Levels of plasma glycan-binding auto-IgG biomarkers improve the accuracy of prostate cancer diagnosis.

Strategies to improve the early diagnosis of prostate cancer will provide opportunities for earlier intervention. The blood-based prostate-specific antigen (PSA) assay is widely used for prostate cancer diagnosis but specificity of the assay is not satisfactory. An algorithm based on serum levels of PSA combined with other serum biomarkers may significantly improve prostate cancer diagnosis. Plasma glycan-binding IgG/IgM studies suggested that glycan patterns differ between normal and tumor cells. We hypothesize that in prostate cancer glycoproteins or glycolipids are secreted from tumor tissues into the blood and induce auto-immunoglobulin (Ig) production. A 24-glycan microarray and a 5-glycan subarray were developed using plasma samples obtained from 35 prostate cancer patients and 54 healthy subjects to identify glycan-binding auto-IgGs. Neu5Acα2-8Neu5Acα2-8Neu5Acα (G81)-binding auto-IgG was higher in prostate cancer samples and, when levels of G81-binding auto-IgG and growth differentiation factor-15 (GDF-15 or NAG-1) were combined with levels of PSA, the prediction rate of prostate cancer increased from 78.2% to 86.2% than with PSA levels alone. The G81 glycan-binding auto-IgG fraction was isolated from plasma samples using G81 glycan-affinity chromatography and identified by N-terminal sequencing of the 50 kDa heavy chain variable region of the IgG. G81 glycan-binding 25 kDa fibroblast growth factor-1 (FGF1) fragment was also identified by N-terminal sequencing. Our results demonstrated that a multiplex diagnostic combining G81 glycan-binding auto-IgG, GDF-15/NAG-1 and PSA (≥ 2.1 ng PSA/ml for cancer) increased the specificity of prostate cancer diagnosis by 8%. The multiplex assessment could improve the early diagnosis of prostate cancer thereby allowing the prompt delivery of prostate cancer treatment.

Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-kappaB-independent, proteasome-mediated mechanism.

BACKGROUND: Cadmium has been classified as a human carcinogen, affecting health through occupational and environmental exposure. Cadmium has a long biological half-life (>25 years), due to the flat kinetics of its excretion. The prostate is one of the organs with highest levels of cadmium accumulation. Importantly, patients with prostate cancer appear to have higher levels of cadmium both in the circulation and in prostatic tissues. RESULTS: In the current report, we demonstrate for the first time that cadmium down-regulates expression of the X-linked inhibitor of apoptosis protein (XIAP) in prostate cancer cells. Cadmium-mediated XIAP depletion occurs at the post-transcriptional level via an NF-kappaB-independent, proteasome-mediated mechanism and coincides with an increased sensitivity of prostate cancer cells to TNF-alpha-mediated apoptosis. Prolonged treatment with cadmium results in selection of prostate cancer cells with apoptosis-resistant phenotype. Development of apoptosis-resistance coincides with restoration of XIAP expression in cadmium-selected PC-3 cells. CONCLUSIONS: Selection of cadmium-resistant cells could represent an adaptive survival mechanism that may contribute to progression of prostatic malignancies.

Evaluation of the Prostate Cancer Prevention Trial Risk calculator in a high-risk screening population.

STUDY TYPE: Diagnostic (exploratory cohort). LEVEL OF EVIDENCE: 2b. OBJECTIVE: To evaluate the Prostate Cancer Prevention Trial (PCPT) risk calculator in a screening cohort of young, racially diverse, high-risk men with a low baseline prostate-specific antigen (PSA) level and enrolled in the Prostate Cancer Risk Assessment Program (PRAP). The PCPT calculator provides an assessment of prostate cancer risk based on age, PSA level, race, previous biopsy, and family history. PATIENTS AND METHODS: Eligibility for PRAP includes men aged 35-69 years who are African-American, have a family history of prostate cancer, or have a known BRCA1/2 mutation. PCPT risk scores were determined for PRAP participants, and were compared to observed prostate cancer rates. RESULTS: In all, 624 participants were evaluated, including 382 (61.2%) African-American men and 242 (38.7%) men with a family history of prostate cancer; the median (range) age was 49.0 (34.0-69.0) years and the median PSA level 0.9 (0.1-27.2) ng/mL. The PCPT risk score correlated with prostate cancer diagnosis, as the median baseline risk score in patients diagnosed with prostate cancer was 31.3%, vs 14.2% in patients not diagnosed with prostate cancer (P < 0.001). The PCPT calculator similarly stratified the risk of diagnosis of Gleason score > or =7 disease, as the median risk score was 36.2% in patients diagnosed with Gleason > or =7 prostate cancer vs 15.2% in all other participants (P < 0.001). CONCLUSION: The PCPT risk calculator score was found to stratify prostate cancer risk in a cohort of young, primarily African-American men with a low baseline PSA level. These results support further evaluation of this predictive tool for assessing the risk of prostate cancer in high-risk men.

