Cytochrome P450 genes expression in human prostate cancer.

CYP-dependent metabolites play a critical role in regulating the cell cycle, as well as the proliferative, invasive, and migratory activity of cancer cells. We conducted a study to analyze the relative gene expression of various CYPs (CYP7B1, CYP27A1, CYP39A1, CYP51, CYP1B1, CYP3A5, CYP4F8, CYP5A1, CYP4F2, CYP2J2, CYP2E1, CYP2R1, CYP27B1, CYP24A1) in 41 pairs of prostate samples (tumor and conventional normal tissues) using qPCR. Our analysis determined significant individual variability in the expression levels of all studied CYPs, both in the tumor and in conventionally normal groups. However, when we performed a paired test between the tumor and normal groups, we found no significant difference in the expression of the studied genes. We did observe a tendency to increase the level of CYP1B1 expression in the tumor group. We also did not find any significant difference between the levels of the studied CYPs in the tumor and conventional normal groups at different stages of prostate cancer and pathomorphological indicators. Correlation analysis revealed the presence of a positive relationship between the expressions of some cholesterol-metabolizing CYP genes, as well as between genes responsible for vitamin D biosynthesis and cholesterol biosynthesis. We observed significant correlative relationships between the expression of CYPs and some prostate cancer-related genes (CDH2, MMP9, SCHLAP1, GCR, CYP17A1, ACTA2, CXCL14, FAP, CCL17, MSMB, IRF1, VDR). Therefore, the expression of CYPs is not directly associated with prostate cancer but is largely determined by genetic, epigenetic factors, as well as endogenous substrates and xenobiotics. The significant correlative relationship between CYPs and genes associated with cancer may indicate common regulatory pathways that may have a synergistic effect on the tumor, ensuring the survival of cancer cells.

Osteonectin (SPARC) prognostic value in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is common malignancy among men worldwide. To date only few molecular markers are available to predict its course and outcome. SPARC is considered to be promising prognostic marker of PCa due to its involvement in various cancer processes. MATERIALS AND METHODS: study was conducted on PCa surgical primary tumor samples, obtained from 84 patients. Level of SPARC mRNA expression was estimated using RT-qPCR. To identify SPARC protein (osteonectin) in prostate tissue, immunohistochemical analysis was conducted. Bioinformatical analysis was performed on UALCAN and TNMplot resources. RESULTS: bioinformatical analysis demonstrated that SPARC mRNA levels are decreased in PCa samples, in comparison to normal tissue. In patients with lymph node metastases its levels are 1.26 times higher; p = 4.66E-02, than in N0 category. Ex vivo study demonstrated that SPARC expression was elevated on both mRNA and protein levels in PCa patients with lymph node metastases (by 2.34 and 1.91, respectively, p < 0.05). We established higher levels of SPARC mRNA and protein in PCa patients with T3 tumors, as well as high Gleason score. Estimation of survival rates demonstrated that PCa patients with a high level of SPARC mRNA and protein have decreased overall 2-year survival. CONCLUSIONS: SPARC protein was overexpressed on mRNA and protein levels in patients with presence of lymph node metastases and higher Gleason score of tumors. Also, both mRNA and protein upregulation were associated with worse survival rates. The current study has therefore provided further evidence that SPARC is indeed linked to the prognosis and aggressiveness of human PCa.

Comparison of aggressiveness in central versus peripheral T1a clear-cell renal cell carcinoma.

