Circulating tumor cells in prostate cancer: Precision diagnosis and therapy.
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ABSTRACT:
SUBMITTER: Liu W
PROVIDER: S-EPMC5529747 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Circulating tumor cells (CTCs) have emerged as a viable solution to the lack of tumor tissue availability for patients with a variety of solid tumors, including prostate cancer. Different approaches have been used to capture this tumor cell population and several of these techniques have been used to assess the potential role of CTCs as a biological marker to predict treatment efficacy and clinical outcome. CTCs are now considered a strong tool to understand the molecular characteristics of prostate cancer, and to be used and analyzed as a 'liquid biopsy' in the attempt to grasp the biological portrait of the disease in the individual patient.
| S-EPMC4149177 | biostudies-literature
Project description:Unmet needs in prostate cancer drug development and patient management are the ability to monitor treatment effects and to identify therapeutic targets in a tumor at the time treatment is being considered. This review focuses on establishing analytically valid biomarkers for specific contexts of use in patients with castration-resistant prostate cancer (CRPC), emphasizing a biomarker currently in clinical use, circulating tumor cells (CTC). The FDA Critical Path provides a road map for these investigations, which, if followed, will facilitate the incorporation of these types of assays into clinical decision-making. CTC enumeration at baseline and post-treatment is prognostic of survival, with no threshold effect, and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. The clinical utility of monitoring CTC changes with treatment, as an efficacy-response surrogate biomarker of survival, is currently being tested in large phase III trials, with the novel antiandrogen therapies abiraterone acetate and MDV3100. Molecular determinants can be identified and characterized in CTCs as potential predictive biomarkers of tumor sensitivity to a therapeutic modality. Additionally, we discuss novel technologies to enrich and characterize CTCs from more patients, the potential clinical uses of CTCs in determining prognosis and monitoring treatment effects, and CTCs as a source of tissue to identify predictive markers of drug sensitivity to guide treatment selection. Prospective studies, designed around the biomarker itself and the specific clinical context for which it is applied, are needed to further assess the role of these and novel markers in clinical practice.
| S-EPMC3743247 | biostudies-literature
Project description:BackgroundProstate-specific antigen (PSA) testing is limited in identifying prostate cancer (PCa) with modestly elevated PSA levels. Therefore, a robust method for the diagnosis of PCa is urgently needed.MethodsA total of 203 men with a PSA level of ≥4 ng/ml were eligible for enrollment in this study from July 2018 to May 2021, and randomly divided into a training set (n=78) and a validation set (n=125). Circulating tumor cells (CTCs) were detected using telomerase-based CTC detection (TBCD), and the diagnostic ability was evaluated using receiver operating characteristic (ROC) and logistic regression analyses.FindingsIn the training set, the area under the curve (AUC) of CTCs was 0.842 with a sensitivity of 80.33% and specificity of 82.35%. In the validation set, the AUC of CTCs was 0.789, with a sensitivity of 79.31% and specificity of 81.58%. There was no significant difference between CTCs (AUC=0.793) and PSA (AUC=0.697) in the range of 4-50 ng/ml. In the ranges of 4-20 ng/ml and 4-10 ng/ml, the AUC of CTCs were 0.811 and 0.825, respectively, which were superior to the AUC of PSA (0.588 and 0.541). The sensitivity and specificity of CTCs in the three PSA groups were higher than 80%. Moreover, we further established a CTC+PSA combined model, which could significantly improve the diagnostic ability of a PSA level of '4-10 ng/ml'.InterpretationTBCD could be a valuable method for distinguishing PCa and benign prostatic disease, especially in the PSA diagnostic gray area of '4-10 ng/ml'.
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Project description:Circulating tumor cell (CTC) enumeration promises to be an important predictor of clinical outcome for a range of cancers. Established CTC enumeration methods primarily rely on affinity capture of cell surface antigens, and have been criticized for underestimation of CTC numbers due to antigenic bias. Emerging CTC capture strategies typically distinguish these cells based on their assumed biomechanical characteristics, which are often validated using cultured cancer cells. In this study, we developed a software tool to investigate the morphological properties of CTCs from patients with castrate resistant prostate cancer and cultured prostate cancer cells in order to establish whether the latter is an appropriate model for the former. We isolated both CTCs and cultured cancer cells from whole blood using the CellSearch® system and examined various cytomorphological characteristics. In contrast with cultured cancer cells, CTCs enriched by CellSearch® system were found to have significantly smaller size, larger nuclear-cytoplasmic ratio, and more elongated shape. These CTCs were also found to exhibit significantly more variability than cultured cancer cells in nuclear-cytoplasmic ratio and shape profile.
