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Liposome encapsulation of drugs is an interesting approach in cancer therapy to specifically release the encapsulated drug at the desired treatment site. In addition to thermo-, pH-, light-, enzyme- or redox-responsive liposomes, which have had promising results in (pre-) clinical studies, ultrasound-triggered sonosensitive liposomes represent an exciting alternative to locally trigger the release from these cargos. Localized drug release requires precise tumor visualization to produce a targeted and ultrasound stimulus. We used ultrasound molecular imaging (USMI) with BR55, a vascular endothelial growth factor receptor 2 (VEGFR2)-targeted ultrasound contrast agent, to guide ultrasound-triggered release of sonosensitive liposomes encapsulating doxorubicin (L-DXR) in an orthotopic prostatic rodent tumor model. Forty-eight hours after L-DXR injection, local release of doxorubicin was triggered with a confocal ultrasound device with two focused transducers, 1.1-MHz center frequency, and peak positive and negative pressures of 20.5 and 13 MPa at focus. Tumor size decreased by 20% in 2 wk with L-DXR alone (n = 9) and by 70% after treatment with L-DXR and confocal ultrasound (n = 7) (p0.01). The effect of doxorubicin on perfusion/vascularity and VEGFR2 expression was evaluated by USMI and immunohistochemistry of CD31 and VEGFR2 and did not reveal differences in perfusion or VEGFR2 expression in the absence or after the triggered release of liposomes. USMI can provide precise guidance for ultrasound-triggered release of liposomal doxorubicin mediated by a confocal ultrasound device; moreover, the combination of B-mode imaging and USMI can help to follow the response of the tumor to the therapy.

Among available methods, supercritical fluid (SCF) technology is a new and suitable approach for producing nano-sized particles. For this purpose, determination of a solid solute solubility such as pharmaceutical materials is an essential step. The present research is the first to measure Tamsulosin (TML) solubility in supercritical carbon dioxide (SC-CO2) under operating conditions of 308 to 338 K and 12 to 27 MPa. The mole fraction of TML ranged from 0.18 × 10−6 to 1.013 × 10−5. Experimental data have been modeled with two main models groups; the first group consisted of semi-empirical and empirical models (e.g., Chrastil; Sodeifian et al.; Kumar & Johnston (K-J); Mendez-Santiago & Teja (MST); Bian et al.; Bartle et al.) and the second group have been SAFT-VR (statistical associating fluid theory of variable range) and Peng-Robinson (PR) equations of state. Furthermore, self-consistency test of the experimental data was performed on the solubility data. Finally, the approximate values Δ H t o t a l , Δ H v a p and Δ H s o l enthalpies have been computed.

Trichomoniasis is the most common curable sexually-transmitted infection. Most Trichomonas vaginalis-infected men are asymptomatic and can remain undiagnosed and untreated, and this has been thought to result in chronic persistent prostatic infection. Chronic inflammation is regarded as the major factor in the pathogenesis and progression of benign prostatic hyperplasia (BPH) and prostatic cancer (PCa). The aim of this study is to identify seropositivity to T. vaginalis in men with prostate tumors (BPH or PCa) visited to Hanyang University Hospital. A total of 183 men were enrolled between October 2013 and November 2014. They consisted of 139 with BPH (mean age: 64.0 ± 0.07) and 44 with prostate cancer (mean age: 73.3±0.18). We carried out ELISA to identify the seropositivity to T. vaginalis. Mixed lysate antigen extracted from 8 strains of T. vaginalis was used in the ELISA. Also 58 male outpatients visited to Health Promotion Center in Hanyang University Hospital were evaluated for comparing group. As a results, seropositivity to T. vaginalis in patients with prostatic diseases was 19.7% (BPH: 18.7%, PCa: 22.7%) and it was significantly higher than the 1.7% of the comparing healthy group (P = 0.001). Therefore, prostatic tumor showed higher seropositivity against T. vaginalis than normal men. As far as we know, this is the first report about seroprevalence in prostatic tumor in Korea.

BACKGROUND To assess the feasibility, toxicity, and outcome of prostate hemi-irradiation with a high-dose-rate brachytherapy (HDR-BT) boost for patients presumed to harbor dominant intra-prostatic tumors in a single lobe. METHODS After 3D conformal external radiotherapy (3DCRT) to 64–64.4 Gy, 77 patients with non-metastatic locally aggressive prostate cancer have been treated from 2000 to 2004, with HDR-BT using temporary open MRI-guided 192Ir implants, to escalate the dose in the boost region. Twenty patients (26%) had one lobe involvement (i.e., one sided endorectal MRI, rectal examination, and biopsies) and were boosted to one side of the gland only. A dose of 12, 14, and 16 Gy in two fractions was delivered to 5, 6, and 9 patients, respectively. RESULTS After a median follow-up 69 months, no differences in late rectal toxicity were observed between the unilaterally and bilaterally irradiated cohorts. Although, grade 2 late urinary toxicity was worse in the hemi-irradiated group (P = 0.03), severe grade ≥3 late urinary toxicity at 5 years was not different: 10% versus 8.8% in the unilaterally and bilaterally irradiated cohorts, respectively. Grade 4 late urinary toxicity, however, was exclusively observed in patients boosted to both lobes (5/57, 8.8%). Five-year biochemical relapse-free survival was 79.7% versus 70.5% for the unilateral and bilateral boost groups, respectively (P = 0.99). CONCLUSION Prostate hemi-irradiation with a HDR-BT boost to the dominant tumor region may be considered when rectal examination, MRI, and biopsies suggest one lobe involvement. Nevertheless, strict dosimetric optimization is needed in order to further reduce the risk of late severe toxicity. Prostate 71:1309–1316, 2011. © 2011 Wiley-Liss, Inc.

