Versican overexpression in human breast cancer lesions: Known and new isoforms for stromal tumor targeting

Kischel, Philippe; Waltregny, David; Dumont, Bruno; Turtoï, Andrei; Greffe, Yannick; Kirsch, Stéphanie; Pauw, Edwin De; Castronovo, Vincenzo

doi:10.1002/ijc.24812

Cited by 128 publications

(94 citation statements)

References 49 publications

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“…Versican is a highly conserved structural component of the ECM that is involved in neuronal development (4)(5)(6)(7)(8), the inflammatory phase of pulmonary-vascular diseases, atherosclerosis (9)(10)(11)(12), and the invasive and metastatic signatures of many cancers (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Four isoforms or spliced variants have been reported for versican, and the roles of V0, V1, and V3 and to a lesser extent V2 isoforms are recognized in cancer, vascular disease, and neuronal development (detailed in refs.…”

Section: Introductionmentioning

confidence: 99%

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

Said¹,

Sänchez‐Carbayo²,

Smith³

et al. 2012

J. Clin. Invest.

131

110

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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. IntroductionOne-half of patients with muscle-invasive (MI) urothelial cancer (UC) of the bladder develop distant metastases, even after radical surgery of the primary tumors. We identified RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI, and abbreviated herein as GDI2) as an invasion and metastasis suppressor in human bladder cancer cell lines (1) and have shown that its expression is inversely associated with clinical outcome after treatment of MI tumors (2). Independently, in comparative gene expression profiling of invasive bladder cancer cell lines and human MI UC samples, we identified versican (VCAN; also known as chondroitin sulfate proteoglycan 2, [CSPG2]) as highly expressed in invasive and metastatic cancers (3).Versican is a highly conserved structural component of the ECM that is involved in neuronal development (4-8), the inflammatory phase of pulmonary-vascular diseases, atherosclerosis (9-12), and the invasive and metastatic signatures of many cancers (13-25). Four isoforms or spliced variants have been reported for versican, and the roles of V0, V1, and V3 and to a lesser extent V2 isoforms are recognized in cancer, vascular disease, and neuronal development (detailed in refs. 8, 26, 27, and the references cited therein). These isoforms contribute to proliferative, adhesive, and migratory states of tumor cells and modulate their interactions with stroma in the tumor microenvironment (26,28,29).Versican expression is regulated by cytokines, chemokines, and hypoxia (6, 7, 9-12, 21, 26, 29-36) via transcription factors such as TCF-4, SP-1, AP-1, and p53, which have bin...

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Section: Introductionmentioning

confidence: 99%

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

Said¹,

Sänchez‐Carbayo²,

Smith³

et al. 2012

J. Clin. Invest.

131

110

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“…7 Recently, a fourth isoform, V4, has been found in breast cancer. 8 The different isoforms are implicated in different biological processes. The V0 isoform is highly expressed during embryonic development, 9 whereas in adult human tissues the V1 isoform is most prevalent.…”

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confidence: 99%

Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer

et al. 2010

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Cervical carcinoma is the second most frequent cancer type in women worldwide. Both inflammatory cells and stromal cells are important for tumor progression. Stromal cells produce growth factors and extracellular matrix and provide an adequate environment for angiogenesis. Versican, a member of the extracellular matrix, has been shown to have a role in tumor progression. The aim of this study was to investigate versican expression, and its association with tumor-infiltrating inflammatory cell subsets and with clinicopathological parameters in human cervical cancers. We have studied the expression of versican in 149 cervical cancers using immunohistochemistry and mRNA in situ hybridization. Versican was predominantly expressed in the stroma (myofibroblasts). Using quantitative real-time-PCR, V0 was found to be the most prominent isoform. High stromal versican expression was significantly associated with a low number of tumor-infiltrating T cells (P ¼ 0.018) and particularly a low number of CD8-positive T cells (cytotoxic T cells; P ¼ 0.002). Stromal versican expression was significantly higher in patients with an infiltration depth 414 mm (P ¼ 0.004) and in patients with parametrial invasion (P ¼ 0.044). Stromal versican expression was not associated with survival. Our results suggest that versican expression in the stromal compartment of cervical cancers results in reduced numbers of intraepithelial CD8-positive T cells and enhanced local invasion.

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“…V3 expression and localization are poorly defined. Recently, a new variant, V4, generated by splicing at a cryptic site within the GAG␤ domain, has been identified in cancer cells (28).…”

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confidence: 99%

Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5

Foulcer

Nelson

Quintero

et al. 2014

Journal of Biological Chemistry

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Background:The mechanisms of versican proteolysis by ADAMTS proteases are unknown. Results: The ADAMTS5 ancillary domain and specific chondroitin sulfate chains of versican are required for proteolysis. Conclusion: Docking between the ADAMTS5 ancillary domain and CS chains is a major mechanism underlying versican proteolysis. Proteolysis by ADAMTS1 has a similar requirement for GAG chains. Significance: The findings suggest strategies for blocking versican cleavage.

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Versican overexpression in human breast cancer lesions: Known and new isoforms for stromal tumor targeting

Cited by 128 publications

References 49 publications

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

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

Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer

Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5

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