Vascular cell adhesion molecule-1 is a regulator of ovarian cancer peritoneal metastasis.
Ovarian cancers metastasize by attaching to and invading through the mesothelium, a single layer of mesothelial cells lining the peritoneal cavity. The presence of invasive peritoneal metastases is associated with a poor prognosis for ovarian cancer (5-year survival <25%). Vascular cell adhesion molecule-1 (VCAM-1) is a cell surface receptor that mediates leukocyte attachment and extravasation across endothelial and mesothelial monolayers at sites of inflammation. Membranous VCAM-1 expression was observed on the mesothelium of 13 of 14 women with ovarian cancer compared with 6 of 15 who were cancer-free. Using a cell culture model system of mesothelial invasion, highly tumorigenic SKOV-3 and ES-2 cells were 2.5 to 3 times more efficient in transmigration through the mesothelial monolayer compared with poorly tumorigenic OVCAR-3 cells. Blocking antibodies to, or small interfering RNA knockdown of, VCAM-1 or its ligand alpha(4)beta(1) integrin significantly decreased, but did not completely inhibit, transmigration of SKOV-3 cells through mesothelial monolayers. Furthermore, using a mouse model of ovarian cancer metastasis, treatment with VCAM-1 function-blocking antibodies decreased tumor burden and increased survival. Together, these observations implicate VCAM-1-alpha(4)beta(1) integrin interactions in the regulation of ovarian cancer cell mesothelial invasion and metastatic progression and offer the possibility of novel therapeutic targets.
Slack-Davis
Jill K
JK
Department of Microbiology, Health Evaluation Sciences and Cancer Center, University of Virginia, Charlottesville, Virginia 22908, USA. jks6a@virginia.edu
Atkins
Kristen A
KA
Harrer
Christine
C
Hershey
E Daniel
ED
Conaway
Mark
M
D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004848:Epithelium / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000473:pathology / Q000556:secondary*; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D012334:RNA, Neoplasm; D019010:Vascular Cell Adhesion Molecule-1