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 1

GDI2 and versican expression and disease outcome.

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GDI2 and versican expression and disease outcome. (A) Kaplan-Meier curve...
(A) Kaplan-Meier curves showing stratification of DSS as a function of GDI2 RNA expression in 2 independent studies (left: Sanchez-Carbayo et al., ref. 44; right: Kim et al., ref. 46). (B) Supervised clustering of microarray analysis of metastatic UMUC3 cells reexpressing GDI2-GFP and GFP controls was limited to 92 significantly differentially expressed probes by more than 3-fold (right). Unsupervised clustering of 92 GDI2-regulated probes in 46 human urothelial carcinomas (43) (left). Stage of the tumor is classified as carcinoma in situ (green), NMI (orange), and MI (black) urothelial bladder cancer. Probes for VCAN mRNA are indicated by arrowheads. (C) Dot plots of standardized (z scored), logged (base 2) expression of VCAN probes comparing NMI and MI urothelial bladder cancer in 4 independent studies shown (upper left: Sanchez-Carbayo et al., ref. 44; upper right: Stransky et al., ref. 45; lower left: Dyrskjot et al., ref. 47; lower right: Kim et al., ref. 46). Differences in distributions were tested by the Mann-Whitney U test. (D) Kaplan-Meier plots showing stratification of DSS as a function of VCAN expression in the same 2 studies as in A (left: Sanchez-Carbayo et al., ref. 44; right: Kim et al., ref. 46). Reproduced with permission from the Journal of Clinical Oncology (44), Molecular Cancer (46), Cancer Research (43), and Nature Genetics (45, 47).