PIWI family proteins as prognostic markers in cancer: a systematic review and meta-analysis.

BACKGROUND: P-element-induced-wimpy-testis-(PIWI)-like proteins are implicated in germ cells' regulation and detected in numerous cancer types. In this meta-analysis, we aimed to associate, for the first time, the prognosis in cancer patients with intratumoral expression of PIWI family proteins. METHODS: PubMed, Embase, and Web of Knowledge databases were searched, and studies investigating the association between intratumoral mRNA or protein expression of different PIWI family proteins and survival, metastasis, or recurrence of various cancer types were reviewed. Study qualities were assessed using the REMARK criteria. Studies' heterogeneity was evaluated using I2 index and Cochran Q test. Publication bias was assessed by funnel plots and Egger's regression. Pooled hazard ratios (HR) with 95% confidence intervals (95% CIs) were calculated for different PIWI family proteins separately. Specifically, log of calculated HR was pooled using random-effects model. RESULTS: Twenty-six studies (4299 participants) were included. The pooled HR of mortality in high versus low expression of PIWIL1, PIWIL2, and PIWIL4 was 1.87 (95% CI: 1.31-2.66, p < 0.05), 1.09 (95% CI: 0.58-2.07, p = 0.79), and 0.44 (95% CI: 0.25-0.76, p < 0.05), respectively. The pooled HR of recurrence in high versus low expression of PIWIL1 and PIWIL2 was 1.72 (95% CI: 1.20-2.49, p < 0.05) and 1.98 (95% CI: 0.65-5.98, p = 0.23), respectively. CONCLUSIONS: Highly variable results were observed for different cancer types. Higher PIWIL1 and lower piwil4 and PIWIL4 expression levels could potentially indicate worse prognosis in cancer. These proteins' expressions could be used for personalized prognosis and treatment in the future.

Circulating tumor cells as Trojan Horse for understanding, preventing, and treating cancer: a critical appraisal.

Circulating tumor cells (CTCs) are regarded as harbingers of metastases. Their ability to predict response to therapy, relapse, and resistance to treatment has proposed their value as putative diagnostic and prognostic indicators. CTCs represent one of the zeniths of cancer evolution in terms of cell survival; however, the triggers of CTC generation, the identification of potentially metastatic CTCs, and the mechanisms contributing to their heterogeneity and aggressiveness represent issues not yet fully deciphered. Thus, prior to enabling liquid biopsy applications to reach clinical prime time, understanding how the above mechanistic information can be applied to improve treatment decisions is a key challenge. Here, we provide our perspective on how CTCs can provide mechanistic insights into tumor pathogenesis, as well as on CTC clinical value. In doing so, we aim to (a) describe how CTCs disseminate from the primary tumor, and their link to epithelial-mesenchymal transition (EMT); (b) trace the route of CTCs through the circulation, focusing on tumor self-seeding and the possibility of tertiary metastasis; (c) describe possible mechanisms underlying the enhanced metastatic potential of CTCs; (d) discuss how CTC could provide further information on the tissue of origin, especially in cancer of unknown primary origin. We also provide a comprehensive review of meta-analyses assessing the prognostic significance of CTCs, to highlight the emerging role of CTCs in clinical oncology. We also explore how cell-free circulating tumor DNA (ctDNA) analysis, using a combination of genomic and phylogenetic analysis, can offer insights into CTC biology, including our understanding of CTC heterogeneity and tumor evolution. Last, we discuss emerging technologies, such as high-throughput quantitative imaging, radiogenomics, machine learning approaches, and the emerging breath biopsy. These technologies could compliment CTC and ctDNA analyses, and they collectively represent major future steps in cancer detection, monitoring, and management.

Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing.