We report a case of gastrointestinal stromal tumor (GIST) arising from the rectum which mimicked prostatic tumor on computed tomography (CT) and magnetic resonance imaging (MRI). Most GISTs arise in the stomach and/or small intestine; GISTs of anorectal origin are rare. We identify characteristic CT and MRI findings of anorectal GISTs and discuss the diagnostic pitfalls.

The aim of this study was to investigate the potential prognostic value of preoperative serum prostate-specific antigen levels adjusted for total tumor volume (PSA-TTV density) for outcome following radical prostatectomy for prostate cancer by retrospective review in 268 patients. Lower PSA-TTV density was not only associated with a significantly higher risk for biological failure (bF), systemic failure and cancer death but also an independent predictor for bF (hazard ratio, 6.3). Therefore, these data suggest that there are subsets of prostate cancer with lower PSA secretion levels, and this phenotype is associated with a higher risk of failure after surgery.

We present an extremely rare case of a 3-year-old child with a primary carcinoid tumor of the prostate. A 3-year-old boy presented with failure to thrive, constipation, recurrent respiratory tract infections, and pain in the genital area. His karyotype was normal and cystic fibrosis and coeliac disease were excluded prior to further investigation. An abdominopelvic computed tomography scan revealed a prostatic mass. Transrectal ultrasound-guided prostate biopsy was therefore performed and pathological examination revealed a carcinoid tumor. A robotic radical prostatectomy was performed. As this is an innovative surgical approach, we describe the surgical technique used.

Prostate cancer (PCa) was estimated to have the second highest global incidence rate for male non-skin tumors and is the fifth most deadly in men thus mandating the need for novel treatment options. MG1-Maraba is a potent and versatile oncolytic virus capable of lethally infecting a variety of prostatic tumor cell lines alongside primary PCa biopsies and exerts direct oncolytic effects against large TRAMP-C2 tumors in vivo. An oncolytic immunotherapeutic strategy utilizing a priming vaccine and intravenously administered MG1-Maraba both expressing the human six-transmembrane antigen of the prostate (STEAP) protein generated specific CD8+ T-cell responses against multiple STEAP epitopes and resulted in functional breach of tolerance. Treatment of mice with bulky TRAMP-C2 tumors using oncolytic STEAP immunotherapy induced an overt delay in tumor progression, marked intratumoral lymphocytic infiltration with an active transcriptional profile and up-regulation of MHC class I. The preclinical data generated here offers clear rationale for clinically evaluating this approach for men with advanced PCa.

The correlation between tumor volume of untreated tumor-bearing nude mice and serum concentration of prostatic acid phosphatase (PAP/RIA) was studied in the hormone-dependent serially transplantable human prostatic tumor models PC-82 and PC-EW. The normal serum level of PAP in control male nude mice without tumor was found to be 0.9 +/- 0.3 ng/ml. Elevated PAP serum concentrations were never found in animals without tumor (a highly specific diagnostic technique). A close correlation was observed between the concentration of PAP in the serum (range 0.3 to 154 ng/ml) and the tumor volume (range 10.0 to 6,530 mm3) of 104 untreated mice bearing a PC-82 or PC-EW human prostatic tumor. This correlation was comparable in both tumor lines (p less than 0.001). The positive effect of endocrine manipulation which resulted in tumor diameter decrease or growth arrest with regressive histological patterns, showed the normal PAP serum level, too. After successful treatment PAP was found to be normal, independent from the residual tumor mass. By contrast, in the event of only retarded tumor growth, the PAP level still correlated with the tumor burden.

Background The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1–4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis. Methods Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence. Results We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector. Conclusions Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease. Prostate © 2015 Wiley Periodicals, Inc.

Foxp3+ T cells play a critical role in maintaining immunological tolerance by regulating functions of other immune cells, thus preventing autoimmunity. Previous studies have demonstrated the importance of Foxp3+ T cells in the tumor, however, the role increasingly recruited FoxP3+ T cells in the programming of prostatic tumor microenvironment is not well illustrated. Therefore, in this study, we have investigated the role of Foxp3+ T cells in the prostatic tumor microenvironment with the notion that increased Foxp3+ T cells facilitate tumor growth. To accomplish this, we carried out tumor induction studies in C57/BL-6 mice using transgenic adenocarcinoma of mouse prostate (TRAMP cell lines: -C1, -C2 and -C3) as tumor models. Mice were administered with TRAMP (C1-3) cells using the Matrigel system. TRAMP-C3 cells are non-tumorigenic while TRAMP-C1 and TRAMP-C2 cells form tumors. Mice were sacrificed by cervical dislocation when tumor sizes reached ~18-20mm in diameter. To prepare single cell suspension, spleen and tumor were dissected out and cells were stained with various cell surface as well as intracellular immune markers to determine the number of Foxp3+ T cells and other immune cells in the prostatic tumor microenvironment. Our findings suggest that the high number of Foxp3+ T cells was found in the spleen and tumor of TRAMP-C1 and TRAMP-C2 mice than the spleen and tiny tumor of TRAMP-C3 mice. Furthermore, the number of cytotoxic T lymphocytes and NK cells were also observed to be low in the tumorigenic TRAMP-C1 and -C2 mice as compared to non-tumorigenic mice (TRAMP-C3). Therefore, our findings suggest that the number of Foxp3+ T cells may play a critical role in shaping the prostatic tumor microenvironment. Citation Format: Sanjay Kumar, James Stoke III, Shalie Malik, Udai P. Singh, Selvarangan Ponnazhagan, Upender Manne, Manoj K. Mishra. FoxP3+T cells program/re-program the prostatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4690.

