Molecular landscape for risk prediction and personalized therapeutics of castration-resistant prostate cancer: at a glance.

Prostate cancer (PCa) is commonly occurred with high incidence in men worldwide, and many patients will be eventually suffered from the dilemma of castration-resistance with the time of disease progression. Castration-resistant PCa (CRPC) is an advanced subtype of PCa with heterogeneous carcinogenesis, resulting in poor prognosis and difficulties in therapy. Currently, disorders in androgen receptor (AR)-related signaling are widely acknowledged as the leading cause of CRPC development, and some non-AR-based strategies are also proposed for CRPC clinical analyses. The initiation of CRPC is a consequence of abnormal interaction and regulation among molecules and pathways at multi-biological levels. In this study, CRPC-associated genes, RNAs, proteins, and metabolites were manually collected and integrated by a comprehensive literature review, and they were functionally classified and compared based on the role during CRPC evolution, i.e., drivers, suppressors, and biomarkers, etc. Finally, translational perspectives for data-driven and artificial intelligence-powered CRPC systems biology analysis were discussed to highlight the significance of novel molecule-based approaches for CRPC precision medicine and holistic healthcare.

TIMP1 shapes an immunosuppressive microenvironment by regulating anoikis to promote the progression of clear cell renal cell carcinoma.

BACKGROUND: The association between ccRCC and Anoikis remains to be thoroughly investigated. METHODS: Anoikis-related clusters were identified using NMF. To identify prognostic anoikis-related genes (ARGs) and establish an optimal prognostic model, univariate Cox and LASSO regression were employed. The E-MTAB-1980 cohort was utilized for external validation. Multiple algorithms were used to evaluate the immune properties of the model. GO, KEGG and GSVA analyses were employed to analyze biological pathway functions. qRT-PCR was employed to measure RNA levels of specific genes. Cell Counting Kit-8, wound healing, and Transwell chamber assays were performed to determine changes in the proliferative and metastatic abilities of A498 and 786-O cells. RESULTS: Based on the expression of 21 prognostic ARGs, we constructed anoikis-related clusters with different prognostic and immune characteristics. The cluster A1 showed a worse prognosis, higher infiltration of immunosuppressive cells and enrichment of several oncogenic pathways. We also calculated the Anoikis Index (AI). Patients in high AI group had a worse prognosis, higher infiltration of immunosuppressive cells and higher expression of immunosuppressive checkpoints. TIMP1 exerted a tumor-promoting role in ccRCC and was significantly associated with immunosuppressive cells and checkpoints. The downregulation of TIMP1 negatively regulated ccRCC cell proliferation and metastasis. CONCLUSIONS: ARGs played crucial roles in tumorigenesis and progression and were positively associated with a poor prognosis. AI had great accuracy in predicting the prognosis and immune characteristics of ccRCC patients. TIMP1 was significantly associated with clinicopathological variables and the immunosuppressive microenvironment, which could be exploited to design novel immunotherapies for ccRCC patients.

Extracapsular extension of transitional zone prostate cancer miss-detected by multiparametric magnetic resonance imaging.

OBJECTIVES: To demonstrate the importance of extracapsular extension (ECE) of transitional zone (TZ) prostate cancer (PCa), examine the causes of its missed detection by Mp-MRI, and develop a new predictive model by integrating multi-level clinical variables. MATERIALS AND METHODS: This retrospective study included 304 patients who underwent laparoscopic radical prostatectomy after 12 + X needle transperineal transrectal ultrasound (TRUS)-MRI-guided targeted prostate biopsy from 2018 to 2021 in our center was performed. RESULTS: In this study, the incidence rates of ECE were similar in patients with MRI lesions in the peripheral zone (PZ) and TZ (P = 0.66). However, the missed detection rate was higher in patients with TZ lesions than in those with PZ lesions (P < 0.05). These missed detections result in a higher positive surgical margin rate (P < 0.05). In patients with TZ lesions, detected MP-MRI ECE may have grey areas: the longest diameters of the MRI lesions were 16.5-23.5 mm; MRI lesion volumes were 0.63-2.51 ml; MRI lesion volume ratios were 2.75-8.86%; PSA were 13.85-23.05 ng/ml. LASSO regression was used to construct a clinical prediction model for predicting the risk of ECE in TZ lesions from the perspective of MRI and clinical features, including four variables: the longest diameter of MRI lesions, TZ pseudocapsule invasion, ISUP grading of biopsy pathology, and number of positive biopsy needles. CONCLUSIONS: Patients with MRI lesions in the TZ have the same incidence of ECE as those with lesions in the PZ, but a higher missed detection rate.

The anti-apoptotic effect on cancer-associated fibroblasts of B7-H3 molecule enhancing the cell invasion and metastasis in renal cancer.

