RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration
Neveen Said, … , Steven C. Smith, Dan Theodorescu
Neveen Said, … , Steven C. Smith, Dan Theodorescu
Published March 12, 2012
Citation Information: J Clin Invest. 2012;122(4):1503-1518. https://doi.org/10.1172/JCI61392.
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Research Article Oncology

RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration

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.

Authors

Neveen Said, Marta Sanchez-Carbayo, Steven C. Smith, Dan Theodorescu

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Figure 10

Involvement of CCL2 and CCR2 in VCAN-mediated lung metastasis.

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Involvement of CCL2 and CCR2 in VCAN-mediated lung metastasis. (A) Scatt...
(A) Scatter plots of the incidence and multiplicity of lung metastases after tail-vein injection of murine MB49 cells (1 × 104 cells/100 μl) in Ccl2–/– and Ccr2–/– mice and their WT counterparts (WT, C57BL/6). *P < 0.05, χ2 test, comparing the incidence; **P < 0.01, Student’s t test, comparing the number of lung metastases between WT and Ccl2–/– aand Ccr2–/– cohorts, 3 weeks after injection of tumor cells. (B) Mac2 IHC of lung sections of mice in A. Bars represent mean ± SEM of the number of macrophages/HPF. *P < 0.05, Student’s t test. (C) WB of murine V1 (β-GAG) and V2 (α-GAG) in tumor-bearing lung lysates. (D) Murine cytokines in WT, Ccl2–/–, and Ccr2–/– lung lysates. Bars represent the mean ± SEM of 3 independent experiments performed in duplicates. *P < 0.01, Student’s t test. (E and F) Scatter plots of the incidence and multiplicity of lung metastases developed after tail-vein injection of transfected/transduced UMUC3 cells in nude mice treated with CCR2 antagonist RS 102895 (RS) and its VC or neutralizing antibody against human CCL2 (anti-CCL2) and isotype control IgG. *P < 0.01, χ2 test, comparing the incidence, and Student’s t test, comparing the number of visible lung metastases.