P-cadherin promotes ovarian cancer dissemination through tumor cell aggregation and tumor-peritoneum interactions.
More than 60% of patients who are diagnosed with epithelial ovarian cancer (EOC) present with extensive peritoneal carcinomatosis. EOC cells typically disseminate by shedding into the peritoneal fluid in which they survive as multicellular aggregates and then implant onto peritoneal surfaces. However, the mechanism that facilitates aggregation and implantation of EOC cells is poorly understood. The cell adhesion molecule P-cadherin has been reported to be induced during early progression of EOC and to promote tumor cell migration. In this study, P-cadherin not only promoted migration of EOC cells, but also facilitated the assembly of floating EOC cells into multicellular aggregates and inhibited anoikis in vitro. Furthermore, inhibiting P-cadherin by short hairpin RNAs (shRNA) or a neutralizing antibody prevented EOC cells from attaching to peritoneal mesothelial cells in vitro. In mouse intraperitoneal xenograft models of EOC, inhibition of P-cadherin decreased the aggregation and survival of floating tumor cells in ascites and reduced the number of tumor implants on peritoneal surfaces. These findings indicate that P-cadherin promotes intraperitoneal dissemination of EOC by facilitating tumor cell aggregation and tumor-peritoneum interactions in addition to promoting tumor cell migration.


CONCLUSIONS
Inhibiting P-cadherin blocks multiple key steps of EOC progression and has therapeutic potential.
The University of Texas MD Anderson Cancer Center, Department of Molecular and Cellular Oncology, 1515 Holcombe Boulevard, Box 108, Houston, TX 77030. hnaora@mdanderson.org.
Akihiro
A
Usui
Song Yi
SY
Ko
Nicolas
N
Barengo
Honami
H
Naora
D000818:Animals; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D002449:Cell Aggregation / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
D015820:Cadherins