Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC); however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS). We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%), 34 (30.9%), and 17 (15.5%) in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l^-1), liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months) as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678-0.836). In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.
Abiraterone Acetate/therapeutic use* ; Adenocarcinoma/secondary* ; Aged ; Aged, 80 and over ; Alkaline Phosphatase/blood* ; Androgen Antagonists/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Bone Neoplasms/secondary* ; Cohort Studies ; Humans ; Kaplan-Meier Estimate ; L-Lactate Dehydrogenase/blood* ; Liver Neoplasms/secondary* ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Metastasis ; Nomograms ; Prognosis ; Proportional Hazards Models ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Serum Albumin/metabolism* ; Survival Rate ; Time Factors

OBJECTIVETo investigate the correlation between a diverse of clinical factors and bone metastases of prostate cancer.

METHODSThe clinical data of 80 patients with prostate cancer were collected and analyzed. The correlations of age, alkaline phosphotase (ALP), prostate specific antigen (PSA), erythrocyte sedimentation rate (ESR), Gleason score, and expressions of androgen receptor (AR) and Ki-67 with bone metastases were analyzed by one-way ANOVA and Logistic regression analysis. The cutoff value, sensitivity and specificity of the independent correlation factors were calculated.

RESULTSForty-five of the 80 patients (56%) were found to have bone metastasis, who had significantly older age and higher levels of ALP, PSA, ESR, Gleason score, and expressions of AR and Ki-67 than those without bone metastasis (P<0.05). Logistic regression analysis identified PSA, Gleason score and AR expression as independent factors correlated with bone metastasis with OR (95% CI) of 1.005 (1.001, 1.009) (P=0.008), 5.356 (1.431, 20.039) (P=0.013), and 18.594 (2.460, 140.524) (P=0.005), respectively. The cutoff values of PSA, Gleason Score and AR were 67.1 ng/ml, 7.5, and 2.5, respectively; their sensitivities were 55.6%, 75.6%, and 84.0% for predicting bone metastasis with specificities of 97.1%, 82.9%, and 91.4%, respectively.

CONCLUSIONOf the factors analyzed, PSA, Gleason score and AR expression, but not age, ALP, PSA, ESR, or Ki-67 expression, are the predictive factors of bone metastasis of prostate cancer.

Alkaline Phosphatase ; metabolism ; Bone Neoplasms ; diagnosis ; secondary ; Humans ; Male ; Neoplasm Grading ; Predictive Value of Tests ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; pathology ; Receptors, Androgen ; metabolism ; Sensitivity and Specificity

PURPOSE: Docetaxel-based chemotherapy (DTX) improves overall survival (OS) of men with metastatic castration-resistant prostate cancer (mCRPC). Considering the potential existence of androgen receptors that remain active at this stage, we aimed to assess the impact of the combined use of androgen deprivation therapy (ADT) with DTX for mCRPC. MATERIALS AND METHODS: We performed a single-institutional retrospective analysis of patients with mCRPC who received either DTX alone (DTX group, n=21) or concurrent DTX and ADT (DTX+ADT group, n=26) between August 2006 and February 2014. All patients received DTX doses of 75 mg/m2 every three weeks for at least three cycles. In the DTX+ADT group, all patients used luteinizing hormone releasing hormone agonist continuously as a concurrent ADT. RESULTS: The median follow-up period was 24.0 months (interquartile range 12.0-37.0) for the entire cohort. The median radiographic progression-free survival (rPFS) was 9.0 months and 6.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.036). On multivariable Cox regression analysis, concurrent administration of ADT was the only significant predictor of rPFS [hazard ratio (HR)=0.525, 95% confidence intervals (CI) 0.284-0.970, p=0.040]. The median OS was 42.0 and 38.0 months in the DTX+ADT and DTX groups, respectively (log-rank p=0.796). On multivariable analysis, hemoglobin level at the time of DTX initiation was associated with OS (HR=0.532, 95% CI 0.381-0.744, p<0.001). CONCLUSION: In chemotherapy-naive patients with mCRPC, the combined use of ADT with DTX improved rPFS. Our result suggests that the concurrent administration of ADT and DTX is superior to DTX alone.
Adenocarcinoma/blood/*drug therapy/secondary ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Disease-Free Survival ; Gonadotropin-Releasing Hormone/administration & dosage/agonists ; Hemoglobins/metabolism ; Humans ; Male ; Middle Aged ; Prostatic Neoplasms, Castration-Resistant/blood/*drug therapy/pathology ; Retrospective Studies ; Survival Rate ; Taxoids/administration & dosage

