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AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

BACKGROUND Focal therapies for prostate cancer (PC) can reduce adverse events and do not lead to androgen-independent progression. Ultrasound could be used for cancer treatments if the repetition frequency is fitted to the purpose. We investigated the possible therapeutic effect of ultrasound irradiation on PC cells. MATERIALS AND METHODS We irradiated two PC cell lines, androgen-dependent LNCaP and -independent PC-3 with ultrasound (3.0 W/cm2 , 3 MHz, irradiation time rate: 20%) for 2 minutes for 1 day or 3 consecutive days at a repetition frequency of 1, 10, or 100 Hz in vitro. Cell proliferation and apoptosis were determined after irradiation. RESULTS Cell proliferation of PC-3 was significantly inhibited after 1 day (P

Medulloblastoma is the most common embryonic brain tumor in children. We investigated a cohort of 52 Asian medulloblastoma patients aged between 0 and 19 years old, who received surgical resections and post-resection treatments in the Taipei Medical University Hospital and the Taipei Veterans General Hospital. Genome-wide RNA sequencing was performed on fresh-frozen surgical tissues. These data were analyzed using the CIBERSORTx immune deconvolution software. Two external clinical and molecular datasets from United States (n = 62) and Canada (n = 763) were used to evaluate the transferability of the gene-signature scores across ethnic populations. The abundance of 13 genes, including DLL1, are significantly associated with overall survival (All Cox regression P

Treating brain tumors presents enormous challenges, and there are still poor prognoses in both adults and children. Application of novel targets and potential drugs is hindered by the function of the blood-brain barrier, which significantly restricts therapeutic access to the tumor. Mesenchymal stem cells (MSCs) can cross biological barriers, migrate to sites of injuries to exert many healing effects, and be engineered to incorporate different types of cargo, making them an ideal vehicle to transport anti-tumor agents to the central nervous system. Extracellular vesicles (EVs) produced by MSCs (MSC-EVs) have valuable innate properties from parent cells, and are being exploited as cell-free treatments for many neurological diseases. Compared to using MSCs, targeted delivery via MSC-EVs has a better pharmacokinetic profile, yet avoids many critical issues of cell-based systems. As the field of MSC therapeutic applications is quickly expanding, this article aims to give an overall picture for one direction of EV-based targeting of brain tumors, with updates on available techniques, outcomes of experimental models, and critical challenges of this concept.

Purpose: The aim of this study was to compare and investigate the efficacy of using the 5α-reductase inhibitor dutasteride after holmium laser enucleation of the prostate (HoLEP) to improve postoperative urination and surgery-related complications. Methods: This is a retrospective observational study comparing patients who received or did not receive 5α-reductase inhibitors prior to HoLEP. Of a total of 270 patients, 40 received the 5α-reductase inhibitor dutasteride. We compared the factors including age, postoperative maximal flow rate (MFR; mL/s), postoperative prostate-specific antigen (PSA) (ng/mL), preoperative MFR (mL/s), preoperative PSA (ng/mL), prostate cancer (%), operative time (min), preoperative residual urine (mL), postoperative residual urine (mL), urinary incontinence (day 1; %), urinary incontinence (1 month; %), urinary incontinence (3 months; %), urethral catheter indwelling period (days), morcellation time (min), enucleation time (min), intraoperative complications (%), postoperative complications (%), prostate volume (mL), enucleated weight (g), and hospitalization period (days). Results: Postoperative PSA (p = 0.0071), morcellation time (p = 0.0444), postoperative complications (p = 0.0350) and prostate volume (p = 0.0069), but not enucleated prostate weight (p = 0.8809), were significantly lower in the dutasteride group. Importantly, enucleation efficiency and morcellation efficiency did not show any significant difference between the dutasteride and the non-dutasteride groups. Conclusions: Use of a preoperative 5α-reductase inhibitor significantly correlated with surgery-related factors, with less morcellation time, fewer postoperative complications, and lower postoperative PSA. Surgeons performing HoLEP may wish to take these findings into account.

BACKGROUND/AIM Epithelial-mesenchymal transition (EMT) via Sonic Hedgehog (Shh) signaling may be one of the mechanisms of progression of castration-resistant prostate cancer (CRPC). In this study, we investigated the possible therapeutic effect of vismodegib, a new Shh inhibitor, in a mouse CRPC model. MATERIALS AND METHODS We determined cell proliferation, apoptosis and the expression of EMT-related genes for three prostate cancer cell lines; androgen-dependent LNCaP and independent C4-2B and PC-3 in the presence of vismodegib in vitro. Fifty mg/kg of vismodegib were orally administered into mice bearing C4-2B and PC-3 tumors, respectively every other week for 3 weeks. RESULTS Vismodegib significantly inhibited cell proliferation and induced cell apoptosis in all cell lines in vitro (p

This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor–stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor–stroma interaction. This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation. This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications. We dedicate this article in our fond memory of Dr. Donald S. Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine. Keywords: Prostate cancer, Castration resistance, Metastasis, Cancer-stromal interaction, Targeted therapy

Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22–2.18) or absence (HR: 2.31, 95% CI = 1.40–3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.

