RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration
Neveen Said, Marta Sanchez-Carbayo, Steven C. Smith, Dan Theodorescu
Neveen Said, Marta Sanchez-Carbayo, Steven C. Smith, Dan Theodorescu
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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 5

GDI2 modulates cancer cell–macrophage interactions through VCAN.

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GDI2 modulates cancer cell–macrophage interactions through VCAN. (A) Sch...
(A) Schema of UMUC3-U937 cocultures. WB showing the expression of VCAN isoforms in UMUC3 or U937 lysates cocultured for 72 hours. (B) qRT-PCR (after 6 hours) in cell lines under the same conditions as in panel A. In all coculture experiments, bars represent evaluated cells (U937 or UMUC3) that appear below the lines in the x axis labels. *P < 0.01, compared with GFP in single-cell culture; **P < 0.01, comparing GFP and GDI2 in cocultures; #P < 0.05, comparing U937 in single and cocultures; ##P < 0.05, comparing U937 cocultured with GFP and GDI2. (C) hIL-6 and hCCL2 in 72-hour CM of single cultures of U937 (gray bars) or UMUC3 (either GFP or GDI2, black bars) and in cocultures of U937 with UMUC3 (either GFP or GDI2, white bars). *P < 0.05, comparing GFP and GDI2; **P < 0.01, comparing single cell to coculture. (D) Cox-2 activity was determined in cell lysates under the same conditions as in A. *P < 0.01, comparing single cells to cocultures; #P < 0.01, comparing cocultures with GFP versus GDI2. Student’s t test was used.