Several tumors express antigens that can be recognized by T lymphocytes, suggesting that T cell-mediated immune response may play a critical role in anti-tumor immunity. Studies demonstrated that Regulatory T cells (TR) suppress the functions of immune cells, which are capable to recognized and eliminate tumor cells. However, there exists an utmost demand for further research how immune cells (CD8+ cells, NK cells, etc.) fail to suppress tumor growth and proliferation in the prostatic tumor microenvironment. To investigate this, tumor induction studies in C57/BL-6 mice using transgenic adenocarcinoma of mouse prostate (TRAMP cell lines: -C1, -C2 and -C3) as tumor models were performed. TRAMP-C3 did not form tumor while TRAMP-C1 and TRAMP-C2 cells are tumorigenic. For tumor induction, mice were administered with TRAMP (C1-3) cells. Mice were sacrificed by cervical dislocation when tumor sizes reached ~18–20mm in diameter. A single cell suspension (obtained from spleen, draining lymph node, and tumor) was stained with various cell surface/intracellular immune markers/cytokines to enumerate CD8+ T/TR/NK/Ly6G/Ly6C+ -MDSC cells. Additionally, the expression of TGF-β, IFN-γ, IL-4, IL-17, PD-1 and PDL-1 and cell cycle analysis for CD8+ T cells was also carried out. Our findings suggest that recruitment of suppressive TR and Ly6G/Ly6C+ -MDSC cells and high expression TGF-β and PD-1 and lower expression of NKG2D and IFN-γ and low number of NK and CD8+ cytotoxic T cells in spleen, draining LN and tumor of TRAMP-C1 and TRAMP-C2 (as compared to TRAMP-C3 mice) facilitated tumor growth. Therefore, the expression of PD-1 and TGF-β on TR suggest that TR might be playing a significant role in facilitating tumor growth and progression.

BACKGROUND Blockade of androgen activity is a major effective therapy for advanced prostate cancer. Estrogen analogs have been used for prostate cancer therapy for years presumably by inhibiting testosterone biosyntheses, but with considerable adverse events due to their classic estrogenic activity. With the discovery of the estrogen receptor (ER) β and its presence in prostate tumor cells, evaluation of estrogen analogs with less classic estrogenic activity in prostate cancer therapy is emerging. METHODS The effects of 17α-estradiol (αE2), a stereo-isomer of 17β-estradiol (βE2), on dihydrotestosterone (DHT)-induced cell growth and gene expressions were examined in androgen-dependent LAPC-4 prostatic tumor cells and in LAPC-4 xenograft animals, and compared to those of βE2. RESULTS Both αE2 and βE2 attenuated DHT induction of PSA gene expression, cell proliferation, and cell growth in cultured LAPC-4 cells. The inhibition of cell proliferation was associated with a blockade of DHT-induced cyclin A and cyclin D1 expression by αE2 and βE2. In LAPC-4 xenograft mice, αE2 significantly inhibited tumor growth without altering the plasma testosterone level, while βE2 failed to inhibit tumor growth even though it significantly inhibited PSA gene expression. CONCLUSION αE2 is an effective agent for inhibition of DHT-induced PSA, cyclin A, cyclin D1 gene expression, and cell proliferation in LAPC-4 cells, and tumor growth in LAPC-4 xenograft mice. Prostate 67: 1719–1728, 2007. © 2007 Wiley-Liss, Inc.

BACKGROUND To investigate the possibilities offered by high intensity focused ultrasound (HIFU) in the field of tumor vaccination, we analyzed how prostatic cancer (CaP) cells react towards heat treatment and whether increased access to CaP cells by the immune system would be the result. METHODS Heat/stress response of CaP cells in situ and of CaP cell lines was analyzed by immunohistochemistry, Western blotting, and Atlas array. A heat-induced change in immune recognition was analyzed functionally using human T-helper (Th)1 and Th2-cytokine release with tumor infiltrating T-lymphocytes (TIL) as responder and autologous CaP cells either heated or untreated as stimulator cells. RESULTS Transcription of 68 out of 500 genes was upregulated by sublethal heat in LNCaP and PC3 cells. Significantly upregulated stress protein (SP) expression (HSP-72, -73, GRP-75, -78) was seen at the border zone of HIFU treatment. Remarkably, even untreated benign prostatic hyperplasia (BPH) specimens revealed relative overexpression of heat shock protein (HSP)-72, -73 and glucose regulated protein (GRP)-75, -78. Heated CaP cells increased Th1-cytokine (IL-2, IFN-γ, TNF-α) release but decreased Th2-cytokine (IL-4, -5, -10) release of TIL. CONCLUSIONS HIFU treatment may alter the presentation of prostate tissue and tumor antigens and this presentation is most likely stimulatory. HSP-72/73 overexpression in untreated BPH may suggest a mechanism by which BPH can incite inflammation. © 2003 Wiley-Liss, Inc.

