay and inoculation into nude mice via subcutaneous and intraperitoneal injection. As expected, the HRAS V12 -transformed FTEs produced tumors through both subcutaneous and intraperitoneal injections, whereas no tumor growth was observed in immortalized FTEs. Unexpectedly, histopathological examination of tumors resulting from subcutaneous as well as intraperitoneal injections revealed largely poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma. The tumor implants invaded extensively to the liver, colon, spleen, omentum, adrenal gland and renal capsule. Immunohistochemical staining of tumor cells showed positive staining for the epithelial cell markers cytokeratin AE1/AE3 and Müllerian lineage marker PAX8. Our study demonstrates that FTEs can generate poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma through genetic modifications. Thus, we provide the first experimental evidence that fimbrial epithelial cells of the fallopian tube could be a potential source of ovarian mucinous adenocarcinoma.