[Show abstract][Hide abstract] ABSTRACT: Penile and/or cutaneous metastases from prostate adenocarcinoma rarely occur. Here, we detail the case of a 78-year-old male suffering from priapism, caused by metastatic prostate cancer with both penile and lower limb cutaneous spread. His serum prostate-specific antigen (PSA) level was 0.09 ng/ml when priapism developed. Corpora cavernosa biopsy was refused by the patient and radical penectomy was performed. Postoperative pathological and immunohistochemical studies revealed un-differentiated prostate adenocarcinoma cells growing in corpora cavernosa. Two months later, the patient presented with multiple, erythematous nodules over the right lower leg. The PSA level was found to be 0.264 ng/ml. Biopsy of a skin nodule revealed neoplastic cells consistent with metastatic prostate adenocarcinoma. This is the first known case of metastatic prostate cancer found in both penis and skin with a low serum PSA level. Priapism presented as the initial clinical manifestation of metastatic prostate cancer.
Preview · Article · Jun 2012 · Journal of Andrology
[Show abstract][Hide abstract] ABSTRACT: Prostate tumor cells frequently show the features of osteoblasts, which are differentiated from bone marrow mesenchymal stem cells. We examined human prostate cancer cell lines and clinical prostate cancer specimens for additional bone marrow mesenchymal stem cell properties.
Prostate cancer cell lines were induced for osteoblastogenic and adipogenic differentiation, detected by standard staining methods and confirmed by lineage-specific marker expression. Abnormal expression of the markers was then assessed in clinical prostate cancer specimens.
After osteoblastogenic induction, cells of the LNCaP lineage, PC-3 lineage, and DU145 displayed osteoblastic features. Upon adipogenic induction, PC-3 lineage and DU145 cells differentiated into adipocyte-like cells. The adipocyte-like cancer cells expressed brown adipocyte-specific markers, suggesting differentiation along the brown adipocyte lineage. The adipogenic differentiation was accompanied by growth inhibition, and most of the adipocyte-like cancer cells were committed to apoptotic death. During cyclic treatments with adipogenic differentiation medium and then with control medium, the cancer cells could commit to repeated adipogenic differentiation and retrodifferentiation. In clinical prostate cancer specimens, the expression of uncoupling protein 1 (UCP1), a brown fat-specific marker, was enhanced with the level of expression correlated to disease progression from primary to bone metastatic cancers.
This study thus revealed that prostate cancer cells harbor the stem cell properties of bone marrow mesenchymal stem cells. The abnormally expressed adipogenic UCP1 protein may serve as a unique marker, while adipogenic induction can be explored as a differentiation therapy for prostate cancer progression and bone metastasis.
Full-text · Article · Feb 2011 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: We have reported that human prostate cancer ARCaP(E) cells undertake epithelial to mesenchymal transition (EMT) when stimulated by certain soluble factors, and that EMT is regulated by surface receptor-elicited signaling pathways through protein phosphorylation. It is known that phorbol ester phorbol-12-myristate-13-acetate (PMA), a potent antagonist to both conventional and novel protein kinase C (PKC) isoenzymes, induces cancer cell scattering.
To assess the effect of PMA on EMT, ARCaP(E) cells were treated with PMA and were assayed for EMT-related morphologic and behavioral changes. Specific inhibitors were used to investigate the PMA-induced EMT.
PMA at 100 nM induced EMT in a time-dependent manner, resulting in a complete change from epithelial to mesenchymal stromal morphology. Concurrently, PMA inhibited expression of epithelial marker E-cadherin and increased the level of stromal marker protein vimentin, while the treated cells showed increased migratory and invasive capacities. Using specific inhibitors, we confirmed that the effect of PMA was mediated by PKC, while isoenzymes of the novel PKC subfamily were implicated as the main mediator. Finally, we determined that the EMT was dependent on newly synthesized proteins, because inhibitors for gene transcription and protein translation could both inhibit the initiation of EMT.
Although PMA is well known for its effects on cell migration and tumor formation, this work is the first to define PMA as an EMT inducer in prostate cancer cells. Further investigation in this experimental model may reveal important regulatory mechanisms and additional molecular changes underlying EMT.