Regulatory T (Treg) cells act as terminators of T cell immune response during prostate cancer progression and development. However, their role and immunosuppressive mechanism(s) in context to programmed death 1 (PD-1) is not completely understood. The present investigation is aimed to determine the role of PD-1 on Treg cells and their impact on CD8+ T cell function in prostatic tumor microenvironment using transgenic adenocarcinoma of the mouse prostate (TRAMP) cells (TRAMP C1, C2 and C3) as a model system. To execute the above aim, tumor induction studies were performed. Briefly, the C57BL/6 mice were administered with serial log concentrations of TRAMP (C1-3) cells. Interestingly, the TRAMP-C3 cells do not form tumor, however, TRAMP-C1 and TRAMP-C2 cells do form tumor. After tumor development, mice were sacrificed by cervical dislocation; tumor, lung, spleen, and draining lymph nodes were harvested when the tumor size reached approximately 20mm. Single cell suspensions were prepared from different organs, cells were then stained with specific antibodies, and flow analyzed for the expression of different immune markers. Our preliminary findings demonstrated that PD-1 expression on Foxp3+ Treg cells displayed greater suppressive capacity against CD8+ T cell function in tumor, lung, spleen, and draining lymph node when compared to the control. More importantly, Foxp3+ Treg(high) PD-1(high) interaction with PDL-1 induced immunosuppression by blocking CD8+ T cells function in prostatic tumor microenvironment. In conclusion, Foxp3+ Treg(high), PD-1(high), and CD8+(low) T cells may enhance tumor progression; thus, targeting the PD-1 on Treg cells may be a possible therapy to treat prostate cancer.

Analysis of ten primary prostatic tumor cultures using fluorescence in-situ hybridization (FISH) with pericentromeric probes for chromosomes 7, 8, 10, 16, 17, and 18 revealed aneusomies in nine of these specimens. Classical cytogenetics by G-banding indicated that only four of those same ten specimens had any (but not consistent) clonal abnormalities. This preliminary study suggests that aneusomy is a common event in early-stage prostatic tumors, and also supports the notion that multiple chromosomes are involved. In combination with routine cytogenetic analysis, FISH is thus likely to be a powerful tool in the evaluation of prostatic cancer.

PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenyl- propyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide], a novel, potent and selective dual 5α-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. Purpose: We investigated the efficacy of treatment with PNU 157706 in combination with the antiandrogen bicalutamide in this prostatic tumor model. Methods: Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.2 and 1 mg/kg per day). Animals were killed 24 h after the last treatment, and ventral prostates were removed for testosterone (T) and dihydrotestosterone (DHT) determination. Results: PNU 157706 reduced the growth of established tumors by 39%; bicalutamide proved ineffective at 0.2 mg/kg per day, but reduced tumor growth by 45% at a dose of 1 mg/kg per day. The combination of PNU 157706 with both doses of bicalutamide caused an additive tumor growth inhibition (50% and 64%). Castration resulted in marked tumor growth inhibition (72%). Ventral prostate weight was markedly reduced by PNU 157706 (78%) treatment and by bicalutamide (59% and 77%); combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (88%), whereas prostatic T increased slightly (60%). Concomitant treatment with bicalutamide antagonized the T increase induced by PNU 157706 and did not modify the already remarkable suppression of DHT. Conclusions: These data show that the inhibitory effect of PNU 157706 and bicalutamide on Dunning prostatic tumor growth is additive, thus suggesting a possible role of PNU 157706 in the therapy of advanced prostate cancer, in combination with antiandrogens, to provide an effective peripheral androgen ablation therapy with minimal side effects.

We report a patient with adenocarcinoma of the prostate, who eventually developed Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion from the tumor. At first, maximal androgen blockade (MAB) therapy was effective for the prostate carcinoma, which was positive for prostate-specific antigen (PSA) and negative for ACTH on the biopsy specimen. However, 3 years later, the patient complained of bilateral leg edema. A chest computed tomographic (CT) scan showed bilateral pleural effusion and inflammatory changes, focused on the right upper-lobe. While his PSA was not elevated, and there were no obvious tumor metastases, his serum cortisol and ACTH levels were elevated, without any evidence of lesions that could release ectopic ACTH. Two weeks later, the patient complained of dyspnea and bilateral pleural effusion, and inflammatory changes were worse. Although the patient was administered inhibitors of adrenocorticoid synthesis-metyrapone, they did not have enough clinical efficiency. Steroid pulse therapy was also administered but the patient's severe pneumonia and pleural effusion did not improve and he finally died of respiratory failure. In contrast to the initial biopsy specimen findings, on autopsy, the tumor was negative for PSA but positive for ACTH. Thus, it would appear that the tumor began to produce and release ectopic ACTH after therapy, which resulted in the development of Cushing syndrome in this patient with prostate carcinoma.

PSP94, for prostatic secretory protein of 94 amino acids, is secreted by the prostate gland and functions as a suppressor of tumor growth and metastasis. The expression of PSP94 is lost in advanced, hormone-refractory prostate cancer and this correlates with an increased expression of the Polycomb protein EZH2 (enhancer of zeste homolog 2), which represses transcription via trimethylation of histone H3 on Lys27 (H3K27). We show here that these events are causally related and that the MSMB gene, which encodes PSP94, is trimethylated on H3K27 in androgen-refractory, but not in androgen-sensitive prostate cancer cells. Chromatin immunoprecipitation experiments confirmed an association of EZH2 with the MSMB gene. The RNAi-mediated knockdown of EZH2 resulted in a loss of H3K27 trimethylation and an increased expression of the MSMB gene. Conversely, the overexpression of EZH2 was associated with a decreased expression of the MSMB gene. We also demonstrate that MSMB is additionally repressed in androgen-refractory prostate cancer cells by the hypoacetylation of histone H3K9 and the hypermethylation of a CpG island in the promoter region. Our data disclose a hitherto unexplored link between the putative oncogene EZH2 and the tumor suppressor PSP94, and show that MSMB is silenced by EZH2 in advanced prostate cancer cells.