Residual prostate cancer after radiotherapy: a study of radical cystoprostatectomy specimens.

OBJECTIVES: The incidence of histologic prostate cancer (CaP) after definitive radiation therapy (RT) for localized disease is rarely quantitated. We investigated the relationship between prostate-specific antigen (PSA) and histologically residual CaP after definitive RT in patients undergoing radical cystoprostatectomy (RCP) for unrelated indications. METHODS: We reviewed our prostate cancer database to identify patients undergoing RCP who previously received definitive RT for localized CaP. Pre-radiation variables examined include PSA, Gleason score, radiation modality, and dose. Post-radiation variables reviewed include PSA, time to RCP, the presence of histologically proven prostate cancer, and Gleason score. RESULTS: We identified 21 patients who underwent RCP at a median of 60 months after RT for localized CaP. Pre-radiation Gleason scores were low (6 or less) to intermediate risk (3+4) in 82% (14 of 17), intermediate (4+3) to high (8 or greater) in 18% (3 of 17), and unavailable in 4 patients. Median pre-radiation PSA was 9 ng/mL. Median PSA before RCP in all patients was 0.8 ng/mL. A total of 52% (11 of 21) of patients demonstrated active CaP in the RCP specimen. Although 89% (16 of 18) of patients met the Phoenix definition of biochemical freedom from disease, 50% (8 of 16) of these patients had histologically residual CaP at the time of RCP. Median PSA was not significantly different between patients with and without active CaP. CONCLUSIONS: Histologic evidence of CaP was noted in 50% of patients demonstrating biochemical freedom from disease at the time of RCP. Although the biological significance of active CaP in this select population is uncertain, our findings demonstrate the limitations of PSA in monitoring CaP disease activity after definitive RT.

Arsenite disrupts mitosis and induces apoptosis in SV40-transformed human skin fibroblasts.

Chronic ingestion of arsenite-contaminated drinking water causes skin, bladder, and liver cancer. The mechanism of arsenite-induced carcinogenesis is unknown. Arsenite is known to disrupt mitosis and to delay transit through M phase in normal diploid fibroblasts. SV40-transformed human fibroblasts were observed to be hypersensitive to the cytotoxic and cytostatic effects of NaAsO(2) compared with normal diploid fibroblasts in concentration-response experiments. Five to 20 microM NaAsO(2) induced cytostasis in cycling normal diploid fibroblasts but not overt lethality in quiescent normal diploid fibroblasts. High concentrations of arsenite were overtly lethal in both cycling and quiescent cells. The IC50 for cycling SV40-transformed fibroblasts was 3.8 and 4.8 microM for the SV40-transformed lines GM4429 and GM0637, respectively, whereas, in cycling normal diploid fibroblasts (GM0024), the IC50 was 24.7 microM. Microscopic examination of NaAsO(2)-treated SV40-transformed fibroblasts suggested a concentration-dependent accumulation of cells in mitosis undergoing apoptosis. Treatment of SV40-transformed fibroblasts with 0-10 microM NaAsO(2) caused a concentration-dependent inhibition of cell proliferation, accumulation of cells having G2/M DNA contents, and increases in the mitotic index. Phase microscopy, annexin V binding, and electron microscopy demonstrated that arrested mitotic cells underwent apoptosis. These results indicate that SV40-transformation sensitizes cells to arsenite-induced mitotic arrest and induction of apoptosis in the mitotic cells.