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What's known on the subject? and What does the study add? Insulin-like growth factor mRNA-binding protein 3 (IMP3) is an oncofetal protein found to be re-expressed in a series of human cancers including bladder cancer. In vitro analyses showed an invasion and proliferation promoting effect for IMP3. Further in vitro studies suggested that IMP3 is able to bind to the mRNAs of CD44 and insulin-like growth factor 2 (IGF2), enhancing their stability and expression. However, this molecular interaction has not yet been analysed in tumour samples. In the present study, we identified for the first time high IMP3 tissue protein expression as an independent predictor of poor patients' survival in muscle-invasive bladder cancer. Furthermore, there was no correlation between IMP3 and its molecular targets in bladder carcinoma specimens and concluded that the tumour-promoting effect of IMP3 is not related to its regulatory action on IGF2 and CD44. OBJECTIVE • To assess the prognostic value and molecular actions of the oncofetal protein insulin-like growth factor mRNA-binding protein 3 (IMP3) in muscle-invasive bladder cancer (BC). PATIENTS AND METHODS • IMP3 expression was analysed by immunohistochemistry, real-time polymerase chain reaction and Western blot analysis in 224 patients with BC. • The molecular targets of IMP3; CD44, insulin-like growth factor 2 (IGF2) and its receptor the IGF1 receptor (IGF1-R) were also investigated. • Expression levels were correlated with clinical follow-up data by using both univariate and multivariate Cox regression analyses. RESULTS • IMP3 mRNA and protein levels were significantly elevated in high-stage and high-grade muscle-invasive BC. • In muscle-invasive BC IMP3 protein but not gene expression proved to be an independent predictor of disease-specific (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.28–4.56, P = 0.004) and overall survival (HR 2.07, 95% CI 1.12–3.82, P = 0.020). • The expression levels of IGF2 and CD44 showed no correlation with that of IMP3. CONCLUSIONS • High IMP3 protein levels may identify patients with BC at high risk of disease progression and may therefore select patients for a more intensive therapy or for a strict follow-up. • Its high expression in high-grade bladder carcinoma cells makes IMP3 for an attractive target for therapy. • The tumour promoting effect of IMP3 is independent from its regulatory action on IGF2 and CD44 expression.

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Recent data suggest that MMP-7 is critically involved in metastasis formation. In accordance, we formerly found significantly elevated MMP-7 tissue expression and serum concentration in samples of patients with metastatic bladder cancer and observed an independent correlation between MMP-7 levels and patients’ prognosis. In the present study we demonstrated that high preoperative urinary MMP-7 concentrations are associated with metastatic bladder cancer. OBJECTIVE • To assess the presence of matrix metalloproteinase (MMP)-7 in urine samples of patients with bladder cancer and to investigate the correlation between MMP-7 urine concentration and clinicopathological variables. PATIENTS AND METHODS • The presence of MMP-7 in the urine of patients with bladder cancer was tested in 32 representative cases using immunoprecipitation followed by western blot analysis. • Urinary MMP-7 concentration levels were analyzed in 132 patients with bladder cancer and 96 controls using an enzyme-linked immunosorbent assay. RESULTS • MMP-7 levels did not differ significantly between patients with localized bladder cancer and controls (P= 0.174). On the other hand, we detected a fourfold, significantly elevated MMP-7 concentration in urine samples of patients with bladder cancer with regional or distant metastasis (P= 0.003). • Using a threshold value of 6.88 ng/ml, determined by receiver-operating characteristic curve analysis, a specificity of 82% and a sensitivity of 78% were observed. • Western blot analysis revealed that the 55-kDa tissue inhibitor of metalloproteinase 1 complexed MMP-7 is the dominant form of urinary matrilysin. CONCLUSIONS • MMP-7 is present in detectable amounts in the urine of patients with bladder cancer. Its concentrations are significantly elevated in patients with metastatic disease. • Determination of urinary matrilysin level could help to detect bladder cancer metastasis, and may therefore provide a more reliable prognosis and influence therapy decisions.