Background: Renal cancer is one of the most common malignancies. However, the mechanisms underlying its development are still ambiguous. B7-H3 has been described as an important tumor antigen in various human tumors. An abnormal high expression of B7-H3 molecules is often observed in tumor cells and tumor stromal cells in the tumor microenvironment. On the basis of the above findings, we hypothesized that cancer-associated fibroblasts (CAFs) clustered in the renal cell microenvironment can survive for a long time with the anti-apoptotic effect of B7-H3, and then secrete cytokines to enhance the malignant behavior of renal cancer cells. Methods: The expression of B7-H3 protein in CAFs was detected in renal cancer tissues. Then, the CAFs cells were stably transfected with shRNA and their expression was silenced to determine the role of B7-H3 in CAFs. Western blot was used to detect the expression of apoptosis-related proteins, hepatocyte growth factor (HGF) protein and stromal cell-derived factor-1 (CXCL12) protein. CAF-NC cells and CAFs-shRNA cells were co-cultured with A498 cells to assess the biological function changes of A498. Results: A group of CAFs were found with B7-H3 expression in renal cancer. B7-H3 can stimulate CAFs to secrete HGF and Cxcl-12, and has strong anti-apoptotic effect on CAFs. We also found that CAFs-NC promotes the proliferation, invasion and migration of A498 cells in vitro and promotes the tumor formation of A498 in vivo. Conclusion: B7-H3+ CAFs promote the invasion and metastasis in renal cancer.

Interleukin-35 as a predictor of prostate cancer in patients undergoing initial prostate biopsy.

BACKGROUND: Interleukin (IL)-35 is a novel inhibitory cytokine and has recently been implicated in tumor immunity. However, the role of IL-35 in prostate cancer (PCa) has not been elucidated. OBJECTIVE: To evaluate the role of plasma IL-35 in the diagnosis and prognosis of PCa in Chinese patients undergoing initial prostate biopsy. MATERIALS AND METHODS: Using ELISA, plasma IL-35 levels were measured in 180 patients, who underwent a prostate biopsy. The clinical correlation of IL-35 with clinicopathological parameters was also evaluated. Univariate and multivariate logistic regression and receiver operating characteristic (ROC) curve analysis were performed to establish the role of IL-35 as a clinical biomarker. RESULTS: Seventy-five (41.6%) of patients were histopathologically confirmed to have PCa. Plasma IL-35 levels were significantly higher in PCa patients (134.48±78.48 pg/mL) compared to non-PCa patients (67.22±24.08 pg/mL). ROC analysis showed that IL-35 was an independent predictor of PCa. Furthermore, IL-35 was found to be a significantly independent predictor of PCa in a group of patients with prostate-specific antigen levels between 4 and 10 ng/mL; was also able to predict advanced PCa from localized PCa and bone metastasis positive PCa from negative PCa. CONCLUSION: Our data suggest for the first time that plasma IL-35 levels are correlated with PCa and is the independent predictor of PCa progression and metastasis. Thus, IL-35 could be utilized as a potential biomarker for diagnosis and prognosis of PCa, could also aid in decision making and predict the stage of the disease.

PSCA rs1045531 Polymorphism and the Risk of Prostate Cancer in a Chinese Population Undergoing Prostate Biopsy.

BACKGROUND AND PURPOSE: This study explored the association between a single-nucleotide polymorphism of prostate stem cell antigen and prostate cancer in Chinese patients undergoing prostate biopsy. MATERIALS AND METHODS: DNA from 416 patients undergoing prostate biopsy was typed for the prostate stem cell antigen rs1045531 single-nucleotide polymorphism. The frequency of the rs1045531 polymorphism in patients with prostate cancer and in patients with benign prostatic hyperplasia was compared. Associations between the polymorphism and the risk of prostate cancer, prostate special antigen, Gleason score, and clinical stage were analyzed. RESULTS: Statistically significant differences in the distribution of the rs1045531 genotypes and alleles were found between prostate cancer and benign prostatic hyperplasia in patients undergoing prostate biopsy ( P = .035 and .046, respectively). We found that the rs1045531 AC genotype was significantly associated with a high risk of prostate cancer in the heterozygote model (AC vs CC; odds ratio = 2.383, 95% confidence interval: 1.198-4.741, χ2 = 6.229, P = .013) and the dominant model (AA/AC vs CC; odds ratio = 2.169, 95% confidence interval: 1.112-4.229, χ2 = 5.228, P = .022). However, susceptibility of prostate cancer was decreased in the homozygote model (AA vs CC; odds ratio = 0.828, 95% confidence interval: 0.143-4.805, P = .601). When considering clinical factors, the rs1045531 showed an association with prostate special antigen of 10 ng/mL or greater, a Gleason score of 7 or greater, and a size of T2 or greater. CONCLUSION: Men with the rs1045531 AC genotype of prostate stem cell antigen were at higher risk of prostate cancer in Chinese patients undergoing prostate biopsy.