The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis.Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence.We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector.Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease.

We have previously reported that adenoviral vector-mediated interferon (IFN)-beta gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immune-competent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) of adenoviral vector encoding for mouse IFN-beta (AdmIFN-beta), but not AdE/1 (a control adenoviral vector), produced approximately 60 ng/10(5) cells/24 h of IFN-beta. The tumorigenicity of AdmIFN-beta-transduced cells was dramatically reduced in the prostates of C57BL/6 mice. A single intratumoral injection of 2 x 10(9) PFU (plaque-forming unit) of AdmIFN-beta inhibited tumor growth by 70% and prolonged survival of tumor-bearing mice. Intriguingly, this AdmIFN-beta therapy did not alter the growth of tumors in inducible nitric oxide synthase (iNOS)-null C57BL/6 mice. Immunohistochemical analysis revealed that treatment of tumors with AdmIFN-beta in wild-type C57BL/6 mice led to increased iNOS expression, decreased microvessel density, decreased cell proliferation, and increased apoptosis. Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-beta therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-beta1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-beta gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-beta antitumoral effects in vivo.

We had previously reported that 6-methylene progesterone, an inhibitor of 5α-reductase, the enzyme which converts testosterone to dihydrotestosterone, markedly inhibited growth of the androgen-dependent Dunning R3327-H rat prostatic tumors. We now find that the progesterone derivatives melengestrol acetate (MGA) and megestrol acetate (MA) inhibit both the androgen-dependent (Dunning R3327-H) and the androgen-independent (Dunning R3327-AT3) prostatic tumors. Growth of the AT3 tumors was suppressed by ~53% after 9 days of daily s.c. injections with MGA at 10 mg/kg body weight. MGA also caused a 54% weight reduction of the ventral prostate and a 53% reduction of the seminal vesicles. Adrenal weights were reduced by 42%. A 24-day oral treatment with MGA (at ~15-17 mg/(kg∙day)) inhibited AT3 tumor growth by 59% and caused a weight reduction in the following tissues: prostate (46%), seminal vesicles (19%), testes (12%), and adrenals (52%). Under the same protocol, MA inhibited AT3 tumor growth by 32% and reduced the weight of the ventral prostate by 49% and the weight of the adrenals by 18%, but had no effect on the seminal vesicles and testes. The extent of the MGA-induced prostatic regression was accompanied by cytological changes similar to those effected by 6-methylene progesterone, i.e., shrinking of the acinar epithelium. The AT3 tumors in MGA-treated rats displayed a limited degree of apoptosis. Atrophy of the adrenal cortex and lowered plasma levels of corticosterone and dihydroepiandrosterone were also observed. A therapeutic role for MGA and MA against androgen-independent prostatic neoplasms in man is forecast by these observations.Key words: prostatic cancer, androgen independent, melengestrol acetate, growth inhibition, steroids.

Purpose: We assessed the outcome of patients with superficial bladder tumors with relapse in the prostate and defined prognostic variables of survival.Materials and Methods: A cohort of 186 men with superficial bladder tumors was followed for 15 years. Tumor relapse in the prostate was classified as noninvasive (prostatic urethra and ducts) or invasive (stroma) with intraurethral or direct prostatic invasion. Bladder tumor stage at the time of prostatic relapse was defined as confined or not confined to the bladder. The end point of the study was disease specific survival. The effects of covariates on survival were estimated on multivariate analysis.Results: Of the 186 patients 72 (39%) had relapse in the prostate after a median followup of 28 months (range 3 to 216), including 45 (62%) with noninvasive prostatic tumor and 27 (38%) with stromal invasion. The survival rate was 82% in patients with prostatic urethra or duct involvement compared to 48% with stromal invasion. Intraurethral stromal inv...

Objectives. In most clinical trials that have investigated the potential beneficial effects of neoadjuvant combined androgen blockade (CAB) in clinically localized prostate cancer, CAB has been given for 3 months, but no data are available on the influence of a longer duration of neoadjuvant CAB on the pathologic features of prostate cancer. Methods. Prostatectomy specimens of 40 patients, randomized to 3 (n = 18) or 6 (n = 22) months of neoadjuvant CAB, were blindly evaluated with regard to tumor volume, pathologic stage, and surgical margins. The morphologically most vital tumor areas were investigated for nucleolar size and MIB-1 defined proliferative activity. Results. The patients treated for 6 months had a median tumor volume 60% lower than the 3-month treatment group ( P = 0.005). In the 6-month treatment group, no residual tumor could be found in 2 cases, but the proportion of prostatectomy specimens with seminal vesical invasion and positive surgical margins was not statistically different from that after 3 months. Compared with untreated controls, tumor proliferative activity assessed by MIB-1 immunoreactivity was significantly lower at 3 and 6 months of neoadjuvant CAB ( P = 0.01). However, in 2 of 17 examined tumors that had been treated for 6 months, high MIB-1 scores suggested a development toward therapy-resistant cancer. Conclusions. Prolonged neoadjuvant CAB for 6 months leads to a further decrease in prostatic tumor volume compared with the findings after 3 months. In a few instances, residual tumor areas with substantial MIB-1 defined proliferative activity persist at 6 months, thus indicating that in at least some cases, despite the overall decrease in tumor size, cancer cells can continue the cell cycle under CAB.

