Alternatively-Activated Macrophages Upregulate Mesothelial Expression of P-Selectin to Enhance Adhesion of Ovarian Cancer Cells

Cancer Res. 2018 Jul 1;78(13):3560-3573. doi: 10.1158/0008-5472.CAN-17-3341. Epub 2018 May 8.


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-1β 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-1β 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-1β and P-selectin, suggesting that this novel multicellular mechanism could 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: Cancer Res; 78(13); 3560-73. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • CCR5 Receptor Antagonists / pharmacology
  • CD24 Antigen / metabolism
  • Carcinoma, Ovarian Epithelial / immunology
  • Carcinoma, Ovarian Epithelial / pathology*
  • Cell Adhesion / drug effects
  • Cell Adhesion / immunology
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Chemokine CCL4 / metabolism*
  • Coculture Techniques
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / immunology
  • Healthy Volunteers
  • Humans
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Monocytes
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / pathology*
  • P-Selectin / metabolism*
  • Peritoneal Neoplasms / immunology*
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / secondary
  • Peritoneum / cytology
  • Peritoneum / pathology
  • Receptors, CCR5 / metabolism
  • Recombinant Proteins / metabolism
  • Up-Regulation
  • Young Adult


  • CCL4 protein, human
  • CCR5 Receptor Antagonists
  • CCR5 protein, human
  • CD24 Antigen
  • Ccl4 protein, mouse
  • Chemokine CCL4
  • P-Selectin
  • Receptors, CCR5
  • Recombinant Proteins
  • SELP protein, human