Süleyman Ergün

Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab.

Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.

Elevated serum matrix metalloproteinase 7 levels predict poor prognosis after radical prostatectomy

Elevated matrix metalloproteinase‐7 (MMP‐7) tissue expression and serum concentration have been shown to be associated with cancer progression and metastasis. The aim of our study was to assess the prognostic value of preoperative circulating MMP‐7 levels in serum samples of patients with clinically localized prostate cancer. Furthermore, we compared the serum MMP‐7 levels between patients with organ confined and metastatic prostate cancer. MMP‐7 levels were measured in 93 patients with localized prostate cancer, 13 patients with distant bone metastasis and in sera of 19 controls using enzyme‐linked immunosorbent assay. The results were compared to the clinical follow‐up data. We did not find any significant difference in MMP‐7 serum levels between patients and controls (p = 0.268). Circulating MMP‐7 serum concentration was significantly elevated in patients with distant metastasis (p < 0.001). For the detection of distant prostate cancer metastasis, using a cut‐off value of 3.7 ng/ml, a specificity of 69% and a sensitivity of 92% were observed. Multivariate analysis identified high MMP‐7 serum concentration as an independent risk factor for prostate cancer‐related death both in a preoperative and a postoperative model (p = 0.003 and 0.018, respectively). Furthermore, the evaluation of predictive models revealed that addition of serum MMP‐7 levels to the preoperatively available predictors improves prognostic accuracy (the concordance index increased from 0.631 to 0.734 when MMP‐7 was included). Based on these, we concluded that MMP‐7 is a potential marker to identify patients with metastatic prostate cancer. In clinically localized prostate cancer, MMP‐7 may provide independent prognostic information, thereby helping to optimize therapy decisions.

Prognostic impact of plasminogen activator inhibitor type 1 expression in bladder cancer.

Recent studies have demonstrated a poor prognosis for patients who have altered expression of plasminogen activator inhibitor type 1 (PAI‐1) in several cancer types. The objective of the current study was to investigate the prognostic impact of PAI‐1 on patients with transitional cell carcinoma (TCC) of the urinary bladder.

The role of lymphangiogenesis in lymphatic tumour spread of urological cancers

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.