Journal
CANCER RESEARCH
Volume 78, Issue 13, Pages 3560-3573Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3341
Keywords
-
Categories
Funding
- University of Wisconsin Optimal Imaging Core Facility
- RARC Breeding services
- American Cancer Society [RSG-13-026-01-CSM]
- NIH [1DP2CA195766, 1R21CA143616, R25GM083252, 5P30CA014520]
- Marsha Rivkin Center for Ovarian Cancer Research Pilot Grant
- Marsha Rivkin Center for Ovarian Cancer Research Scientific Scholar Fellowship
- NSF Graduate Research Fellowship
- Wisconsin Alumni Research Foundation
- Department of Defense [W81XWH-04-1-0102]
- Department of Obstetrics and Gynecology
- Wisconsin Ovarian Cancer Alliance
- [NIH5P30CA014520]
Ask authors/readers for more resources
Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a coculture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAM) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1 beta activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling underflow. C57/BL6 mice treated with MIP-1 beta exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo. Analysis of samples from patients with HGSOC confirmed increased MIP-1 beta and P-selectin, suggesting that this novel multicellular mechanismcould be targeted to slow or stop metastasis in HGSOC by repurposing anti-CCR5 and P-selectin therapies developed for other indications. Significance: This study reports novel insights on the peritoneal dissemination occurring during progression of ovarian cancer and has potential for therapeutic intervention. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3560/F1.large.jpg. (C) 2018 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available