[Show abstract][Hide abstract] ABSTRACT: The alpha2 chain of the interleukin-13 receptor (IL13Ralpha2) is a high-affinity receptor and a candidate target for cytotoxic killing of cancer cells. Availability of a human prostate cancer cell line with high level of IL13Ralpha2 expression will facilitate the development of therapeutic modalities.
ARCaP(E) and ARCaP(M) human prostate cancer cell lines were subjected to comparative analyses of gene expression. Expression of the IL13Ralpha2 protein was confirmed by Western blotting and immunostaining. IL13Ralpha2 proteins in xenograft tumors and clinical human prostate cancer specimens were detected by specific antibodies. LNCaP prostate cancer cells stably transfected with IL13Ralpha2 were examined for accelerated growth in athymic mice.
We found that IL13Ralpha2 proteins could be detected in both the ARCaP(E) and ARCaP(M) cells, but the expression level in ARCaP(M) was more than 17-fold higher than in ARCaP(E) cells. Importantly, the ARCaP lineage represented the only human prostate cancer cell line that expresses IL13Ralpha2 proteins at the level detectable by Western blotting. Expression of IL13Ralpha2 was accompanied by resistance to the anti-tumor activity of interleukin-13 (IL-13). ARCaP cells were found to be insensitive to growth inhibition upon IL-13 treatment, while overexpression of IL13Ralpha2 in LNCaP cells promoted intratibial tumor growth in athymic mice.
Differential IL13Ralpha2 expression may account for the high tumorigenic and metastatic potential of ARCaP(M) cells. The unique expression of IL13Ralpha2 makes ARCaP lineage an attractive model for evaluating the targeting efficacy of therapeutic agents based on IL13Ralpha2 protein expression.
[Show abstract][Hide abstract] ABSTRACT: Prostate stromal cells may play binary roles in the process of prostate cancer development. As the first to be encountered by infiltrating prostate cancer cells, prostate stromal cells form the first defense line against prostate cancer progression and metastasis. However, interaction between prostate cancer and stromal cells may facilitate the formation of a tumor microenvironment favoring cancer cell growth and survival. To establish an experimental system for studying the interaction between cancer and stromal cells, we isolated three matched pairs of normal and cancer-associated human prostate stromal clones. In this report, we describe the morphologic and behavioral characteristics of these cells and their effect on LNCaP prostate cancer cells in co-culture. Unlike LNCaP prostate cancer cells, the isolated prostate stromal clones are large fibroblast-like cells with a slow proliferation rate. Growth and survival of these clones are not affected by androgens. The stromal cells display high resistance to serum starvation, while cancer-associated stromal clones have differentiated survival ability. In co-culture experiments, the stromal cells protected some LNCaP prostate cancer cells from death by serum starvation, and cancer-associated stromal clones showed more protection. This work thus established a panel of valuable human prostate stromal cell lines, which could be used in co-culture to study the interaction between prostate cancer and prostate stromal cells.
[Show abstract][Hide abstract] ABSTRACT: The mechanism of epithelial to mesenchymal transition (EMT) could be adopted by tumor cells for migration and invasion. We have reported that ARCaP(E) human prostate cancer cells undergo EMT-like changes during xenograft growth in athymic mice.
In this report, we assessed the extent of EMT by tracking changes in cloned ARCaP(E) cells expressing red fluorescence protein during successive orthotopic prostate tumor formation. Cancer cells with stromal-like morphology were isolated and examined for EMT-like changes.
EMT-like morphologic and expression changes were detected after one round of in vivo tumor formation. Importantly, when recovered tumor cells were used in second round xenograft tumor formation, a large fraction of ARCaP(E) cells showed drastic EMT-like changes, with markedly enlarged cell size and divergent cell shapes similar to those of mesenchymal stromal cells. The morphologic change was accompanied by increased growth and metastasis, as tumor incidence increased while red fluorescent tumor cells could be detected from circulating blood, bone marrow, peritoneal ascites, and lung of the tumor-bearing mice. Recovered clones from these samples had lost epithelial markers but many showed activated stromal marker vimentin expression. The EMT appeared permanent since the newly acquired morphology was sustained after continuous passages.
