Abstract
Half of patients with muscle-invasive bladder cancer develop metastatic disease, and this is responsible for most of the deaths from this cancer. Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI) is associated with metastatic disease in patients with muscle-invasive bladder cancer. Moreover, a reduction in metastasis is observed upon reexpression of RhoGDI2 in xenograft models of metastatic cancer. Here, we show that RhoGDI2 suppresses lung metastasis in mouse models by reducing the expression of isoforms V1 and V3 of the proteoglycan versican (VCAN; also known as chondroitin sulfate proteoglycan 2 [CSPG2]). In addition, we found that high versican levels portended poor prognosis in patients with bladder cancer. The functional importance of tumor expression of versican in promoting metastasis was established in in vitro and in vivo studies in mice that implicated a role for the chemokine CCL2 (also known as MCP1) and macrophages. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. In summary, we demonstrate what we believe to be a new mechanism of metastasis suppression that works by reducing host responses that promote metastatic colonization of the lung. Therapeutic targeting of these interactions may provide a novel adjuvant strategy for delaying the appearance of clinical metastasis in patients.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Carcinoma, Transitional Cell / immunology
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Carcinoma, Transitional Cell / metabolism
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Carcinoma, Transitional Cell / prevention & control
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Carcinoma, Transitional Cell / secondary*
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Cell Line, Tumor
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Chemokine CCL2 / biosynthesis
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Chemokine CCL2 / deficiency
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Chemokine CCL2 / genetics
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Chemokine CCL2 / physiology
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Clodronic Acid / pharmacology
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Coculture Techniques
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Female
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Gene Expression Regulation, Neoplastic*
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Guanine Nucleotide Dissociation Inhibitors / genetics
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Guanine Nucleotide Dissociation Inhibitors / physiology*
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Humans
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Inflammation
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Kaplan-Meier Estimate
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Lung Neoplasms / immunology
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Lung Neoplasms / metabolism
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary*
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Macrophages / drug effects
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Macrophages / physiology*
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Mice
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Mice, Nude
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Molecular Targeted Therapy
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasm Transplantation
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Prognosis
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Protein Isoforms / biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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Tumor Microenvironment
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U937 Cells
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Urinary Bladder Neoplasms / immunology
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Urinary Bladder Neoplasms / metabolism
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Urinary Bladder Neoplasms / pathology*
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Versicans / biosynthesis*
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Versicans / genetics
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Versicans / physiology
Substances
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CCL2 protein, human
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Chemokine CCL2
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GDI2 protein, human
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Guanine Nucleotide Dissociation Inhibitors
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Neoplasm Proteins
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Protein Isoforms
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VCAN protein, human
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Clodronic Acid
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Versicans