PTEN loss in the fallopian tube induces hyperplasia and ovarian tumor formation.

Abstract

The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of human ovarian pathogenesis. To uncover the mechanism underlying the invasion of cancerous oviductal cells to the ovary, PTEN-deficient murine oviductal cells were developed and tagged with green fluorescent protein. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin independent manner. Human tumor microarrays and ovarian cancer cells lines confirmed WNT4 expression in cancer and its role in migration. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.

• Authors: Angela Russo, Austin A Czarnecki, Matthew Dean, Dimple A Modi, Daniel D Lantvit, Laura Hardy, Seth Baligod, David A Davis, Jian-Jun Wei, Joanna E Burdette
• Journal: Oncogene (Oncogene) Vol. 37 Issue 15 Pg. 1976-1990 (04 2018) ISSN: 1476-5594 [Electronic] England
• PMID: 29367766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Wnt4 Protein
• PTEN Phosphohydrolase
• PTEN protein, human
• Pten protein, mouse

Topics

• Animals
• Carcinogenesis (genetics)
• Cell Movement (genetics)
• Cells, Cultured
• Cystadenocarcinoma, Serous (genetics, pathology)
• Fallopian Tubes (metabolism, pathology)
• Female
• Gene Deletion
• Humans
• Hyperplasia (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasm Invasiveness
• Ovarian Neoplasms (genetics, pathology)
• PTEN Phosphohydrolase (genetics)
• Tissue Array Analysis
• Wnt4 Protein (genetics, metabolism)