Libo Liu

Incidental prostate cancer in Asian men: High prevalence of incidental prostatic adenocarcinoma in Chinese patients undergoing radical cystoprostatectomy for treatment of bladder cancer and selection of candidates for prostate-sparing cystectomy

Previous studies report a low prevalence of incidental prostate cancer in Chinese patients (3–7%). We evaluated incidental prostatic adenocarcinoma (PCa) and urothelial carcinoma (UCa) involvement of the prostate in cystoprostatectomy specimens.

Prognostic and predictive value of epigenetic biomarkers and clinical factors in upper tract urothelial carcinoma.

AIM We conducted this study to identify gene promoter methylation status and clinical predictors for upper tract urothelial carcinoma (UTUC) patients. MATERIALS & METHODS Using methylation-sensitive PCR, we examined ten genes promoter methylation status in 687 UTUC patients. RESULTS A methylated promoter of three genes to predict higher tumor stage (T3 and T4), five genes to predict higher tumor grade (G3) and one gene to predict pN+ were certified in this study. Nine factors were significantly associated with poor cancer-specific survival. Six factors were considered as predictors to develop bladder recurrence after surgery. CONCLUSION Methylation occurs commonly in UTUCs, may affect carcinogenic mechanisms, and is a well predictive factor for cancer-specific survival and bladder recurrence in UTUCs.

Prognostic Significance of Preoperative Albumin-Globulin Ratio in Patients with Upper Tract Urothelial Carcinoma

Background Preoperative albumin-globulin ratio (AGR) reflects both malnutrition and systemic inflammation in cancer patients. In particular, systemic inflammation has been reported to contribute to tumor progression and poor oncological outcome in various malignancies. However, the prognostic value of preoperative AGR in upper tract urothelial carcinoma (UTUC) has not been examined. Methods We retrospectively reviewed medical data of 187 operable UTUC patients in a Chinese cohort with a high incidence of chronic kidney disease (CKD). AGR was calculated as [AGR = albumin/(serum total protein—albumin)]. The associations of preoperative AGR with clinicopathologic characteristics and prognosis were assessed. Multivariate analyses using Cox regression models were performed to determine the independent prognostic factors. Results The median (IQR) preoperative AGR was 1.50 (1.30–1.70), and the optimal cutoff value was determined to be 1.45 according to the receiver operating curve analysis. Low AGR was significantly associated with female gender, high CKD stage and tumor grade (P < 0.05). Eighty-three patients died before the follow-up endpoint. Kaplan-Meier analysis showed that an AGR < 1.45 predicted significantly poorer overall and cancer-specific survivals compared to an AGR ≥ 1.45 (P < 0.001 and P = 0.008, respectively). Multivariate analyses showed that an AGR < 1.45 was an independent risk factor for poorer overall and cancer-specific survivals (P = 0.002 and P = 0.015, respectively). Conclusions Preoperative AGR can act as an effective biomarker with easy accessibility for evaluating the prognosis of patients with UTUC. AGR should be applied in UTUC patients for risk stratification and determination of optimal therapeutic regimens.

CCDC34 is up-regulated in bladder cancer and regulates bladder cancer cell proliferation, apoptosis and migration

The coiled coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. The aim of this study was to investigate the critical role of Coiled-coil domain-containing protein 34 (CCDC34) in bladder carcinogenesis, which has never been reported to date. Here, we found CCDC34 expression was elevated in bladder cancer tissues and cell lines. The knockdown of CCDC34 via lentivirus-mediated siRNA significantly suppressed bladder cancer cells proliferation and migration, and induced cell cycle arrest at G2/M phase and increased apoptosis in vitro. In addition, CCDC34 knockdown suppressed bladder tumor growth in nude mice. Moreover, CCDC34 silencing decreased the phosphorylation of MEK, ERK1/2, JNK, p38 and Akt, and the expressions of c-Raf and c-Jun, indicating MAPK and AKT pathways (ERK/MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt) might be involved in CCDC34 regulation of bladder cancer cell proliferation and migration. Our findings revealed for the first time a potential oncogenic role for CCDC34 in bladder carcinoma pathogenesis and it may serve as a biomarker or even a therapeutic target for bladder cancer.

Adult renal cell carcinoma with rhabdoid differentiation: incidence and clinicopathologic features in Chinese patients

Renal cell carcinoma (RCC) with rhabdoid differentiation is a recently described variant of RCC, which has seldom been reported in China. This form of differentiation has been generally associated with a poor prognosis and is often present in tumors with a poorly differentiated morphology. The development of a rhabdoid morphology appears to represent a common dedifferentiation pathway for renal parenchymal malignancies. The aim of this study is to evaluate the incidence and clinicopathologic features of RCC rhabdoid differentiation in Chinese adult patients and to further investigate its origin. We reviewed 723 cases of RCC obtained between January 2012 and March 2014 in Peking University First Hospital. From these cases, 10 (1.4%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for vimentin, cytokeratin (CK) (pan-cytokeratin (AE1/AE3), CK20, CK5/6, CK7, and CK8/18), RCC, CD10, Pax-2, Pax-8, CD117, desmin, muscle-specific actin, CD68, p53, and Ki-67 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with clear cell RCC, papillary RCC (II type), and sarcomatoid RCC. We compared the morphologic and immunohistochemical features between rhabdoid and nonrhabdoid components. In our cases, rhabdoid differentiation was characterized by the presence of cohesive large epithelioid cells with abundant pink cytoplasm and central eosinophilic intracytoplasmic inclusions and 1 or more large, oval, eccentric, or irregular nuclei containing prominent nucleoli. Most of the rhabdoid areas showed a solid growth pattern. In our series, RCC with rhabdoid differentiation had an aggressive biological behavior, and rhabdoid components were most likely associated with high-grade tumors of advanced stage. In all cases, the rhabdoid and nonrhabdoid tumoral areas without sarcomatoid differentiation exhibited the very similar immunophenotype as follows: vimentin (+/-), AE1/AE3 (+), CK8/18(+), CK7(+/-), CK5/6 (-), CK20 (-), RCC (focal +), CD10 (focal +), Pax-2 (+), Pax-8 (+), CD117 (+/-), desmin (-), muscle-specific actin (-), and CD68 (-). On p53 and Ki-67 immunohistochemistry, the positive rate of rhabdoid cells for both p53 and Ki-67, similar to sarcomatoid cells, was higher than that of nonrhabdoid tumor cells without sarcomatoid differentiation. Our results indicate that the incidence rate of rhabdoid differentiation in Chinese adult RCC patients is lower than that of foreign reports. We support that the rhabdoid and nonrhabdoid tumor cells originate from the same clone, and the rhabdoid components present high proliferative activity and indicate a poor prognosis.

