The differential role of L1 in ovarian carcinoma and normal ovarian surface epithelium.
Epithelial ovarian carcinoma (EOC) arises from the ovarian surface epithelium (OSE), a monolayer of poorly differentiated epithelial cells that lines the ovary. The molecular mechanisms underlying EOC invasion into the surrounding stroma and dissemination to the peritoneum and to retroperitoneal lymph nodes are still unclear. Here, we analyzed the expression and the functional role of the cell adhesion molecule L1 during EOC development. In patient-derived samples, L1 was expressed both in OSE and in a subset of EOC, in the latter being mostly restricted to the invasive areas of the tumors. The expression of L1 correlated significantly with poor outcome and with unfavorable clinicopathologic features of the disease. The peculiar expression pattern of L1 in normal OSE and invasive EOC raised the possibility that this adhesion molecule serves a different function in nontransformed versus neoplastic ovarian epithelial cells. Indeed, we showed that in OSE cells L1 supports cell-cell adhesion and enhances apoptosis, whereas it has no effect on cell proliferation and invasion. In contrast, L1 inhibits cell-cell adhesion and apoptosis in ovarian carcinoma cells, where it promotes malignancy-related properties, such as cell proliferation, Erk1/2-dependent and phosphoinositide 3-kinase-dependent invasion, and transendothelial migration. Interestingly, a crosstalk with the fibroblast growth factor receptor signaling is implicated in the promalignant function of L1 in tumor cells. Our findings point to L1 as an EOC biomarker correlating with poor prognosis, and highlight a switch in L1 function associated to the neoplastic transformation of ovarian epithelial cells, thus implicating L1 as a potential therapeutic target.
Zecchini
Silvia
S
FIRC Institute of Molecular Oncology, Milano, Italy.
Bianchi
Marco
M
Colombo
Nicoletta
N
Fasani
Roberta
R
Goisis
Giovanni
G
Casadio
Chiara
C
Viale
Giuseppe
G
Liu
Jinsong
J
Herlyn
Meenhard
M
Godwin
Andrew K
AK
Nuciforo
Paolo G
PG
Cavallaro
Ugo
U
D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020239:Receptor Cross-Talk; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D039842:Neural Cell Adhesion Molecule L1; D034741:RNA, Small Interfering; D017468:Receptors, Fibroblast Growth Factor