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RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration
Neveen Said1, Marta Sanchez-Carbayo, Steven C Smith
1Department of Urology, University of Virginia, Charlottesville, Virginia, USA.
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.
Insights
RhoGTP dissociation inhibitor 2 (RhoGDI2) suppresses bladder cancer metastasis by reducing versican expression and altering tumor inflammation. This finding offers a new therapeutic strategy to delay metastatic spread in patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Muscle-invasive bladder cancer frequently metastasizes, leading to poor patient outcomes.
- Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2) correlates with metastatic bladder cancer.
- Restoring RhoGDI2 levels inhibits metastasis in preclinical cancer models.
Purpose of the Study:
- To investigate the mechanism by which RhoGDI2 suppresses metastasis in bladder cancer.
- To identify the molecular targets of RhoGDI2 involved in metastasis.
- To explore the role of the tumor microenvironment in RhoGDI2-mediated metastasis suppression.
Main Methods:
- Utilized mouse models of lung metastasis.
- Assessed expression levels of RhoGDI2 and versican (VCAN) in patient samples and experimental models.
- Performed in vitro and in vivo studies to evaluate the roles of VCAN, CCL2, and macrophages in metastasis.
- Analyzed alterations in tumor microenvironment inflammation.
Main Results:
- RhoGDI2 suppresses lung metastasis by downregulating versican (VCAN) V1 and V3 isoforms.
- High versican levels predict poor prognosis in bladder cancer patients.
- Tumor-expressed versican promotes metastasis via the chemokine CCL2 and macrophages.
- RhoGDI2 inhibits metastasis by modulating inflammation within the tumor microenvironment.
Conclusions:
- RhoGDI2 suppresses bladder cancer metastasis through a novel mechanism involving reduced VCAN expression and altered inflammatory responses.
- Targeting the RhoGDI2-versican-inflammation axis may offer a new adjuvant therapy to prevent or delay metastatic disease in bladder cancer patients.