| S-EPMC3885705 | biostudies-literature
Project description:Following radical prostatectomy, success of adjuvant and salvage radiation therapy (RT) is dependent on the absence of micrometastatic disease. However, reliable prognostic/predictive factors for determining this are lacking. Therefore, novel biomarkers are needed to assist with clinical decision-making in this setting. Enumeration of circulating tumor cells (CTCs) using the regulatory-approved CellSearch System (CSS) is prognostic in metastatic prostate cancer. We hypothesize that CTCs may also be prognostic in the post-prostatectomy setting.Patient blood samples (n=55) were processed on the CSS to enumerate CTCs at 0, 6, 12 and 24 months after completion of RT. CTC values were correlated with predictive/prognostic factors and progression-free survival.CTC status (presence/absence) correlated significantly with positive margins (increased likelihood of CTC(neg) disease; P=0.032), and trended toward significance with the presence of seminal vesicle invasion (CTC(pos); P=0.113) and extracapsular extension (CTC(neg); P=0.116). Although there was a trend toward a decreased time to biochemical failure (BCF) in baseline CTC-positive patients (n=9), this trend was not significant (hazard ratio (HR)=0.3505; P=0.166). However, CTC-positive status at any point (n=16) predicted for time to BCF (HR=0.2868; P=0.0437).One caveat of this study is the small sample size utilized (n=55) and the low number of patients with CTC-positive disease (n=16). However, our results suggest that CTCs may be indicative of disseminated disease and assessment of CTCs during RT may be helpful in clinical decision-making to determine, which patients may benefit from RT versus those who may benefit more from systemic treatments.
| S-EPMC4788488 | biostudies-literature
Project description:Circulating tumor cells (CTCs) are promising biomarkers in prostate cancer (PC) because they derive from primary tumor and metastatic tissues. In this study, we used quantitative real-time PCR (qPCR) to compare the expression profiles of 41 PC-related genes between paired CTC and spinal column metastasis samples from 22 PC patients that underwent surgery for spinal cord compression. We observed good concordance between the gene expression profiles in the CTC and metastasis samples in most of the PC patients. Expression of nine genes (AGR2, AKR1C3, AR, CDH1, FOLH1, HER2, KRT19, MDK, and SPINK1) showed a significant correlation between the CTC and metastasis samples. Hierarchical clustering analysis showed a similar grouping of PC patients based on the expression of these nine genes in both CTC and metastasis samples. Our findings demonstrate that CTCs mirror gene expression patterns in tissue metastasis samples from PC patients. Although low detection frequency of certain genes is a limitation in CTCs, our results indicate the potential for CTC phenotyping as a tool to improve individualized therapy in metastatic prostate cancer.
| S-EPMC6047665 | biostudies-literature
Project description:Circulating tumor cells (CTCs), an advantageous target of liquid biopsy, is an important biomarker for the prognosis and monitoring of cancer. Currently, detection techniques for CTCs are mainly based on the physical and/or epithelial characteristics of tumor cells. However, biofunctional activity markers that can indicate the high metastatic capacity of CTCs are lacking.Functional microarray, quantitative real-time polymerase chain reaction, and Western blot were used on five prostate cancer cell lines with different metastatic capacities to identify the metastasis-related metabolic genes. The identified genes were detected in the CTCs of 64 clinical samples using the RNA in situ hybridization. A multi-criteria weighted model was used to determine the optimal metabolic markers for the CTCs test. Based on five fluorescent signals targeting DAPI, CD45, metabolic, epithelial (EpCAM/CKs), and mesenchymal (Vimentin/Twist) markers, the filtration-enriched CTCs were classified as GM+CTCs/GM-CTCs (metabolic types) or E-CTCs/H-CTCs/M-CTCs (EMT types). Correlation analysis and ROC curve were conducted on 54 prostate cancer samples to evaluate the clinical significance of CTCs subtypes.Eight metastasis-related metabolic genes were identified, including HK2, PDP2, G6PD, PGK1, PHKA1, PYGL, PDK1, and PKM2. Among them, PGK1 and G6PD were determined as optimal glucose metabolic (GM) markers for CTCs. GM+CTCs (marked by PGK1/G6PD) were detectable in 64.8% (35/54) of prostate cancer patients, accounting for 46.5% (134/288) of total CTCs. An increased GM+CTCs level was associated with advanced tumor stage and metastasis (P?<? 0.05). In the discrimination of cancer metastasis from non-metastasis, GM+CTCs presented a higher AUC of the ROC curve (0.780) compared with the EMT CTCs subtypes (E-CTCs 0.729, H-CTCs 0.741, and M-CTCs 0.648). A triple tPSA-Gleason-GM+CTCs marker increased the AUC to 0.904, which was better than that of the tPSA-Gleason-H-CTCs marker (0.874).The metabolic marker (PGK1/G6PD) is determined as the indicator for the biofunctional activity analysis of CTCs, compared with the existing morphological (EMT) classification on CTCs. The metabolic characterization of CTCs demonstrates that hypermetabolic GM+CTCs are promising biomarkers for prostate cancer metastasis.