Solidago virgaurea (goldenrod) has traditionally been used as an anti-inflammatory herbal medicine for the treatment of various symptoms, including prostatic diseases. The plant has also been reported to have antibacterial, spasmolytic, and carminative properties. During the course of our screening for antineoplastic activities in various herbal plants, we found that the extract of S. virgaurea exhibits strong cytotoxic activities on various tumor cell lines. The active component mostly resides in the leaves of the plant and is soluble in water. When the extract was fractionated by a Sephadex G-100 column, the active fraction corresponded to a molecular weight of approximately 40,000. This cytotoxic activity is effective on various tumor cell lines, including human prostate (PC3), breast (MDA435), melanoma (C8161), and small cell lung carcinoma (H520). To examine the effect of the cytotoxic activity on tumor cells in vivo, we used the rat prostate cell line (AT6.1) and an SCID mouse model. AT6.1 cells were injected into the flank of SCID mice, and then the G-100 fraction of S. virgaurea was administered intraperitoneally or subcutaneously every 3 days. The size of the tumor was measured for up to 25 days. The growth of the tumor was significantly suppressed by the G-100 fraction at 5 mg/kg without any apparent side effects. Therefore, S. virgaurea is considered to be promising as an antineoplastic medicine with minimal toxicities.

We are interested in studying the possibility of modulating prostatic cell growth by manipulating apoptosis. Here we show that 1 microM staurosporine (STS) induces a human androgen-independent prostatic tumor cell line, DU145, to undergo dramatic changes in morphology and results in programmed cell death. Several genes involved in apoptosis were analyzed for expression in STS-treated and untreated DU145 cells. It was observed that these genes were differentially regulated. The expression level of bcl-2, bcl-xL, Ich-1L remains unchanged in treated and untreated cells. On the other hand, DAD1 and interleukin-1 beta-converting enzyme (ICE) were downregulated while bcl-xs and Ich-1s were upregulated. By blocking bcl-2 gene expression using antisense oligonucleotides, it was determined that the anti-bcl-2 oligonucleotides have no effect on the proliferation of DU145 or STS-treated DU145 cells. These results demonstrate that programmed cell death can be induced in an androgen-independent prostatic cancer cell line and BCL-2 was found not to play an important role in preventing STS-induced apoptosis in the DU145 cell line.

Bone is the most common metastatic site for prostate cancer which affects approximately 70% of patients with advanced disease. Despite this clinical importance, the exact molecular mechanism of the bone-specific metastasis has not been clearly defined. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re-growth. According to the recent cancer stem cell theory, which still remains a hypotheses, recurrent tumor must arise from a dormant tumor stem cell. However, the precise mechanism of dormancy is virtually unknown, and identifying the responsible factors and understanding the underlining mechanism are crucial for developing a novel therapeutic approach. Our recent preliminary data suggest that BMP7 (bone morphogenetic protein 7) which is secreted from bone stromal cells is able to induce senescence to prostate tumor cells and that this induction is mediated by activation of the tumor metastasis suppressor gene, NDRG1 (N-myc downstream regulated gene 1). Therefore, we hypothesize that a prostatic tumor stem cell becomes dormant in the bone through the BMP7-mediated activation of p38 and NDRG1.

Although it is evident that prostatic epithelial stem cells are responsible for maintaining normal and malignant tissues, it is well recognized that epithelial cells do not exist independently, but act in concert with the stromal microenvironment. Prostatic stroma is pivotal for normal development and homeostasis. The genetic and morphological changes that occur in prostatic epithelial cells, as they progress from a normal to malignant phenotype, have been well described. However, it is evident that the surrounding microenvironment also plays a major role in cancer cell growth, survival, invasion and metastatic progression. Prostatic tumor stroma provides a niche environment for cancer stem cells and therefore contributes to self-renewal and differentiation. In order to target the tumor microenvironment and develop new therapeutics for prostate cancer, we must understand the role of the tumor stroma, specifically the events mediating the interactions between the cancer stem cell and its immediate microenvironment during cancer initiation and progression. This article presents the rationale and discusses the challenges to targeting prostatic tumor stroma in cancer therapies that will potentially treat prostate cancer.

We describe a novel technique for tumor implantation into the prostate of a nude mouse, using a perineal approach. This technique offers the benefit of being able to accurately implant malignant cells into the dorsal prostate without entering the abdominal cavity.

The PSM antigen is an exciting new molecule with many potentially valuable applications. Further research with PSM may help us to elucidate the complex process of prostatic neoplasia better. Current avenues of research with PSM include the generation of new and improved monoclonal antibodies targeting different portions of PSM and PSM', which may improve the results of imaging and targeting prostate cancer. Gene therapy using the PSM promoter to drive prostate-specific expression of various cytokines and other factors is another exciting potential application deserving of attention, and refinement of serum PSM assays may greatly add to the present array of diagnostic modalities offered to patients with suspected prostate cancer. Thus, PSM is a potentially valuable addition to our armamentarium of prostate markers. Additionally, a host of other potential markers to increase our understanding of the complex biology of the normal and malignant prostate are on the horizon. Just how far away that horizon is awaits further basic and clinical investigations.