OBJECTIVETo investigate the action mechanisms of the FZD5 gene in prostate cancer bone metastasis and search for some new treatments for this disease.

METHODSWe determined the expression level of the FZD5 gene in prostate cancer PC3 cells and, after transfection of siRNA into the PC3 cells and silence of the FZD5 gene, observed the changes in the migration and proliferation of the cells. We established the model of prostate cancer bone metastasis by tibial injection of prostate cancer cells in the nude mice. Then we injected control siRNA and FZD5-silenced siRNA into the tibia of the mice followed by evaluation of tumor-induced bone destruction by X-ray imaging at 0, 1, and 3 weeks and by HE staining at 3 weeks after injection.

RESULTSAfter transfection of FZD5-silenced siRNA into the prostate cancer PC3 cells, the expression of the FZD5 gene was decreased about 70%. The rate of cell proliferation was significantly lower in the gene silencing group than in the control (P < 0.05), and that of cell migration dropped by 30% in the former as compared with the latter group at 48 hours after FZD5 silencing (P < 0.05). At 3 weeks after injection of control siRNA or FZD5-silenced siRNA into the tibia of the mice, osteolytic damage was observed in both groups, though less in the FZD5 silencing group, with only a few remaining bone trabeculae visible.

CONCLUSIONSilencing the FZD5 gene can reduce the migration and proliferation of prostate cancer cells, help to suppress bone metastasis and destruction, and thereby improve the survival rate and quality of life of the patients.

Animals ; Bone Neoplasms ; genetics ; prevention & control ; secondary ; Cell Line, Tumor ; Cell Movement ; genetics ; Cell Proliferation ; genetics ; Frizzled Receptors ; genetics ; physiology ; Gene Expression ; Gene Silencing ; Male ; Mice ; Mice, Nude ; Osteolysis ; Prostatic Neoplasms ; genetics ; metabolism ; pathology ; Quality of Life ; RNA, Small Interfering ; administration & dosage ; genetics ; Transfection

Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process of bone metastasis, the roles of the Wnt signaling, and the available experimental models and treatments.
Animals ; Bone Neoplasms ; drug therapy ; metabolism ; radiotherapy ; secondary ; surgery ; Breast Neoplasms ; metabolism ; pathology ; Disease Models, Animal ; Drug Delivery Systems ; Female ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Male ; Mice ; Prostatic Neoplasms ; metabolism ; pathology ; Wnt Proteins ; metabolism ; Wnt Signaling Pathway ; beta Catenin ; metabolism

