Inhibitory Role of the Small Leucine-Rich Proteoglycan Biglycan in Bladder Cancer

Christian Niedworok,Tibor Szarvas,Nadine Nagy,Frank Vom Dorp,Till Freudenberger,Herbert Rübben,Henning Reis,Jens W Fischer,Inga Kretschmer,Katharina Röck,Nikos K Karamanos

doi:10.1371/journal.pone.0080084

Abstract

BackgroundUrothelial bladder cancer is the ninth most common cancer. Despite surgical and chemotherapeutic treatment the prognosis is still poor once bladder cancer progresses to a muscle-invasive state. Discovery of new diagnostic markers and pathophysiologic effectors might help to contribute to novel diagnostic and therapeutic options. The extracellular matrix microenvironment shaped by the extracellular matrix critically affects tumor cell and stroma cell functions. Therefore, aim of the present study was to assess the possible implication of the small leucine-rich proteoglycan biglycan in progression of human urothelial bladder cancer.Methods and ResultsFor this purpose tumor biopsies of 76 bladder cancer patients with different tumor stages (pTa, pT1-T4) were investigated with respect to biglycan expression and correlated with a long-term (10 years) clinical follow-up. Interestingly, higher biglycan mRNA expression was associated with higher tumor stages and muscle invasiveness. In vitro knock-down of endogenous biglycan in human urothelial carcinoma cells (J82 cells) increased proliferation, whereas addition of recombinant biglycan and overexpression of biglycan inhibited tumor cell proliferation. In line with this growth-inhibitory effect of biglycan, transplantation of J82 cells after knock-down of biglycan resulted in significantly increased growth of subcutaneous xenograft tumors in nude mice in vivo. Furthermore, treatment with two anti-proliferative, multi-receptor tyrosine kinase inhibitors—sunitinib and sorafenib—strongly upregulated biglycan expression. Collectively, the experimental data suggest that high biglycan expression is associated with reduced tumor cell proliferation. In accordance, Kaplan-Meier analysis revealed higher 10-year survival in patients with high biglycan mRNA expression in tumor biopsies.ConclusionIn conclusion, the present data suggest that biglycan is an endogenous inhibitor of bladder cancer cell proliferation that is upregulated in response to anti-proliferative tyrosine kinase inhibitors. In addition, high biglycan expression is associated with favorable prognosis.

Highlights

Urothelial bladder cancer is the ninth most common human malignant cancer with growing incidence and prevalence [1]
In conclusion, the present data suggest that biglycan is an endogenous inhibitor of bladder cancer cell proliferation that is upregulated in response to anti-proliferative tyrosine kinase inhibitors
High biglycan expression is associated with favorable prognosis

Summary

Introduction

Urothelial bladder cancer is the ninth most common human malignant cancer with growing incidence and prevalence [1]. Non-muscle invasive bladder cancer is treated by transurethral resection and adjuvant instillation therapy in case of high grade disease or in cases with multiple, frequently recurring tumors. The low grade non-muscle invasive disease can progress to muscle invasive high risk bladder cancer. The treatment of choice for muscle invasive bladder cancer is radical cystectomy [2,3] which provides still only a low (~50%) 5-year survival. Cisplatin in combination with gemcitabine represents the first-line adjuvant treatment option for patients with locally advanced or metastatic bladder cancer. Despite surgical and chemotherapeutic treatment the prognosis is still poor once bladder cancer progresses to a muscle-invasive state. Aim of the present study was to assess the possible implication of the small leucinerich proteoglycan biglycan in progression of human urothelial bladder cancer

Objectives

Methods

Results

Conclusion