Angiopoietin-like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial-mesenchymal transition (EMT)-driven sorafenib resistance, cancer stemness and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the ERK/AKT–dependent Egr-1 pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness and poor clinical outcomes in HCC patients. Conclusions: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT via inhibition of the MET receptor−AKT/ERK−Egr-1−Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. This article is protected by copyright. All rights reserved.

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

Suicide gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene, combined with the prodrug ganciclovir (GCV) medication, is a promising approach for the treatment of malignant tumors, including prostate cancer. The success of this therapeutic strategy requires tissue- or tumor-specific gene expression and efficient gene delivery. In this chapter, we describe the experimental protocols of key methodologies, including promoter construction, reporter assay, adenoviral vector construction and preparation, HSV-tk enzymatic assay and cytotoxicity assay to evaluate the specificity and efficacy of osteonectin promoter-mediated HSV-tk/GCV suicide gene therapy of prostate cancer.

The effect of dyslipidemia on peritoneal dialysis (PD) patients based on the presence of residual renal function (RRF; renal creatinine clearance >2 mL/min/1.73 m2) is unknown. Data from the Taiwan Renal Registry Data System between 2005 and 2012 were analyzed to estimate the association between dyslipidemia and mortality in PD patients. Long-term PD patients (n = 8032) were divided into groups with (RRF; n = 2691, 33.5%) and without RRF (non-RRF; n = 5341, 66.5%). The primary outcome was three-year mortality, and multivariate Cox regression was used for survival analysis. After stratifying the total cholesterol (TC) level between the first and third years, the hazard ratio for mortality was estimated. In the non-RRF group, TC < 120 mg/dL was associated with independently increased risk of mortality. In the RRF group, low TC was not independently correlated with increased mortality, but TC > 285 mg/dL was associated with increased risk. PD patients with higher level of TC (>200 mg/dL) in both first and third years of dialysis had significantly lower risk of mortality. In this nationwide cohort study, PD patients without RRF who had low TC level had the highest mortality, in contrast to those with RRF. Malnutrition in long-term PD patients without RRF is an important issue to be monitored.

Objective This study compared urinary tract infection (UTI) pathogens and antibiotic susceptibilities between Kobe, Japan and Taipei, Taiwan to investigate the regional resistance pattern of UTI-causative bacteria. Methods UTI-causative bacteria and antibiotic susceptibility for 4519 samples from Kobe University Hospital, Kobe and 25,131 samples from Shuang-Ho Hospital, Taipei from 2015 to 2017 were retrospectively analyzed to compare the differences between these hospitals. Results Escherichia coli was the most common pathogen in both areas (30.0% in Kobe, 41.2% in Taipei). The prevalence of cephalosporin and gentamicin-resistant E. coli tended to be higher in Taipei than in Kobe. Additionally, antibiotic susceptibilities of Klebsiella pneumonia and Pseudomonas aeruginosa tended to be higher in Kobe than in Taipei. The ratio of extended-spectrum β-lactamase-producing K. pneumoniae was significantly higher in Taipei than in Kobe (up to 40% vs. 14.8%), but this was not observed for E. coli. Conclusion Variations in the type of UTI-causative bacteria and antibiotic susceptibility between the two hospitals may be influenced by the use of different antibiotics. Further surveillance of resistance patterns is necessary for effective treatment.

Mari et al . described the factors leading to post-surgical complications of partial nephrectomy. The areas of study included 3 approaches: open, laparoscopy, and robotic-assisted. In total, their study included 2,584 patients, and analyzed the following: significant potential risk factors such as age, ASA score, clinical stage (T2 vs . T1a), PADUA score, preoperative anemia, and open and laparoscopic approach vs . robotic-assisted. Using these factors for analyses, they developed the predicting nomogram for post-surgical complications (1).

Introduction Recent studies demonstrated the importance of ADAM9 in prostate cancer relapse upon therapy. In this study, we determined the role of ADAM9 in the therapeutic resistance to radiation and chemotherapy.

HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancerARCaPEandARCaPMcells in an EMT model. CoculturedARCaPEorARCaPMcells with HS-27a, developed increased colony forming capacity and growth advantage, withARCaPEexhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment inARCaPEcells compared toARCaPMcells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in bothARCaPE- andARCaPM-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation.