An inhibitory effect of TZP-4238, a newly synthesized antiandrogen, on the growth of Dunning R3327 rat prostatic tumor was studied and compared with that of chlormadinone acetate (CMA). TZP-4238 markedly suppressed the growth of R3327 tumor. The inhibitory effect of TZP-4238 on the tumor was more potent than that on the prostate. While the inhibitory effect of TZP-4238 on the weight of the ventral prostate was about 6 times as great as that of CMA, the suppressive effect of TZP-4238 on tumor weight was about 40times as great as that of CMA. Serum levels of testosterone and dihydrotestosterone showed no obvious changes after the administration of either TZP-4238 or CMA. The inhibitory effect of TZP-4238 on the growth of R3327 tumor indicated the application of the compound to human prostatic cancer.

Rising life expectancy has swollen the ranks of men of middle age and beyond. These individuals have a 43 % risk of symptoms of benign prostatic hyperplasia (BPH) and a 9 % chance of being diagnosed with prostate cancer. Although not always life-threatening, prostate diseases are often associated with a significant reduction in quality of life not only for the sufferer but also for his partner. Men beyond middle age are increasingly reluctant to accept restrictions on their day-to-day activities as they grow older. As a consequence, prostate diseases are now acknowledged as an important determinant of men’s health and therefore worthy of proper scrutiny, treatment, and enhanced research. In this chapter, the role of imaging modalities in evaluation of prostate disorders in elderly is illustrated, with emphasis both on current clinical practice and on the evolving imaging modalities that will affect treatment in the future

We have examined the expression of 2 tumor-associated metalloproteinases, MMP-2 and MMP-9, in 48 primary cultures of prostatic carcinoma (PRCA) and 33 cultures of benign prostatic hyperplasia (BPH). PRCA cultures secrete significantly more MMP-9 than their benign counterparts. Secreted MMP-2 did not differ significantly in cultures but was lower in PRCA cultures. Two cultures of benign origin exhibited high MMP-9 secretion and growth patterns consistent with a malignancy. Both cases were followed and successively re-evaluated histologically and rediagnosed as organ-confined PRCA. MMP expression in culture may be of predictive value in the identification of incidental PRCA. MMP-9 secretion and its ratio with MMP-2 were highest in epithelial cultures from invasive, metastatic tumors when compared both to disease confined to prostate gland and to locally extensive disease. MMP-9 secretion was greatest also in cultures derived from tissues of high Gleason histological grade. Active MMP-9 species were detected in 15 cultures (31%) of PRCA. Active MMP-2 species were observed in cultures of both BPH and PRCA origin in almost the same amounts. Although average levels were not significantly different, as a ratio to proform species, a significant elevation was observed in cultures of PRCA origin. We propose, therefore, that an elevated expression of MMP-9 and a high ratio of MMP-9 to MMP-2 in short-term prostate epithelial cultures is of potential diagnostic and prognostic significance.

The biological mechanisms involved in androgen-dependent and -independent prostate cancer growth after castration were analyzed in the LuCaP 23.1 human prostate cancer xenograft model. Athymic mice (n = 82) bearing LuCaP 23.1 xenograft were castrated and tumors were harvested at different time points from day 0 to day 112 post castration. In each group of mice, tumor growth rate (TGR), serum PSA concentration, percentage of tumor cells incorporating bromodeoxyuridine (BUdR index), percentage of apoptotic tumor cells assessed by morphological analysis (apoptotic index), and presence of apoptosis-related DNA "ladder" were analyzed. Castration induced a significant decrease in TGR and serum PSA from day 1 to day 7, and a progressive increase in the 2 parameters from day 14 to day 112, heralding androgen-independent tumor relapse. Meanwhile the BUdR and apoptotic indexes varied as follows after castration: an increase was noted for both at day 3, a significant increase in apoptotic index with a decrease in BUdR index from day 5 to day 14, and a progressive decrease in apoptotic index while BUdR index remained at 50% of the pre-castration value from day 28 to day 112. DNA ladder was present sparsely in tumors grown in non-castrated hosts, universally present in tumors from day 1 to day 28 post castration, and frequent in tumors from day 56 to 112. Castration-induced effects in LuCaP 23.1 tumors were characterized by an increase in number of apoptotic cells and a decrease in proliferative activity. The androgen-independent tumor relapse after castration was associated with a low apoptotic index with no increase in proliferative activity.

Because there is extremely limited information on the intrinsic radiosensitivity of human prostatic cancer cells, we have investigated the in vitro radiation response of exponentially growing LNCaP cells. Due to the very poor colony-forming potential of the LNCaP cells, radiation survival was investigated using the dose-dependent (0-6 Gy) changes seen after X-irradiation in the shapes of regrowth curves. Survival was described using both the single-hit, multitarget (SHMT) equation and the linear-quadratic (LQ) equation. The values and 95% confidence limits of the extrapolation number (n), quasi-threshold dose (Dq), and mean lethal dose (Do) in SHMT terminology were respectively: 0.9 (0.7-1.0), 0.0 Gy, and 1.39 (0.11) Gy. The LQ alpha and beta parameters were respectively 6.80 (1.13) and -0.53 (2.89). The X-ray dose response of the LNCaP line is, therefore, purely exponential. The mean survival at the clinically relevant dose of 2 Gy (S2) was 51.2% for the LNCaP line. Comparison of the S2 value for the LNCaP line with previous investigations with other human prostatic cancer cell lines (DU145 and PC-3) indicates a mean S2 value of 47.6%, which suggests that human prostate cancer cells might lie toward the resistant side of the spectrum for various classes of human neoplasms. © 1994 Wiey-Liss, Inc.

