Abstract
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.
Highlights
Ovarian cancer is the deadliest of the gynecologic malignancies
We investigated the role of Vascular cell adhesion molecule-1 (VCAM-1) in the regulation of one aspect of ovarian cancer metastasis: mesothelial invasion
VCAM-1 and Ovarian Cancer Metastasis positively for VCAM-1 in biopsies obtained from cancer patients (Fig. 1B, C, and F, arrowheads)
Summary
Ovarian cancer is the deadliest of the gynecologic malignancies. 22,000 new cases of ovarian cancer are diagnosed and 15,000 deaths occur each year [1]. The relatively poor prognosis for ovarian cancer is due largely to the advanced stage of disease at the time of diagnosis [2]. 75% of patients are diagnosed with stage III or IV ovarian cancer, which is characterized by peritoneal or distant metastases, respectively, and is accompanied by a 5-year survival of 25%. The majority of patients with metastatic ovarian cancer initially respond well to surgical resection and chemotherapy, 50% to 75% of these patients will have recurrent disease [3]. Ovarian cancer metastasizes initially by spreading throughout the peritoneal cavity, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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