BACKGROUND: Human sex hormone-binding globulin (SHBG) regulates free sex steroid concentrations in plasma and modulates rapid, membrane based steroid signaling. SHBG is encoded by an eight exon-long transcript whose expression is regulated by a downstream promoter (P(L)). The SHBG gene was previously shown to express a second major transcript of unknown function, derived from an upstream promoter (P(T)), and two minor transcripts. RESULTS: We report that transcriptional expression of the human SHBG gene is far more complex than previously described. P(L) and P(T) direct the expression of at least six independent transcripts each, resulting from alternative splicing of exons 4, 5, 6, and/or 7. We mapped two transcriptional start sites downstream of P(L) and P(T), and present evidence for a third SHBG gene promoter (P(N)) within the neighboring FXR2 gene; PN regulates the expression of at least seven independent SHBG gene transcripts, each possessing a novel, 164-nt first exon (1N). Transcriptional expression patterns were generated for human prostate, breast, testis, liver, and brain, and the LNCaP, MCF-7, and HepG2 cell lines. Each expresses the SHBG transcript, albeit in varying abundance. Alternative splicing was more pronounced in the cancer cell lines. P(L)- P(T)- and P(N)-derived transcripts were most abundant in liver, testis, and prostate, respectively. Initial findings reveal the existence of a smaller immunoreactive SHBG species in LNCaP, MCF-7, and HepG2 cells. CONCLUSION: These results extend our understanding of human SHBG gene transcription, and raise new and important questions regarding the role of novel alternatively spliced transcripts, their function in hormonally responsive tissues including the breast and prostate, and the role that aberrant SHBG gene expression may play in cancer.

Sex hormone-binding globulin influences gene expression of LNCaP and MCF-7 cells in response to androgen and estrogen treatment.

Sex hormone-binding globulin (SHBG), a plasma protein that binds androgens and estrogens, also participates in the initial steps of a membrane-based steroid signaling pathway in human prostate and breast. We have recently shown that SHBG is expressed at the mRNA and protein levels in the prostate and breast. In this study, we addressed whether locally expressed SHBG: (1) Functions to regulate activation of membrane-based steroid signaling and (2) influences activation of the androgen (AR) and estrogen (ER) receptors. Using microarray analysis, we identified specific genes that are influenced by SHBG expression in LNCaP and MCF-7 cells in a manner consistent with each of these properties. These findings suggest that locally expressed SHBG can play a functional role in the steroid responsiveness of prostate and breast cells through multiple signaling pathways and that perturbations in local SHBG expression could contribute to prostate and breast cancer.

Phase I/II prospective trial of cancer-specific imaging using ultrasound spectrum analysis tissue-type imaging to guide dose-painting prostate brachytherapy.

PURPOSE: To assess the technical feasibility, toxicity, dosimetry, and preliminary efficacy of dose-painting brachytherapy guided by ultrasound spectrum analysis tissue-type imaging (TTI) in low-risk, localized prostate cancer. METHODS AND MATERIALS: Fourteen men with prostate cancer who were candidates for brachytherapy as sole treatment were prospectively enrolled. Treatment planning goal was to escalate the tumor dose to 200% with a modest de-escalation of dose to remaining prostate compared with our standard. Primary end points included technical feasibility of TTI-guided brachytherapy and equivalent or better toxicity compared with standard brachytherapy. Secondary end points included dose escalation to tumor regions and de-escalated dose to nontumor regions on the preimplant plan, negative prostate biopsy at 2 years, and freedom from biochemical failure. RESULTS: Thirteen of fourteen men successfully completed the TTI-guided brachytherapy procedure for a feasibility rate of 93%. A software malfunction resulted in switching one patient from TTI-guided to standard brachytherapy. An average of 2.7 foci per patient was demonstrated and treated with an escalated dose. Dosimetric goals on preplan were achieved. One patient expired from unrelated causes 65 days after brachytherapy. Toxicity was at least as low as standard brachytherapy. Two-year prostate biopsies were obtained from six men; five (83%) were definitively negative, one showed evidence of disease with treatment effect, and none were positive. No patients experienced biochemical recurrence after a median followup of 31.5 (24-52) months. CONCLUSIONS: We have demonstrated that TTI-guided dose-painting prostate brachytherapy is technically feasible and results in clinical outcomes that are encouraging in terms of low toxicity and successful biochemical disease control.

Interactions of sex hormone-binding globulin with target cells.

Sex hormone-binding globulin (SHBG) was initially described as a plasma protein synthesized in, and secreted by, the liver. It was discovered by its ability to bind certain androgens and estrogens and, for many years, was believed to serve as a transporter/reservoir for the steroids which it bound. Subsequently, it became clear that the cell membranes of selected tissues contained a receptor for SHBG (R(SHBG)). This review deals with what is known of that receptor - its anatomy, physiology and biochemistry.