To investigate the possibilities offered by high intensity focused ultrasound (HIFU) in the field of tumor vaccination, we analyzed how prostatic cancer (CaP) cells react towards heat treatment and whether increased access to CaP cells by the immune system would be the result.Heat/stress response of CaP cells in situ and of CaP cell lines was analyzed by immunohistochemistry, Western blotting, and Atlas array. A heat-induced change in immune recognition was analyzed functionally using human T-helper (Th)1 and Th2-cytokine release with tumor infiltrating T-lymphocytes (TIL) as responder and autologous CaP cells either heated or untreated as stimulator cells.Transcription of 68 out of 500 genes was upregulated by sublethal heat in LNCaP and PC3 cells. Significantly upregulated stress protein (SP) expression (HSP-72, -73, GRP-75, -78) was seen at the border zone of HIFU treatment. Remarkably, even untreated benign prostatic hyperplasia (BPH) specimens revealed relative overexpression of heat shock protein (HSP)-72, -73 and glucose regulated protein (GRP)-75, -78. Heated CaP cells increased Th1-cytokine (IL-2, IFN-gamma, TNF-alpha) release but decreased Th2-cytokine (IL-4, -5, -10) release of TIL.HIFU treatment may alter the presentation of prostate tissue and tumor antigens and this presentation is most likely stimulatory. HSP-72/73 overexpression in untreated BPH may suggest a mechanism by which BPH can incite inflammation.

Bone is the most common metastatic site for prostate cancer. The growth of the tumor cells in the bone is generally slow and they often become dormant until an appropriate microenviroment is established for their re-growth. The recent stem cell theory predicts that the metastatic cells are a small population of stem-like cells in the primary tumor. However, the precise mechanism of dormancy is virtually unknown, and identifying the responsible factors and understanding their underlining mechanism are crucial for developing a novel therapeutic approach. Our preliminary data indicate that (i) bone morphogenetic protein 7 (BMP7) which is secreted from bone marrow stromal cells is able to induce senescence to prostate tumor cell and (ii) this induction is mediated by activation of the tumor metastasis suppressor gene, N-myc downstream regulated gene 1 (NDRG1). These results strongly suggest that the BMP7-NDRG1axis plays a critical role in dormancy of prostate tumor cells in the bone. The overall goal of this proposal is to elucidate the mechanism of BMP7-induced dormancy in tumor stem cells and explore a possibility of using BMP7 as an anti-metastatic drug for prostate cancer.

Prostate cancer is a leading cause of cancer death in American males. Currently, there is no curative therapy available once prostate cancer has metastasized. A major systemic therapy for metastatic prostate cancer is anti-androgen therapy. Unfortunately this therapy is only palliative and rarely curative, and eventually the tumor cells develop resistance to further hormone manipulation. It is therefore imperative to develop alternative effective therapies. In the present study, the effect of a Chinese herbal formula, ZYD88, on regulation of cell growth and cell apoptosis was examined in prostatic tumor cells. ZYD88 decreased cell viability of multiple prostatic tumor cell lines, DU-145, PC-3, MDA-PCa 2b and LNCaP in a time- and dose-dependent manner. It also produced a rapid and dose-dependent increase in caspase 3 activity in LNCaP and PC-3 cells, and induced DNA fragmentation in LNCaP cells, indicating cell apoptosis. In cotransfection assays, ZYD88 inhibited androgen-induced prostate specific antigen (PSA) gene promoter activity, and induced estrogen-target gene promoter activity. These data suggest that ZYD88 is a potential agent for prostate cancer therapy, and deserves further study.

To assess the feasibility, toxicity, and outcome of prostate hemi-irradiation with a high-dose-rate brachytherapy (HDR-BT) boost for patients presumed to harbor dominant intra-prostatic tumors in a single lobe.After 3D conformal external radiotherapy (3DCRT) to 64-64.4 Gy, 77 patients with non-metastatic locally aggressive prostate cancer have been treated from 2000 to 2004, with HDR-BT using temporary open MRI-guided (192) Ir implants, to escalate the dose in the boost region. Twenty patients (26%) had one lobe involvement (i.e., one sided endorectal MRI, rectal examination, and biopsies) and were boosted to one side of the gland only. A dose of 12, 14, and 16 Gy in two fractions was delivered to 5, 6, and 9 patients, respectively.After a median follow-up 69 months, no differences in late rectal toxicity were observed between the unilaterally and bilaterally irradiated cohorts. Although, grade 2 late urinary toxicity was worse in the hemi-irradiated group (P = 0.03), severe grade ≥3 late urinary toxicity at 5 years was not different: 10% versus 8.8% in the unilaterally and bilaterally irradiated cohorts, respectively. Grade 4 late urinary toxicity, however, was exclusively observed in patients boosted to both lobes (5/57, 8.8%). Five-year biochemical relapse-free survival was 79.7% versus 70.5% for the unilateral and bilateral boost groups, respectively (P = 0.99).Prostate hemi-irradiation with a HDR-BT boost to the dominant tumor region may be considered when rectal examination, MRI, and biopsies suggest one lobe involvement. Nevertheless, strict dosimetric optimization is needed in order to further reduce the risk of late severe toxicity.