PURPOSE: This study aimed to estimate the difference between peripheral and central small renal lesions in terms of their oncologic potential. METHODS: Cross-sectional retrospective analysis of patients with small renal masses (T1a) who underwent surgical treatment between January 2008 and July 2019 at the affiliated hospital. Only patients with ccRCC pathology were included. Cases were divided into 2 groups depending on tumor location (central or peripheral) based on the R.E.N.A.L and local nephrometry scoring. Presence of nodal involvement, distant metastases, ISUP grade and endophytic growth were defined as aggressiveness predictors. Statistical analyses was performed using a standard statistical software (IBM SPPS Statistics Ver. 22), with P < 0.05 considered statistically significant. Associations between tumor location and Fuhrman grade, exo-/endophytic growth, TNM classification, and type of operation were tested using the Pearson χ² test and 1-way ANOVA test. RESULTS: Patients with centrally located tumors had a higher incidence of clinical and pathological lymph node involvement (P = 0.02, χ2 = 5.1). Patients in both groups had an equal number of distant metastases at the time of diagnosis (P = 0.3, χ2 = 0.8). The operation time was significantly longer in patients with central lesions, which obviously showed higher tumor complexity in this group (P < 0.005). Pathological evaluation revealed differences between ISUP grades in both groups (P < 0.005, χ2 = 29.9). Central masses were characterized by higher aggressiveness, indicating a worse prognosis. Furthermore, the cases in the first group were more often endophytic (P = 0.03, χ2 = 0.9). Nevertheless, this did not affect the surgical strategy in most cases with a tendency toward partial nephrectomy. Eventually, organ-sparing treatment was preferable in both groups (P = 0.13, χ2 = 2.29). CONCLUSION: Centrally located kidney cancer has showed in present study a higher incidence of high ISUP grade, regional nodal involvement and endophytic growth type. Endophytic growth type was associated with worse ISUP grading. Distribution of ISUP grade was not age depended, thus showing no difference by this criterion, when comparing different age groups. Higher ISUP grade was strongly associated with presence of distant metastases in T1a kidney tumors. Further analysis is needed to investigate aggressiveness of centrally located T1a RCC, as it may influence current conservative management options.

Efficacy of combined organ-sparing management of invasive upper urinary tract urothelial carcinoma.

Introduction: The study aimed to evaluate the objective response level to neoadjuvant platinum-based chemotherapy and tumour complexity reduction in patients with invasive upper tract urothelial cancer (UTUC), and to estimate the functional and oncological outcomes of the combined organ-sparing approach compared to radical nephroureterectomy. Material and methods: This prospective, non-randomised cohort study was conducted by the National Cancer Institute of Ukraine. Patients with invasive UTUC were enrolled between October 2016 and January 2021. Patients were allocated to one of two cohorts depending on the estimated glomerular filtration rate (eGFR) of the affected kidney. In cases where eGFR was preserved, neoadjuvant chemotherapy with an organ-sparing approach was used; all other cases proceeded directly to radical nephroureterectomy. Results: A total of 64 patients (32 in each cohort) with invasive UTUC were enrolled. Both groups were comparable in terms of age, sex, T stage, maximal tumour size, eGFR, Eastern Cooperation Oncology Group (ECOG) performance status, body mass Index (BMI), and haemoglobin level. After four cycles of chemotherapy, there were no cases of progressive disease, stable disease [16 (50%), partial response; 12 (38%); and complete response, 4 (12%)]. The average maximal tumour size decreased by 2.3 cm. Prior to surgical treatment, total GFR according to scintigraphy did not statistically differ in both groups (р = 0.13). However, 3 months after surgery patients who underwent the organ-sparing approach had a better total eGFR (р = 0.0039), which was probably owing to the preserved kidney function (18.9 +5.1 mL/min). Better 2-year recurrence-free survival was also observed in the organ-sparing management group (85% vs 72%, log-rank test; p = 0.03). Conclusions: Neoadjuvant systemic therapy reduces the surgical complexity of invasive UTUC without influencing the safety profile. The gemcitabine/cisplatin regimen leads to high regression rates among invasive UTUC, which could result in an organ-sparing approach in selected cases. Kidney function preservation remains a key parameter that can increase the possibility of effective systemic treatment.

Advantages of organ-sparing treatment approaches in metastatic kidney cancer.

PURPOSE: This study analyzed oncological outcomes of patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with cytoreductive partial nephrectomy or nephrectomy. METHODS: This prospective non-randomized cohort study included 109 patients with metastatic ccRCC who underwent surgical treatment between 2011 and 2020. Patients were stratified into cytoreductive partial nephrectomy or nephrectomy groups. Survival curves were estimated, and Cox-regression analysis was performed to identify factors affecting potential lethality. RESULTS: The groups differed significantly in terms of T stage and International metastatic RCC database consortium (IMDC) risk groups, but not international society of urological pathology (ISUP) grading. The average blood loss volume was higher in the partial nephrectomy group. In contrast, the duration of post-operative stay, complication rate; and 30-day hospital readmission rate were similar between two groups. There was a significant difference in overall survival in favor of the partial nephrectomy group, who had better 7-year survival rates. Standardization based on the clinical complexity of the patients showed that cytoreductive partial nephrectomy was associated with a lower risk of death compared to nephrectomy. CONCLUSION: Partial nephrectomy is a safe method of choice in patients with metastatic ccRCC. Kidney preservation in a metastatic setting can play a role in reducing potential adverse systemic therapy events and in decreasing the risk for concomitant pathology deterioration.

