Wanzhong Wang

Cyclooxygenase-2 Expression Correlates with Local Chronic Inflammation and Tumor Neovascularization in Human Prostate Cancer

Purpose: Chronic inflammation is linked to the development of cancer in several organs, including the prostate. Up-regulated cyclooxygenase-2 (COX-2) may play a role in influencing cell proliferation, differentiation, apoptosis, or angiogenesis. This study aimed to derive data from human prostate cancer to investigate whether chronic inflammation and angiogenesis were correlated with the expression of COX-2. Experimental Design: In this study, we did double-immunohistochemical analysis of a set of 43 human prostate cancer for COX-2 expression and the correlation with T-lymphocyte and macrophage densities and CD31-marked microvessel density (MVD) in situ. Results: COX-2 positive staining was detected in 40/43 cancer samples with the very heterogeneous expression. Elevated COX-2 expression was associated with high Gleason score (P = 0.002). Foci of chronic inflammation were found in all 43 samples. COX-2–positive areas were noted with high T-lymphocyte and macrophage densities than COX-2–negative tumor areas (P < 0.0001 and P = 0.001, respectively). MVD were also found higher in COX-2–positive areas than in COX-2–negative tumor areas (P = 0.001). Conclusions: This study shows a novel relationship between COX-2 expression and the local chronic inflammation within prostate cancer and the increased angiogenesis. It is likely that the proinflmmatory cytokines, released by T-lymphocytes and macrophages, up-regulate COX-2 in adjacent tumor cells and stimulate the angiogenesis in stromal tissues. These findings suggest that COX-2 may be an effective therapeutic target in prostate cancer treatment.

Morphological transition of proliferative inflammatory atrophy to high-grade intraepithelial neoplasia and cancer in human prostate

Inflammation has been implicated as a potential etiological agent in human prostate cancer (PCa). Proliferative inflammatory atrophy (PIA) in prostate consists of areas of glandular atrophy associated with chronic inflammation and epithelial cell proliferation. It has been suggested that PIA is a candidate precursor of prostate malignancy. We aimed to explore the morphological transition between PIA and co‐existing high‐grade prostate intraepithelial neoplasia (HGPIN) and/or PCa.

N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelial-mesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.

The Combination of a Tumor Necrosis Factor Inhibitor and Antibiotic Alleviates Staphylococcal Arthritis and Sepsis in Mice

BACKGROUND Despite advances in medical practices, in recent decades permanent reductions in joint function have not been achieved, and the high mortality rate of patients with staphylococcal septic arthritis has not substantially improved. METHODS We evaluated the effects of a combined tumor necrosis factor (TNF) inhibitor and antibiotic therapy on the course of Staphylococcus aureus arthritis and sepsis in mice. RESULTS Treatment with the combination of a TNF inhibitor and an antibiotic resulted in a quicker relief of clinical arthritis in mice with septic arthritis, compared with an antibiotic monotherapy. Both histopathologically verified synovitis and the extent of joint destruction were reduced by this combined treatment. Importantly, anti-TNF treatment significantly improved the survival rate of mice with S. aureus sepsis and staphylococcal enterotoxin shock syndrome; this effect might be the result of a partial restoration of the hemostatic balance between coagulation and fibrinolysis. Finally, we demonstrated that anti-TNF treatment downregulates high-mobility group protein B1 in staphylococcal enterotoxin shock syndrome. CONCLUSIONS Thus, simultaneous systemic TNF inhibition and antibiotic therapy has beneficial effects on the outcome of S. aureus arthritis and sepsis in a mouse model, suggesting that the combination of a TNF inhibitor and antibiotics represents a novel therapeutic strategy for the treatment of staphylococcal infections.

Castration resistant prostate cancer is associated with increased blood vessel stabilization and elevated levels of VEGF and Ang‐2

Angiogenesis is important for the progression of prostate cancer and may be a target for treatment in castration resistant (CR) disease. This study was performed to investigate blood vessel stabilization and expression of the pro‐angiogenic factors vascular endothelial growth factor (VEGF) and Angiopoietin‐2 (Ang‐2) in CR and hormone naïve (HN) prostate cancer. The effect of androgen deprivation therapy (ADT) on these parameters was also studied.