The formation of osteolytic bone lesions is a key process for osteolytic cancer to metastasize to the bone and is under the control of a set of transcription factors. Recently, the inhibitor of differentiation 1 (Id1) has been linked with angiogenesis, tumorigenesis, metastasis and bone formation. However, the function of Id1 during the process of bone destruction caused by cancer in vivo has not yet been elucidated. We, therefore, examined whether and how Id1 affects the ability of cancer to form osteolytic lesion in vivo. The study used a lentiviral vector overexpressing short hairpin RNA (shRNA) targeting Id1 gene. PC3 cells, a prostate cancer cell line, were transduced with Id1 shRNA or negative control (NC) shRNA before implantation in BALB/c mice. Cells were implanted in a tibial injection model. Tumor formation in bone was monitored by X-ray. The relationship between parathyroid hormone-related protein (PTHrP), an osteolytic factor, and Id1 was analyzed by using immunohistochemistry in tissue sections from osteolytic lesion of the BALB/c mice. Our results showed that Id1 shRNA delivery to PC3 cells by lentivirus caused efficient and stable Id1 gene silencing. In the intratibial model, PC3 cells produced primarily osteolytic lesions in the bone. Eleven of 14 mice in Id1 shRNA group but only 4 of 14 mice in the NC shRNA group developed osteolytic lesions with cortical destruction at 4th week. Mice treated with Id1 shRNA had larger tumor volume in the bone and larger cortical destruction. The expression of PTHrP protein in PC3 cells was not affected by Id1 knockdown in vivo. These results indicate that Id1 may down-regulate the ability of PC3 cells to form osteolytic lesions in vivo and the signal pathway needs to be further investigated.
Animals ; Bone Neoplasms ; genetics ; metabolism ; secondary ; Cell Line, Tumor ; Gene Silencing ; Humans ; Inhibitor of Differentiation Protein 1 ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Osteolysis ; genetics ; metabolism ; pathology ; Prostatic Neoplasms ; genetics ; metabolism ; pathology

OBJECTIVETo investigate diagnostic values of the detection of TMPRSS2-ERG gene fusion in metastatic prostate cancer.

METHODSA total of 32 fine needle aspiration (FNA) specimens of metastatic prostate carcinomas were retrieved from the pathology files at MD Anderson Cancer Center. The metastatic sites included the pelvic and remote lymph nodes, liver, bone, and thyroid gland. Immunohistochemical staining for PSA, PAP, synaptophysin, chromogranin A was performed. TMPRSS2-ERG gene fusion was evaluated on sections of cell blocks by fluorescence in situ hybridization (FISH) using ERG gene break-apart probes.

RESULTSThe mean age of the patients was 67 years. Twenty-six patients had a previous history of prostatic adenocarcinoma, while 6 patients presented initially with metastasis. In 11 patients, the metastatic lesions showed characteristic features of small cell carcinoma (SCC) and were positive for synaptophysin (9/9), chromogranin A (7/8), but negative for prostatic specific antigen (7/7). FISH analysis demonstrated a rearrangement of ERG gene in 10 of 32 cases (31.3%), and the rearrangement was associated with deletion of the 5' ERG gene in 6 cases. In addition, the copy number of ERG rearrangement gene locus was increased in 8 cases. Among the 11 cases with SCC features, a rearrangement of ERG gene was present in 5 cases, of which a deletion of the 5' ERG gene and increased copy number were seen in 3 cases.

CONCLUSIONSTMPRSS2-ERG gene fusion can be evaluated in FNA specimens of metastatic prostate cancer. Metastatic prostate cancers have a high prevalence of TMPRSS2-ERG gene fusion along with a frequent copy number increase of ERG gene. TMPRSS2-ERG gene fusion persists in metastatic prostate cancers and even in those with poorly differentiated SCC features. Therefore, an identification of the TMPRSS2-ERG gene fusion may be used to establish the prostatic origin of metastasis.

Acid Phosphatase ; Adenocarcinoma ; genetics ; metabolism ; pathology ; secondary ; surgery ; Aged ; Aged, 80 and over ; Biopsy, Fine-Needle ; Carcinoma, Small Cell ; genetics ; metabolism ; pathology ; secondary ; surgery ; Chromogranin A ; metabolism ; Follow-Up Studies ; Gene Fusion ; Gene Rearrangement ; Humans ; In Situ Hybridization, Fluorescence ; Liver Neoplasms ; genetics ; metabolism ; pathology ; secondary ; surgery ; Lymphatic Metastasis ; Male ; Middle Aged ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Prostate-Specific Antigen ; metabolism ; Prostatic Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Protein Tyrosine Phosphatases ; metabolism ; Synaptophysin ; metabolism

OBJECTIVETo detect the expression of RhoC and Rho kinase 1 (ROCK-1) in prostate carcinoma, and explore the possible mechanism of RhoC/ROCK-1 in the pathogenesis of prostate carcinoma.