Long-term treatment with finasteride in men with symptomatic benign prostatic hyperplasia: 10-year follow-up.

OBJECTIVES: To evaluate the safety and efficacy of finasteride 5 mg during a 10-year period in men with enlarged prostates from a single center who participated in the double-blind and extension phases of the multicenter, Phase III, North American benign prostatic hyperplasia (BPH) trial. It is important that the long-term safety and efficacy of drugs intended for chronic administration in men with BPH be well understood. METHODS: The Phase III North American BPH trial involved a 1-year, placebo-controlled, double-blind study, followed by a 5-year open extension with finasteride 5 mg/day. The trial enrolled men with symptomatic BPH, an enlarged prostate on digital rectal examination, and no evidence of prostate cancer. Of the 46 patients originally enrolled from our institution, 43 were randomized to receive finasteride or placebo, of whom 41 (95%) completed the double-blind study and entered the 5-year extension. Thirty (73%) of these 41 patients completed the 5-year extension. Patients continued to be followed up by their physicians for an additional 5 years, for a total follow-up of at least 10 years. RESULTS: Twenty-four (56%) of the original 43 patients randomized to finasteride or placebo were judged as successfully treated during the 10-year finasteride follow-up (17 patients taking finasteride alone at 10 years and 7 patients who were taking finasteride alone when they discontinued during the 10-year follow-up for reasons not related to finasteride treatment). Altogether, 22 (51%) of the original 43 randomized patients continued finasteride treatment at 10 years (17 taking finasteride alone, 4 taking finasteride plus an alpha-blocker, and 1 taking finasteride for treatment of hematuria). Finasteride was well tolerated, with no new adverse experiences occurring with increasing duration of exposure to the drug. CONCLUSIONS: This long-term follow-up study has demonstrated that appropriately selected patients with symptomatic BPH and enlarged prostates are likely to have a long-term response to taking finasteride 5 mg daily.

Sex hormone-binding globulin in the human prostate is locally synthesized and may act as an autocrine/paracrine effector.

Sex hormone-binding globulin (SHBG) is a plasma protein synthesized and secreted by the liver. Its initial description stemmed from its ability to bind estrogens and androgens and its capacity to regulate the free concentration of the steroids that bind to it. Additionally, it participates in signal transduction for certain steroid hormones at the cell membrane. It binds with high affinity to a specific membrane receptor (R(SHBG)) in prostate stromal and epithelial cells, wherein the SHBG.R(SHBG) complex forms. An appropriate steroid binds to this complex and results in increases of intracellular cAMP. These two disparate functions of SHBG, regulation of the concentration of free steroids in plasma and signal transduction in selected tissues, raise the question of how its synthesis and secretion might be regulated so as to best perform these two disparate functions. In this paper we demonstrate that SHBG is produced in human prostate cancer cell lines (LNCaP, DU 145, and PC 3) as well as in cultured human prostate epithelial and stromal cells. In addition, in tissue sections of human prostate, we demonstrate the presence of SHBG (immunocytochemistry) and SHBG mRNA (in situ hybridization). These observations are consistent with the hypothesis that SHBG, destined to participate in signaling at the cell membrane, is locally regulated and produced.

Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia.

OBJECTIVES: To summarize the 6-year clinical trial data with finasteride. Benign prostatic hyperplasia is a chronic and progressive disease and therefore assessment of long-term safety and efficacy is important. METHODS: The North American and International Phase III Finasteride trials enrolled symptomatic men with enlarged prostate glands. The initial 1-year placebo-controlled study was followed by a 5-year open-label extension. In total, 6-year finasteride data were available in 487 patients originally randomized to finasteride, and 5-year data were available on 238 patients originally randomized to placebo. RESULTS: After 6 years of treatment with finasteride 5 mg, the mean quasi-American Urological Association Symptom Score improved by 4.0 points, the median prostate volume decreased by 24%, and the mean maximal urinary flow rate increased by 2.9 mL/s (P <0.001 for all parameters). Long-term finasteride treatment was well tolerated, with a low incidence of drug-related sexual adverse events occurring during the first year and even fewer occurrences during the 5-year open extension. CONCLUSIONS: Treatment with finasteride leads to durable improvement in urinary tract symptoms, flow rate, and prostate volume, with no increase in the prevalence of drug-related adverse events over time.