Changes in genomic and phenotypic expression of progressing prostate tumors and their stroma occur in a dynamic fashion based on bidirectional signaling from stromal–epithelial interactions. These interactions may underlie the ability of prostate cancer cells to survive and proliferate in the prostate and bone. By investigating the phenotypic and genotypic changes of stromal cells adjacent to cancer cells and the reciprocal changes of cancer cells, novel molecular markers may be developed to diagnose cancer earlier before pathologic appearance of cancer cells at the primary site. Attacking epithelial and stromal elements together is a unique approach to both localized and metastatic prostate cancer therapy. Co-targeting both tumor cells and stroma requires identifying a reliable tumor and tissue-specific cis -DNA element, such as osteocalcin (OC) promoter. OC expression is elevated in prostate tumor cells and in prostate and bone stromal cells interdigitating with both localized and metastatic prostate epithelium. We have previously designed an adenovirus-based therapeutic gene vehicle and demonstrated that a replication-competent adenoviral vector (Ad vector) is highly efficient in blocking the growth of cancer cells in culture, including cells without androgen receptor as well as cells that do or do not make prostate-specific antigen. In vivo, intravenous administration of an Ad-OC vector was effective against preexisting human prostate cancer subcutaneous and bone xenografts. The addition of vitamin D 3 enhanced further viral replication at target sites. Co-targeting tumor cells and stroma using systemic Ad vector is a viable and promising option for treatment of both localized and metastatic prostate cancer.

Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

Introduction: To identify a specific biomarker for malignant prostate cancer progression and therapeutic target, we had demonstrated the correlation of ADAM9 expression and cancer progression. The aim is to clarify the association of ADAM9 and interactive proteins in malignant phenotypic progression. Methods: Knockdown of ADAM9 expression was conducted to explore its role in cell motility and metastasis activities. Pull-down assays were performed to identify the proteins that interact with ADAM9 during cancer cell migration. Proximity ligation assay (PLA) was carried out to validate the protein-protein interaction. Transmission electron microscope (TEM) analysis to confirm ADAM9 and plectin interaction. Protein degradation test was conducted to determine the regulation pathway. Results: Our study demonstrated that ADAM9 play an important role in the regulation of prostate cancer migration, invasion and metastasis in the in vitro assay and xenograft animal models. The combination of ADAM9 pull-down assays and mass spectrum analysis demonstrated hemidesmosome components, plectin, ladinin, and cytoskeleton were pull-down with ADAM9. However, the key element of hemidesmosome, integrin α6β4, did not pull-down together. Both TEM and PLA confirmed the interaction of ADAM9 and plectin in the protrusion end of migrating cells. This interaction can be strengthened after knockdown integrin β4; and vice verse, knockdown of ADAM9 increased interaction of integrin β4 and plecin. These results indicated ADAM9 and integrin β4 compete for plectin binding. Furthermore, shADAM9 attenuated the degradation of integrin β4. Clinical evaluation of 96 patient samples in TMU demonstrated increased of ADAM9 and plectin interaction in tumor region when compared to the benign part of the same patient. Conclusions: Our studies demonstrated that ADAM9 promotes cancer metastasis through alteration of hemidesmosome dynamic by enhancing of integrin β4 degradation. Therefore, these results indicated possible to use ADAM9-plectin interaction to predict prostate cancer malignancy progression. Citation Format: Che-Ming Liu, Chia-Ling Hsieh, Shian-Ying Sung. ADAM9-plectin interaction involved in prostate cancer malignancy progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2017-912

The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease. Cancer Res; 74(18); 5229–43. ©2014 AACR.

Previous studies of soluble factors in the tumor associated stromal cells demonstrated the elevation of CCL5 expression in prostate cancer patient sera that correlated wit malignant cancer progression. To evaluate the expression level of chemokine receptors in response to chemokines released by reactive stroma, quantitative PCR to evaluate the mRNA level of chemokine receptors was performed. We noticed the significant increased of CCRL2 (86-fold) and CXCR4 (45-fold) in androgen independent prostate cancer (AIPC) cells. This increased of CCRL2 expression also confirmed in malignant lung, breast and rental cells. Knockdown of CCRL2 declined 75% of migration activities induced by CCL5, suggests CCRL2 involve in CCL5 induce cancer migratory activities (t-test, p Citation Format: Chia-Ling Hsieh, Che-Ming Liu, Shian-Ying Sung. CCR5-CCRL2 regulates CCL5-induced organ specific metastasis: the in vitro and in vivo studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1559.