Results from this study demonstrate that through interaction with the host tumor microenvironment, cancer cells acquire cellular plasticity. During xenograft tumor formation and metastasis, a single clone of cancer cells could yield a heterogeneous population, with a substantial number of tumor cells adopting mesenchymal stroma-like phenotypes.
[Show abstract][Hide abstract] ABSTRACT: We have reported isolation and characterization of the prostate-specific and androgen-regulated PrLZ gene abnormally expressed in prostate cancer. PrLZ is a potential biomarker for prostate cancer and a candidate oncogene promoting cell proliferation and survival in prostate cancer cells. A full delineation of the PrLZ gene and its gene products may provide clues to the mechanisms regulating its expression and function. In this report, we identified three additional exons in the PrLZ gene and recognized five transcript variants from alternative splicing that could be detected by RT-PCR and Western blotting. Structural comparison demonstrated that the PrLZ proteins are highly conserved among species. PrLZ contains multiple potential sites for interaction with other proteins. We used mammalian two-hybrid assays to demonstrate that PrLZ isoforms interact with 14-3-3 proteins, and multiple sites in the PrLZ may be involved in the interaction. Alternative splicing may contribute to abnormally enhanced PrLZ levels in prostate cancer, and interaction with 14-3-3 proteins may be a mechanism by which PrLZ promotes cell proliferation and survival during prostate cancer development and progression. This information is a valuable addition to the investigation of the oncogenic properties of the PrLZ gene.
Full-text · Article · Oct 2009 · Biochemical and Biophysical Research Communications
[Show abstract][Hide abstract] ABSTRACT: To develop a sensitive method for the detection of bladder cancer cells in the urine castoff cells of patients with bladder cancer, we examined the feasibility of using molecular beacon (MB) probes specific for tumor-specific survivin mRNA.
MBs are single-stranded oligonucleotide hybridization probes that form a stem-and-loop structure and have high sensitivity and specificity. Western blot analysis showed that a high level of survivin gene expression is detected in human bladder cancer 5637 and J82 cell lines but not in normal human prostate fibroblast cells. These cell lines were incubated with survivin MBs, and the fluorescence intensity was examined in those cells using a fluorescence microscope.
We found that survivin MBs could detect expression of the survivin gene and generated fluorescent signals in the cancer cells. However, the fluorescence signal was not detected in the normal prostate fibroblast cells. The green fluorescent signal was present in the exfoliated cells of patients with bladder cancer but not in the healthy adult after incubating with survivin MBs.
Our results have demonstrated that the survivin MB is a specific and sensitive molecular probe for detecting bladder cancer cells and urine castoff cells of patients with bladder cancer. It has great potential for the development of a clinical diagnostic procedure for the early detection of bladder cancer and follow-up after surgery.
[Show abstract][Hide abstract] ABSTRACT: Hedgehog signaling is thought to play an important role in rodent prostate organogenesis and morphogenesis. However, the role of this signaling pathway in human fetal prostate development has not been investigated.
Twenty-five human fetal prostates at various developmental stages (10-39 weeks) were included. Fifteen specimens were processed for H&E and immunohistochemical staining of the Hedgehog signaling components: Sonic Hedgehog (SHH), Desert Hedgehog (DHH), Patched-1(PTC1), Patched-2 (PTC2), Smoothened (SMO), GLI1, and proliferating cell nuclear antigen (PCNA). SHH, DHH, and GLI1 expression was also analyzed in ten snap-frozen specimens by Western blot.
SHH, DHH, SMO, PTC1, GLI1, and PCNA expression, assessed by a semi-quantitative immunohistochemical method, was found mainly in the developing prostatic epithelial ducts, beginning at 10 weeks and peaking at 16 and 28 weeks with a dip occurring at 20 weeks, with the exception of PTC2.