Preoperative Plasma Fibrinogen Level Represents an Independent Prognostic Factor in a Chinese Cohort of Patients with Upper Tract Urothelial Carcinoma.

Background Increased plasma fibrinogen is thought to contribute to tumor progression and metastasis. The association of plasma fibrinogen with clinicopathological characteristics, and the optimal cutoff with an ideal predictive value has not been fully determined in patients with upper tract urothelial carcinoma (UTUC). We aimed to investigate the clinical significance of this parameter in a Chinese cohort of patients with UTUC. Methods A retrospective study was conducted to analyze the clinical data of 184 operable UTUC patients in a Chinese cohort with a high incidence of chronic kidney disease (CKD). An optimal cutoff was set for further analysis according to validated web-based software. The associations of plasma fibrinogen with clinicopathological characteristics and survival were assessed. Multivariate analyses were performed to determine the independent prognostic factors. Results Elevated plasma fibrinogen was significantly associated with tumor necrosis, lymph node involvement, and a higher preoperative CKD stage, pathological tumor stage and grade (all P < 0.05). Kaplan-Meier analysis showed that plasma fibrinogen ≥ 3.54 g/L predicted a poorer overall and cancer-specific survival than < 3.54 g/L (P < 0.001 for both). Multivariate analyses revealed that elevated preoperative plasma fibrinogen was an independent negative prognostic factor for overall survival (HR = 2.026; 95% CI: 1.226–3.349; P = 0.006) and cancer-specific survival (HR = 1.886; 95% CI: 1.019–3.490; P = 0.043). Conclusions Increased plasma fibrinogen was an independent prognostic risk factor for poor outcomes in UTUC. This parameter may serve as an effective biomarker with easy accessibility for evaluating prognosis for patients with UTUC.

CD8+ T cells promote proliferation of benign prostatic hyperplasia epithelial cells under low androgen level via modulation of CCL5/STAT5/CCND1 signaling pathway

Previous studies by our group have shown that low intra-prostatic dihydrotestosterone (DHT) induced BPH epithelial cells (BECs) to recruit CD8+ T cells. However, the influence of the recruited CD8+ T cells on BECs under a low androgen level is still unknown. Here, we found CD8+ T cells have the capacity to promote proliferation of BECs in low androgen condition. Mechanism dissection revealed that interaction between CD8+ T cells and BECs through secretion of CCL5 might promote the phosphorylation of STAT5 and a higher expression of CCND1 in BECs. Suppressed CCL5/STAT5 signals via CCL5 neutralizing antibody or STAT5 inhibitor Pimozide led to reverse CD8+ T cell-enhanced BECs proliferation. IHC analysis from Finasteride treated patients showed PCNA expression in BECs was highly correlated to the level of CD8+ T cell infiltration and the expression of CCL5. Consequently, our data indicated infiltrating CD8+ T cells could promote the proliferation of BECs in low androgen condition via modulation of CCL5/STAT5/CCND1 signaling. The increased secretion of CCL5 from the CD8+ T cells/BECs interaction might help BECs survive in a low DHT environment. Targeting these signals may provide a new potential therapeutic approach to better treat BPH patients who failed the therapy of 5α-reductase inhibitors.

M2 macrophage-mediated interleukin-4 signalling induces myofibroblast phenotype during the progression of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a progressive disease in elderly men, but potential factors accelerating its progression remain largely unknown. The aim of this study was to elucidate the factors affecting BPH progression by understanding the complex mechanisms causing early- progressed BPH, which progresses rapidly and requires surgical intervention before the age of 50. Three groups of human prostate tissue samples, from patients with early-progressed BPH, age-matched prostate and elderly BPH tissues, were collected (n = 25 each). We compared these tissues to determine the histologic features and molecular mechanisms underlying BPH progression. We found that early-progressed BPH samples were characterised by aberrant stromal hyper-proliferation, collagen deposition and increased M2 macrophage infiltration, compared to those from age-matched prostate and elderly BPH tissues. The M2 macrophage–fibroblast co-culture system demonstrated that the myofibroblast phenotypes were strongly induced only in fibroblasts from the early-progressed BPH samples, while the co-cultured M2 macrophages expressed high levels of pro-fibrotic cytokines, such as IL4 and TGFβ1. M2 macrophage-derived IL4, but not TGFβ1, selectively induced the myofibroblast phenotype through the JAK/STAT6, PI3K/AKT and MAPK/ERK signalling pathways in the early-progressed BPH prostate fibroblasts. Taken together, our results indicate that induction of the myofibroblast phenotype may lead to BPH progression through M2 macrophage-mediated IL4 signalling, and that IL4 may represent a potential therapeutic target, allowing the prevention of M2 macrophage activation and fibroblast-to-myofibroblast differentiation.