Staphylokinase Promotes the Establishment of Staphylococcus aureus Skin Infections While Decreasing Disease Severity

Skin infections are frequently caused by Staphylococcus aureus and can lead to a fatal sepsis. The microbial mechanisms controlling the initiation and progression from mild skin infection to a severe disseminated infection remain poorly understood. Using a combination of clinical data and in vitro and ex vivo assays, we show that staphylokinase, secreted by S. aureus, promoted the establishment of skin infections in humans and increased bacterial penetration through skin barriers by activating plasminogen. However, when infection was established, the interaction between staphylokinase and plasminogen did not promote systemic dissemination but induced the opening and draining of abscesses and decreased disease severity in neutropenic mice. Also, increased staphylokinase production was associated with noninvasive S. aureus infections in patients. Our results point out the dual roles of staphylokinase in S. aureus skin infections as promoting the establishment of infections while decreasing disease severity.

The expression of thrombospondin-1 in benign prostatic hyperplasia and prostatic intraepithelial neoplasia is decreased in prostate cancer

To evaluate the immunohistochemical expression of thrombospondin (TSP), a potent inhibitor of angiogenesis, in human benign prostatic hyperplasia (BPH) and prostate cancer.

ADAMTS1, a putative anti-angiogenic factor, is decreased in human prostate cancer.

To investigate the expression of ‘ADAM metallopeptidase with thrombospondin type I motif, 1’ (ADAMTS1) in human prostate cancer, and to study its relationship to microvessel density (MVD) and metastasis. ADAMTS1 has been described as an anti‐angiogenic and antitumour factor, but its function in prostate cancer is unknown.

Increased p53 immunoreactivity in proliferative inflammatory atrophy of prostate is related to focal acute inflammation

Proliferative inflammatory atrophy (PIA) of prostate has been proposed as a precursor lesion of prostate cancer. The aim of the current study was to evaluate the expression of p53 protein in PIA lesions and to investigate the relationship between p53 staining and Ki‐67, glutathione S‐transferase‐π (GSTP1) and cyclooxygenase‐2 (COX‐2) immunohistochemical expression. The results revealed that p53 nuclear immunostaining appeared in PIA lesions in 2.1±3.4% (mean±SD) of the basal and 0.9±2.3% of the luminal epithelial cells. Both these values were significantly higher than those in normal‐appearing acini (p<0.0001). Increased p53 expression in luminal cells was related to focal infiltration of polymorphonuclear leucocytes. A positive correlation between p53 expression and Ki‐67 was found in COX‐2‐positive PIA lesions (r=0.610, p<0.0001). Half of the p53‐positive epithelial cells expressed diffuse GSTP1 immunostaining in the same lesions. The present study demonstrates an increased p53 expression in PIA lesions, and inflammation, especially acute inflammation, may play a role in the induction of p53 over‐expression, particularly as cells in PIA lesions are known to have a reduced defence against DNA damage.

PBX3 is a putative biomarker of aggressive prostate cancer

There is a great need to identify new and better prognostic and predictive biomarkers to stratify prostate cancer patients for optimal treatment. The aims of this study were to characterize the expression profile of pre‐B cell leukemia homeobox (PBX) transcription factors in prostate cancer with an emphasis on investigating whether PBX3 harbours any prognostic value. The expression profile of PBX3 and PBX1 in prostate tissue was determined by immunohistochemical and immunoblot analysis. Furthermore, the expression of PBX3 transcript variants was analyzed by RT‐PCR, NanoString Technologies®, and by analyzing RNA sequence data. The potential of PBX3 to predict prognosis, either at mRNA or protein level, was studied in four independent cohorts. PBX3 was mainly expressed in the nucleus of normal prostate basal cells, while it showed cytosolic expression in prostatic intraepithelial neoplasia and cancer cells. We detected four PBX3 transcript variants in prostate tissue. Competing risk regression analysis revealed that high PBX3 expression was associated with slower progression to castration resistant prostate cancer (sub‐hazard ratio (SHR) 0.18, 95% CI: 0.081–0.42, p values < 0.001). PBX3 expression had a high predictive accuracy (area under the curve (AUC) = 0.82) when combined with Gleason score and age. Patients undergoing radical prostatectomy, with high levels of PBX3 mRNA, had improved prostate cancer specific survival compared to patients expressing low levels (SHR 0.21, 95% CI: 0.46–0.93, p values < 0.001, and AUC = 0.75). Our findings strongly indicate that PBX3 has potential as a biomarker, both as part of a larger gene panel and as an immunohistochemical marker, for aggressive prostate cancer.