Both SHH and DHH signaling components were detected during human fetal prostate development. Despite the high expression of PTC2 in the epithelium as well as the stroma in the early time of development, the expression of SHH, DHH, SMO, PTC1, and a SHH/DHH target transcription factor, GLI-1, were all largely restricted to epithelium in the developing prostate, suggesting that SHH/DHH signaling is primarily through an autocrine mechanism in human fetal prostate organogenesis.
[Show abstract][Hide abstract] ABSTRACT: We compared the validity (evaluated by sensitivity and specificity), reliability (evaluated by reproducibility) and yield (evaluated by predictive value, examining complexity and cost) of individual and combined tests for bladder tumour antigen stat (BTAstat), nuclear matrix protein 22 (NMP22), hyaluronic acid (HA), survivin, CD44v6, vascular endothelial growth factor (VEGF), and voided urine cytology (VUC) in detecting bladder cancer. And at the same time we evaluated the clinical value of these seven detecting methods in the diagnosis of bladder cancer.
The six markers and VUC were detected in the urine of cancer group (151 patients with bladder cancer) and two control groups (50 patients with benign urological diseases and 50 healthy controls). The sensitivity, specificity, predictive value, reproducibility, examining complexity and checking cost of each marker and combined markers were calculated.
There was a significant difference between bladder cancer group and the two control groups. The sensitivity, specificity and positive predictive value were as follows: VUC (36.4%, 100.0%, 100%), BTAstat (76.8%, 87.0%, 89.9%), NMP22 (77.5%, 81.0%, 86.0%), HA (82.8%, 83.0%, 88.0%), survivin (70.2%, 85.0%, 87.6%), CD44v6 (50.3%, 79.0%, 78.4%), and VEGF (68.2%, 93.0%, 93.6%). The highest sensitivities were 91.4% for NMP22 + BTAstat and HA + NMP22, whereas the combined marker with the lowest sensitivity (62.3%) was VUC + CD44v6. The highest specificity was 93.0% for the combined use of VUC + VEGF and HA + CD44v6 had the lowest specificity (73.0%). The most convenient examining method was the detection for BTAstat, the lowest cost was the detection for HA, and the best reproducibility were the detection for BTAstat and VUC.
All the markers have obvious clinical value in diagnosis of bladder cancer. The use of BTAstat + HA or NMP22 + BTAstat are better examining methods in terms of validity, reliability, and yield.
Preview · Article · Dec 2006 · Chinese medical journal
[Show abstract][Hide abstract] ABSTRACT: To investigate whether the sonic hedgehog signaling pathway is involved in the development of human fetal prostate, and to evaluate the changing staining patterns of its molecules, sonic hedgehog (SHH), patchedl (PTC1), smoothened (SMO), and GLI1, in the human fetal prostate at various gestation stages.
Fifteen human fetal prostate specimens at various developmental stages (10 - 39 weeks) were included in this study. SHH, PTC1, SMO and GLI1 were detected in all the specimens by immunohistochemical technique. All the slides were observed and assessed under the light microscope.
SHH, PTC1, SMO and GLI1 could be detected in human fetal prostate tissues, and their expression formed two surges, the former at week 16, and the latter at week 28. The staining of SHH and SMO was distributed only in the ductal epithelium but not in the stroma. The expression of PTC1 and GLI1 could be found mainly in the epithelium, with minimal staining in the stroma.
The sonic hedgehog signaling pathway is involved in the development of the human fetal prostate. The high expression of its molecules at early gestation stages might be associated with the induction of prostatic buds, while their abundant expression at later gestation stages might be related to the prostate ductal branching, growth, differentiation and morphogenesis.