| S-EPMC6025832 | biostudies-other
Project description:BackgroundThe low specificity of serum PSA resulting in the inability to effectively differentiate prostate cancer from benign prostate conditions is a persistent clinical challenge. The low sensitivity of serum PSA results in false negatives and can miss high-grade prostate cancers. We describe a non-invasive test for detection of prostate cancer based on functional enrichment of prostate adenocarcinoma associated circulating tumor cells (PrAD-CTCs) from blood samples followed by their identification by immunostaining for pan-cytokeratins (PanCK), prostate specific membrane antigen (PSMA), alpha methyl-acyl coenzyme-A racemase (AMACR), epithelial cell adhesion molecule (EpCAM), and common leucocyte antigen (CD45).MethodsAnalytical validation studies were performed to establish the performance characteristics of the test using VCaP prostate cancer cells spiked into healthy donor blood (HDB). The clinical performance characteristics of the test were evaluated in a case-control study with 160 known prostate cancer cases and 800 healthy males, followed by a prospective clinical study of 210 suspected cases of prostate cancer.ResultsAnalytical validation established analyte stability as well as acceptable performance characteristics. The test showed 100% specificity and 100% sensitivity to differentiate prostate cancer cases from healthy individuals in the case control study and 91.2% sensitivity and 100% specificity to differentiate prostate cancers from benign prostate conditions in the prospective clinical study.ConclusionsThe test accurately detects PrAD-CTCs with high sensitivity and specificity irrespective of stage, serum PSA or Gleason score, which translates into low risks of false negatives or overdiagnosis. The high accuracy of the test could offer advantages over PSA based prostate cancer detection.
| S-EPMC10166919 | biostudies-literature
Project description:Circulating tumor cells (CTCs) have received intense scientific scrutiny because they travel in the bloodstream and are therefore well situated to mediate hematogenous metastasis. However, the potential of CTCs to actually form new tumors has not been tested. Popular methods of isolating CTCs are biased towards larger, more differentiated, non-viable cells, creating a barrier to testing their tumor forming potential. Without relying on cell size or the expression of differentiation markers, our objective was to isolate viable prostate CTCs from mice and humans and assay their ability to initiate new tumors. Therefore, blood was collected from transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and from human patients with metastatic castration-resistant prostate cancer (PCa). Gradient density centrifugation or red cell lysis was used to remove erythrocytes, and then leukocytes were depleted by magnetic separation using CD45 immunoaffinity beads. CTCs fractions from TRAMP mice and PCa patients were verified by immunocytochemical staining for cytokeratin 8 and EpCAM, and inoculated into immunodeficient mice. TRAMP tumor growth was monitored by palpation. Human tumor growth formation was monitored up to 8 months by ultrasensitive PSA assays performed on mouse serum. We found viable tumor cells present in the bloodstream that were successfully isolated from mice without relying on cell surface markers. Two out of nine immunodeficient mice inoculated with TRAMP CTCs developed massive liver metastases. CTCs were identified in blood from PCa patients but did not form tumors. In conclusion, viable CTCs can be isolated without relying on epithelial surface markers or size fractionation. TRAMP CTCs were tumorigenic, so CTCs isolated in this way contain viable tumor-initiating cells. Only two of nine hosts grew TRAMP tumors and none of the human CTCs formed tumors, which suggests that most CTCs have relatively low tumor-forming potential. Future studies should identify and target the highly tumorigenic cells.
| S-EPMC3717304 | biostudies-literature
Project description:BackgroundLung cancer has the highest fatality rate of all cancer types. To improve patients' survival and life quality, it is therefore very important to screen for and detect it at an early stage.MethodsA negative enrichment-fluorescence in situ hybridization (NE-FISH) approach was used to detect circulating tumor cells (CTCs) in lung cancer patients, and levels of lung cancer-associated serum markers were also measured in the peripheral blood of these same patients. The correlation between CTCs, serum cancer markers (carcinoembryonic antigen [CEA], CA 125, CYFRA 21-1, and SCC), and clinicopathological characteristics was then investigated. Moreover, the potential clinical use of the combination of CTCs and tumor markers for the diagnosis of lung cancer, especially at early stages, was also explored.ResultsCTC frequencies in lung cancer patients were significantly higher than in healthy control volunteers or patients with benign lung disease, and the area under the receiver operating characteristics curve for the control group was 0.846 (95% CI 0.796-0.887, P < 0.001). The rate of CTC positivity in lung cancer patients was 68.29% when the CTC cutoff value was 2, and the sensitivity of this means of lung cancer detection rose to 82.93% by combining CTC-based detection with measurements of serum tumor markers. Similarly, the diagnostic sensitivity of this approach in early-stage lung cancer patients (I-II) was improved from 63.93% to 78.69%. Detection of CTCs can thus assist with the identification of benign and malignant pulmonary nodules.ConclusionsIt is potentially helpful and effective to employ a combination of CTCs and serum tumor markers for the clinical diagnosis of lung cancer.
| S-EPMC6639255 | biostudies-literature