An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression.

Abstract

RhoGDI2 specifically suppresses bladder cancer metastasis but not primary tumor growth, which involves tumor-associated macrophages. We report that macrophage-secreted osteopontin binds to CD44s on the tumor cells and promotes invasion and clonal growth. These effects are RhoGDI2-sensitive and require CD44s binding to the Rac GEF TIAM1. Osteopontin expression correlates with tumor aggressiveness and poor clinical outcome in patients. Inhibiting this pathway potently blocked lung and lymph node metastasis; however, primary tumors and established metastasis were less sensitive. Osteopontin-CD44s-TIAM1 promotes clonal growth in vitro but not at high cell density. These data identify osteopontin-CD44-TIAM1-Rac1 axis as a RhoGDI2-sensitive pathway and potential therapeutic target in bladder cancer metastasis. They also elucidate the mechanism behind RhoGDI2 specificity for metastasis over established tumors.

• Authors: Mansoor Ahmed, Joseph L Sottnik, Garrett M Dancik, Divya Sahu, Donna E Hansel, Dan Theodorescu, Martin A Schwartz
• Journal: Cancer cell (Cancer Cell) Vol. 30 Issue 3 Pg. 432-443 (09 12 2016) ISSN: 1878-3686 [Electronic] United States
• PMID: 27593345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Hyaluronan Receptors
• rho Guanine Nucleotide Dissociation Inhibitor beta
• Osteopontin

Topics

• Animals
• Humans
• Hyaluronan Receptors (metabolism)
• Lung Neoplasms (pathology, secondary)
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Osteopontin (metabolism)
• Urinary Bladder Neoplasms (metabolism, pathology)
• rho Guanine Nucleotide Dissociation Inhibitor beta (metabolism)