No preview · Article · Nov 2006 · Zhonghua nan ke xue = National journal of andrology
[Show abstract][Hide abstract] ABSTRACT: The promyelocytic leukemia gene (PML) encodes a growth/tumor suppressor protein that is essential for the induction of apoptosis in response to various apoptotic signals. The mechanism by which PML plays a role in the regulation of cell death is still unknown. Our previous study demonstrated that overexpression of PML suppress the growth of bladder cancer cells by inducing apoptosis and cell cycle arrest. To further elucidate the mechanism of PML induced apoptosis in bladder cancer, we constructed a PML inducible stable cell line. We found that the increased expression of PML significantly inhibit the growth of the UM-UC-2/PML clone cells and present apparent massive apoptosis in 24 h post-induction, while the UM-UC-2/PMEP4 cells are not. We also examined the effect of PML on the cell cycle distribution in UM-UC-2 cells. We showed overexpression of PML cause a cell cycle arrest in G1 phase. In additional, increased expression of PML in bladder cancer UM-UC-2 cells reduce Survivin expression and up regulated Caspase-3, and cleaved PARP expression, these suggested that PML might regulate apoptosis through Caspase dependent pathways. Our results demonstrate a novel mechanism of PML-induced apoptosis by down-regulation of Survivin and activation of Caspase dependent pathway.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the sensitivity and specificity of BTAstat, NMP22, HA, Survivin, CD44v6, VEGF, and VUC in detection of bladder cancer.
We detect VUC, BTAstat, NMP22, HA, Survivin, CD44v6, VEGF in the urine of 10 normal case (healthy volunteers), 11 benign urological diseases patients and 52 bladder cancer patients. The sensitivity, specificity the coefficient of variation, the examining time duration and the checking costs of each marker and combined markers were assessed to evaluate the clinical value.
There is a significant difference between the cancer group and the two control groups. The overall sensitivity and specificity of urinary tumor markers were: 42.3% and 100% for VUC; 78.8% and 90.5% for BTAstat; 76.9% and 81.0% for NMP22; 86.5% and 90.5% for HA; 67.3% and 85.7% for Survivin; 50.5% and 85.7% for CD44 and 69.2% and 95.2% for VEGF. The highest sensitivity of combined markers was 96.2% for NMP22 + HA and HA + CD44v6, whereas the lowest sensitivity of combined markers was 67.3% for VUC + CD44v6. The highest specificity (95.2%) was the combined use of VUC + NMP22 and combined use of VUC + VEGF, whereas, method that achieved the lowest specificity (66.7%) was the combined use of HA + Survivin. The most convenient examining method was the detection for BTAstat; the lowest cost examining method was the detection for HA; methods which had the best repeatability were the detection for BTAstat and urine cytology examination.
Each marker had achieved its obvious clinical value in diagnosis of bladder cancer. The sensitivity of all the markers was increased with the progression of tumor grades and clinical stages, except the CD44v6. The combined use of BATstat and HA is the best examining method concerning sensitivity, specificity, feasibility and cost in each different method.
No preview · Article · Oct 2005 · Zhonghua yi xue za zhi
[Show abstract][Hide abstract] ABSTRACT: Study the affection of inducing expression of PML in the apoptosis and the molecular mechanism of bladder cancer.
PMEP4/PML inducible expression vector was transfected into bladder cancer UM-UC-2 cells by lipofectamine 2000 system. The positive clone cells were selected by 300 microg/ml hygromycin B and confirmed by laser confocal imaging system. Then, using the in vitro DNA ladder apoptotic assay and Western blot, the affection of inducing expression of PML on apoptosis and its molecular mechanism of bladder cancer cell was studied.
Comparing with the vector control group, PML specific nuclear speckle significantly increased in the PMEP4/PML bladder cells. DNA ladder assay demonstrated bladder cancer cell expressing PML occurred apoptosis while the control vector cells were not influenced. Overexpression of PML could reduce Survivin expression and upregulate caspase3 and cleaved PARP protein expression
Our results demonstrated that overexpression of PML could induce bladder cancer cell apoptosis through the caspase dependent pathways.
No preview · Article · Aug 2005 · Zhonghua yi xue za zhi
[Show abstract][Hide abstract] ABSTRACT: To investigate the significance of the determination of IL-8 and TNF-alpha in prostatic secretions in the evaluation of chronic prostatitis.
IL-8 and TNF-alpha levels in EPS were evaluated by ELISA in 90 men: controls (n = 12), CBP (n = 12), CPPS IIIA (n=38), CPPS IIIB (n=28). And the difference was analyzed between CBP or CPPS IIIA and CPPS IIIB or controls.