Transperitoneal uretercutaneostomy with use of mesosigmoid colon peritoneum in patients with bladder cancer after radical cystectomy.

OBJECTIVE: The aim of the study was to we describe the new surgical approach of constructing single site transperitoneal cutaneostomy with the use of sigmoid colon accompanied by skin modified fixation technique and its clinical outcomes. PATIENTS AND METHODS: Materials and methods: 89 patients were included in a single center study from January 2015 to May 2019. All patients underwent single-site modified transperitonial ureterocutanesotomy. Clinical and surgical data were analyzed. Statistical analyses were performed using SPSS 22.0. RESULTS: Results: Majority of the patients had a low performance status and rationale for cystectomy was palliative cytoreduction. Almost half of the patients had upper tract obstruction at diagnosis with 40% of patients presenting with a decreased kidney function. Surgical procedure was safe taking to account locally advanced. All the surgeries were performed with acceptable complications rate. Blood loss didn't exceeded 1000 ml and median operation time was 194 minutes. Early and late postoperative complications were analyzed and stomal stenosis that needed continuous restenting or reoperation was seen in 20% of cases. CONCLUSION: Conclusions: Single-site modified transperitonial ureterocutanesotomy is safe and effective surgical approach with acceptable complication rates and duration. Such surgery may be used as a major urinary diversion approach in advanced bladder cancer patients with severe symptoms and low-performance status. Further external validation studies needed to evaluate efficacy of the proposed technique.

An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells.

Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations. Cancer Res; 76(9); 2637-51. ©2016 AACR.

Aldehyde Dehydrogenase Is Regulated by ß-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells.

Radiotherapy is a curative treatment option in prostate cancer. Nevertheless, patients with high-risk prostate cancer are prone to relapse. Identification of the predictive biomarkers and molecular mechanisms of radioresistance bears promise to improve cancer therapies. In this study, we show that aldehyde dehydrogenase (ALDH) activity is indicative of radioresistant prostate progenitor cells with an enhanced DNA repair capacity and activation of epithelial-mesenchymal transition (EMT). Gene expression profiling of prostate cancer cells, their radioresistant derivatives, ALDH(+) and ALDH(-) cell populations revealed the mechanisms, which link tumor progenitors to radioresistance, including activation of the WNT/ß-catenin signaling pathway. We found that expression of the ALDH1A1 gene is regulated by the WNT signaling pathway and co-occurs with expression of ß-catenin in prostate tumor specimens. Inhibition of the WNT pathway led to a decrease in ALDH(+) tumor progenitor population and to radiosensitization of cancer cells. Taken together, our results indicate that ALDH(+) cells contribute to tumor radioresistance and their molecular targeting may enhance the effectiveness of radiotherapy.

Epigenetic alterations of chromosome 3 revealed by NotI-microarrays in clear cell renal cell carcinoma.

This study aimed to clarify epigenetic and genetic alterations that occur during renal carcinogenesis. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI-clones associated with 188 genes for hybridization with 23 paired normal/tumor DNA samples of primary clear cell renal cell carcinomas (ccRCC). Twenty-two genes showed methylation and/or deletion in 17-57% of tumors. These genes include tumor suppressors or candidates (VHL, CTDSPL, LRRC3B, ALDH1L1, and EPHB1) and genes that were not previously considered as cancer-associated (e.g., LRRN1, GORASP1, FGD5, and PLCL2). Bisulfite sequencing analysis confirmed methylation as a frequent event in ccRCC. A set of six markers (NKIRAS1/RPL15, LRRN1, LRRC3B, CTDSPL, GORASP1/TTC21A, and VHL) was suggested for ccRCC detection in renal biopsies. The mRNA level decrease was shown for 6 NotI-associated genes in ccRCC using quantitative PCR: LRRN1, GORASP1, FOXP1, FGD5, PLCL2, and ALDH1L1. The majority of examined genes showed distinct expression profiles in ccRCC and papillary RCC. The strongest extent and frequency of downregulation were shown for ALDH1L1 gene both in ccRCC and papillary RCC. Moreover, the extent of ALDH1L1 mRNA level decrease was more pronounced in both histological types of RCC stage III compared with stages I and II (P = 0.03). The same was observed for FGD5 gene in ccRCC (P < 0.06). Dedicated to thememory of Eugene R. Zabarovsky.