An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression.
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.
Department of Internal Medicine (Cardiology), Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520, USA. Electronic address: mansoornccs@gmail.com.
Mansoor
M
Ahmed
Department of Surgery, University of Colorado, Aurora, CO 80045, USA.
Joseph L
JL
Sottnik
Mathematics and Computer Science Department, Eastern Connecticut State University, Willimantic, CT 06226, USA.
Garrett M
GM
Dancik
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Divya
D
Sahu
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Donna E
DE
Hansel
Department of Surgery, University of Colorado, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA; University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. Electronic address: dan.theodorescu@ucdenver.edu.
Dan
D
Theodorescu
Department of Internal Medicine (Cardiology), Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520, USA; Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT 06520, USA. Electronic address: martin.schwartz@yale.edu.
Martin A
MA
Schwartz
D000818:Animals; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D053495:Osteopontin / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta / Q000378:metabolism*
D018960:Hyaluronan Receptors; D062949:rho Guanine Nucleotide Dissociation Inhibitor beta; D053495:Osteopontin