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 3

GDI2 overexpression reduces lung metastasis and VCAN expression.

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GDI2 overexpression reduces lung metastasis and VCAN expression. (A) WBs...
(A) WBs showing the expression of GFP and GFP in UMUC3 cells. Tub, tubulin. (B) The expression of VCAN transcripts (left) and protein (right) in GFP and GDI2 cells was determined by qRT-PCR and WB of cell lysates and CM. Bars represent mean ± SEM, n = 3. *P < 0.05; **P < 0.01 (compared with GFP, Student’s t test). Relative expression was normalized to the housekeeping gene GUS-B. Equal protein loading was confirmed by tubulin. (C) Tumor cell burden in lungs was determined by qPCR of human 12p chromosome at indicated time points after tail-vein injection of cancer cells. Bars represent mean ± SEM, n = 3. *P < 0.05, Student’s t test, comparing GFP and GDI2. **P < 0.001, 1-way ANOVA with Tukey’s multiple comparison post-hoc test. (D) Photos of lung metastasis (mets) (circled in yellow) and scatter plot of the incidence and number of visible metastases 6 weeks after injection of cancer cells. *P < 0.05, χ2 test, comparing the incidence; **P < 0.01, Student’s t test, comparing the number of metastases. (E) WB of VCAN isoforms in representative lung lysates (n = 3) 6 weeks after injection of cancer cells shown in D.