IL-8 and TNF-alpha levels in EPS were higher in men with CBP [(10967.5 +/- 3477.7) pg/ml, (84.1 +/- 54.7) pg/ml] or CPPS IIIA [(9268.4 +/- 2034.6) pg/ml and (32.6 +/- 18.6) pg/ml], but lower in men with CPPS IIIB [(2726.1 +/- 277.5) pg/ml, (12.6 +/- 7.1) pg/ml] or controls [(2800.0 +/- 320.2) pg/ml and (12.9 +/- 10.1) pg/ml] respectively. There was significant difference between CBP or CPPS IIIA and CPPS IIIB or controls (P < 0.01).
IL-8 and TNF-alpha are elevated in the EPS of the men with CBP and CPPS IIIA, and provide a novel means for the identification and characterization of chronic nonbacterial prostatitis/chronic pelvic pain syndrome. The cut-points for IL-8 and TNF-alpha to discriminate CBP or CPPS IIIA from CPPS IIIB or controls need further investigation.
No preview · Article · Oct 2004 · Zhonghua nan ke xue = National journal of andrology
[Show abstract][Hide abstract] ABSTRACT: To evaluate the normal distribution of serum prostate-specific antigen (PSA) levels in healthy Chinese men, because, until recently, studies conducted to establish normal serum PSA values have not involved a Chinese population.
Between September 1999 and December 2001, 1096 healthy Chinese men aged 23 to 85 years, who had undergone a routine health examination, were recruited to this study. All underwent detailed clinical examinations, including serum PSA determination and digital rectal examination. All men with abnormal digital rectal examination findings and/or an abnormal serum PSA level (greater than 4.0 ng/mL) underwent transrectal ultrasound-guided sextant biopsy.
The median serum PSA concentration was 0.50 ng/mL (95th percentile 1.20) for men 23 to 29 years old (n = 77); 0.55 ng/mL (95th percentile 1.21) for men 30 to 39 years old (n = 189); 0.54 ng/mL (95th percentile 1.23) for men 40 to 49 years old (n = 233); 0.82 ng/mL (95th percentile 2.35) for men 50 to 59 years old (n = 177); 0.93 ng/mL (95th percentile 3.20) for men 60 to 69 years old (n = 265); and 1.17 ng/mL (95th percentile 3.39) for men 70 years old or older (n = 155). The serum PSA concentration correlated with age (P <0.001), with an increase of approximately 1.1% annually. No change occurred in the median serum PSA value and 95th percentile in men younger than 50 years old; a gradual increase was observed in men older than 50 years. In those 50 years old or older, the median and 95th percentile serum PSA values for Chinese men were significantly lower than those for other races and even for other Asian men.
These findings further confirm that the serum PSA level correlates with age. Moreover, the distribution and cutoff value of the serum PSA level differs along ethnic lines. In addition, our findings raise the question of whether lowering the PSA cutoff may enhance the detection of cancer in Chinese men who have the lowest prostate cancer rate.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the age-specific reference ranges for serum prostate-specific antigen in Chinese men.
Serum tPSA and fPSA were measured by enzyme-linked immunosorbent assay (ELISA) and fPSA/tPSA ratio was calculated in 1,096 health Chinese men of 23 - 85 years old. The relationship between age and PSA indexes was analyzed with simple linear regression.
The recommended age-specific reference range (95th percentile) for serum PSA for Chinese were: 1.20 microg/L for 20-29 years; 1.21microg/L for 30-39 years; 1.23 microg/L for 40-49 years; 2.35 microg/L for 50-59 years; 3.20 microg/L for 60-69 years; 3.39 microg/L for >or= 70 years. The serum PSA concentration correlated directly with age. The age-specific reference range was lower for Chinese men than not only for white and black men, but also for Japanese and Koreans men.
The age-specific reference ranges for serum PSA are lower significantly for Chinese men than for black, white men, even for Japanese and Koreans men. Study the normal upper limit of PSA and the age-specific reference ranges for serum prostate-specific antigen in Chinese men is very important.
No preview · Article · Oct 2003 · Zhonghua yi xue za zhi