What's known on the subject? and What does the study add? Insulin-like growth factor mRNA-binding protein 3 (IMP3) is an oncofetal protein found to be re-expressed in a series of human cancers including bladder cancer. In vitro analyses showed an invasion and proliferation promoting effect for IMP3. Further in vitro studies suggested that IMP3 is able to bind to the mRNAs of CD44 and insulin-like growth factor 2 (IGF2), enhancing their stability and expression. However, this molecular interaction has not yet been analysed in tumour samples. In the present study, we identified for the first time high IMP3 tissue protein expression as an independent predictor of poor patients' survival in muscle-invasive bladder cancer. Furthermore, there was no correlation between IMP3 and its molecular targets in bladder carcinoma specimens and concluded that the tumour-promoting effect of IMP3 is not related to its regulatory action on IGF2 and CD44.To assess the prognostic value and molecular actions of the oncofetal protein insulin-like growth factor mRNA-binding protein 3 (IMP3) in muscle-invasive bladder cancer (BC).IMP3 expression was analysed by immunohistochemistry, real-time polymerase chain reaction and Western blot analysis in 224 patients with BC. The molecular targets of IMP3; CD44, insulin-like growth factor 2 (IGF2) and its receptor the IGF1 receptor (IGF1-R) were also investigated. Expression levels were correlated with clinical follow-up data by using both univariate and multivariate Cox regression analyses.IMP3 mRNA and protein levels were significantly elevated in high-stage and high-grade muscle-invasive BC. In muscle-invasive BC IMP3 protein but not gene expression proved to be an independent predictor of disease-specific (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.28-4.56, P = 0.004) and overall survival (HR 2.07, 95% CI 1.12-3.82, P = 0.020). The expression levels of IGF2 and CD44 showed no correlation with that of IMP3.High IMP3 protein levels may identify patients with BC at high risk of disease progression and may therefore select patients for a more intensive therapy or for a strict follow-up. Its high expression in high-grade bladder carcinoma cells makes IMP3 for an attractive target for therapy. The tumour promoting effect of IMP3 is independent from its regulatory action on IGF2 and CD44 expression.

• To assess the presence of matrix metalloproteinase (MMP)-7 in urine samples of patients with bladder cancer and to investigate the correlation between MMP-7 urine concentration and clinicopathological variables.• The presence of MMP-7 in the urine of patients with bladder cancer was tested in 32 representative cases using immunoprecipitation followed by western blot analysis. • Urinary MMP-7 concentration levels were analyzed in 132 patients with bladder cancer and 96 controls using an enzyme-linked immunosorbent assay.• MMP-7 levels did not differ significantly between patients with localized bladder cancer and controls (P= 0.174). On the other hand, we detected a fourfold, significantly elevated MMP-7 concentration in urine samples of patients with bladder cancer with regional or distant metastasis (P= 0.003). • Using a threshold value of 6.88 ng/ml, determined by receiver-operating characteristic curve analysis, a specificity of 82% and a sensitivity of 78% were observed. • Western blot analysis revealed that the 55-kDa tissue inhibitor of metalloproteinase 1 complexed MMP-7 is the dominant form of urinary matrilysin.• MMP-7 is present in detectable amounts in the urine of patients with bladder cancer. Its concentrations are significantly elevated in patients with metastatic disease. • Determination of urinary matrilysin level could help to detect bladder cancer metastasis, and may therefore provide a more reliable prognosis and influence therapy decisions.

Metastases to regional lymph nodes are a common early event in many malignant diseases and have a poor prognosis, including in urological cancers. Molecular pathways contributing to lymphatic tumour dissemination and lymph node metastasis remain poorly understood. Besides the process of lymphovascular invasion (LVI), recent studies suggested de novo lymphatic vessel formation (i.e. lymphangiogenesis) as a potential mechanism of lymphatic tumour spread. Specific markers for lymphatic endothelium have recently been discovered, enabling basic morphological studies on lymphatic vessel density. There is a gap in the knowledge of the functional relationship between tumoral lymphatic vessels, LVI, lymphangiogenesis and the formation of lymph node metastases. The identification of lymph-specific growth factors (e.g. vascular endothelial growth factor-C and -D) as promoters of lymphatic metastasis has resulted in the interesting idea of targeting the pathways involved in lymphatic tumour progression. We summarize preliminary evidence on the role of lymphangiogenesis during the formation of lymphatic metastasis in the most common urological cancers.