METHODSTissue specimens from 73 patients with prostate carcinoma and corresponding paracancerous tissues were obtained by prostate cancer biopsy or radical prostatectomy. The expression of RhoC/ROCK-1 mRNA was detected by RT-PCR. Western blot and immunohistochemistry were performed to dertect the expression of RhoC/ROCK-1 protein. Eukaryotic expression plasmids of RhoC were constructed and transfected into PC-3M-2B4 cells. p-MAPK and p-Akt were detected by Western bolt.

RESULTSThe expression levels of RhoC and ROCK-1 mRNA in the prostate carcinomas were significantly higher than those in corresponding paracancerous tissues [72.6% (53/73) vs. 34.2% (25/73); 68.5% (50/73) vs. 38.4% (28/73), P < 0.01], respectively. The results indicated that RhoC/ROCK-1 mRNA expression had no significant correlation with Gleason grade. However, the expression of RhoC/ROCK-1 mRNA showed a significant positive correlation with distant metastasis. The RhoC/ROCK-1 protein expression in prostate cancer was also higher than corresponding paracancerous tissues, and showed a significant positive correlation with p-MAPK and p-Akt expression levels. In addition, p-MAPK and p-Akt expression levels were up-regulated in the transcripts.

CONCLUSIONExpression levels of RhoC and ROCK-1 in prostate carcinoma are higher than those in corresponding paracancerous tissues, showing a significant positive correlation with distant metastasis. RhoC/ROCK-1 may be involved in the development, invasion and metastasis of prostate carcinoma.

Bone Neoplasms ; metabolism ; secondary ; Cell Line, Tumor ; Humans ; Male ; Mitogen-Activated Protein Kinases ; metabolism ; Neoplasm Grading ; Neoplasm Staging ; Phosphorylation ; Prostatectomy ; Prostatic Neoplasms ; metabolism ; pathology ; surgery ; Proto-Oncogene Proteins c-akt ; metabolism ; RNA, Messenger ; metabolism ; Transfection ; Up-Regulation ; rho GTP-Binding Proteins ; genetics ; metabolism ; rho-Associated Kinases ; genetics ; metabolism ; rhoC GTP-Binding Protein

Metastasis represents by far the most feared complication of prostate carcinoma and is the main cause of death for patients. The skeleton is frequently targeted by disseminated cancer cells and represents the sole site of spread in more than 80% of prostate cancer cases. Compatibility between select malignant phenotypes and the microenvironment of colonized tissues is broadly recognized as the culprit for the organ-tropism of cancer cells. Here, we review our recent studies showing that the expression of platelet-derived growth factor receptor alpha (PDGFRα) supports the survival and growth of prostate cancer cells in the skeleton and that the soluble fraction of bone marrow activates PDGFRα in a ligand-independent fashion. Finally, we offer pre-clinical evidence that this receptor is a viable target for therapy.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Bone Marrow ; enzymology ; pathology ; Bone Neoplasms ; prevention & control ; secondary ; Enzyme Activation ; Humans ; Male ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptor, Platelet-Derived Growth Factor alpha ; antagonists & inhibitors ; genetics ; immunology ; metabolism ; Signal Transduction ; Transcriptional Activation

Adenocarcinoma ; metabolism ; pathology ; Adult ; Combined Modality Therapy ; Diagnosis, Differential ; Follow-Up Studies ; Humans ; Keratins ; metabolism ; Lung Neoplasms ; secondary ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Prostate-Specific Antigen ; metabolism ; Prostatectomy ; Prostatic Neoplasms ; metabolism ; pathology ; secondary ; surgery ; Sarcoma, Synovial ; metabolism ; pathology ; surgery ; Vimentin ; metabolism