Cancer-stromal interaction results in the co-evolution of both the cancer cells and the surrounding host stromal cells. As a consequence of this interaction, cancer cells acquire increased malignant potential and stromal cells become more inductive. In this review we suggest that cancer-stromal interaction can best be investigated by three-dimensional (3D) co-culture models with the results validated by clinical specimens. We showed that 3D culture promoted bone formation in vitro, and explored for the first time, with the help of the astronauts of the Space Shuttle Columbia, the co-culture of human prostate cancer and bone cells to further understand the interactions between these cells. Continued exploration of cancer growth under 3D conditions will rapidly lead to new discoveries and ultimately to improvements in the treatment of men with hormonal refractory prostate cancer.

Environmental factors have profoundly influence on cancer cell directional migration and metastasis. Previously, we have showed the increasing of CCL5 in tumor associated stromal cells and in patient sera with cancer progression. To verify the role of CCL5 in organ specific cancer metastasis, cellular and molecular studies of cancer migratory activities induced by CCL5 was conducted. Cell tracking assays indicated CCL5 strongly involved in the directional migration. Furthermore, quantitative PCR indicated significant increasing of CCRL2 in AIPC that can be confirmed by western blot and flow cytometry analyses. Knockdown of CCRL2 declined 75% of migration activities induced by CCL5, suggests CCRL2 involve in CCL5 induce cancer metastasis. To verify the interaction between CCRL2 and CCL5, biotinylated CCL5 binding assay demonstrated CCL5 independently binding to both CCR5 and CCRL2. Knockdown of CCRL2 decreased prostate cancer directional migration induced by CCL5. However, shCCRL2 did not decrease CCR5 downstream signal activities, suggests differential biological activities of CCR5 and CCRL2 induced by CCL5. Reduction of CCRL2 expression decreased CCR5 polarization into the leading edge of migration front after treating with CCL5, indicated CCRL2 assisting CCR5 polarization. Knockdown of CCRL2 significantly decreased CDC42 GTP and GDP turn-over rate. Immunohistochemical studies of CCRL2 expression in prostate cancer patient samples revealed increasing of CCRL2 expression in malignant prostate cancer locus, whereas no CCRL2 can be detected in the benign region of same patient. T2 stage prostate cancer showed lower of CCRL2 expression compared to T4 stage. In addition, increased of CCRL2 expression can be detected at invasion front. By contrast, bone metastasis tissue showed no CCRL2 expression. This suggests CCRL2 transiently increasing during initial metastasis once sensing environmental cues and decreased the expression after settled at the distant organs. To determine the role of CCRL2 in initiation of metastasis, cell sorting of CCRL2lo and CCRL2hi into two groups and cultured for additional two weeks showed ≥90% of CCRL2hi converted back to CCRL2lo with only ≤10% remain in high-expression group. Cell tracking assay demonstrated strong directory migration activities exists in cancer cells with CCRL2hi compared to CCRL2lo. These data suggests transient increasing expression of CCRL2 play a central role in cancer directional cell migration induced by CCL5. Our data indicating organ specific metastasis might through the cooperation of multiple factors that determine cancer initial migration and invasion, and metastasis activities. (This work was supported by a grant NHRI EX-100-9902BI, Taiwan to SY Sung). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 302. doi:1538-7445.AM2012-302

Alteration of integrin composition is highly correlated with cancer malignancy and metastasis. Recent evidence demonstrated the metastasis activities involved the interaction of integrin and ADAM gene family, such as ADAM8, ADAM9, ADAM10 and ADAM17. These may either stabilized or cleavage of integrin-matrice interaction at the lamellipodia of cancer cell. Mahimakar et al., recently demonstrated the interaction of ADAM9 with integrins alpha3, alpha6 and beta1 by pull down assay, suggests ADAM9 might work together with β1 class integrins. To further analyze their roles and possible downstream regulatory proteins, we perform knockdown of ADAM9 using shRNA and determine its role in cancer metastasis both in vitro and in vivo. Western blotting confirmed the knockdown of ADAM9 in prostate cancer, and oral cell carcinoma. Cell migration assay was performed using micro-slide Chemotaxis chambers either with or without collagen coating. Time-Lapse microscope analysis of cell migration was plotted and analyzed. Interestingly, we observed the opposite cell migration behavior in which faster and longer cell migration activities was observed in cancer cell with knockdown of ADAM9 expression in the chamber coated with collagen, whereas less migration activities was observed in chamber without collagen coating. This may reflect the possible role of ADAM9 in alteration of integrin composition or function. Flow Cytometry analyses of integrin composition on the surface of prostate cancer cells revealed no integrin composition change in knockdown strain compared to parental. We also notice highly expression of integrin alpha2beta1 and alpha6beta4 in C4-2 and PC3 cells. Analyses of signaling pathways demonstrated no significant changes in p-FAK, p-Erk and p-Akt, suggesting not through beta1 downstream signal regulation. Immunoprecipitation of ADAM9 demonstrated the highly associated with integrin beta4 but not beta1. Intra-cardiac injection of prostate cancer cell line, PC3-pSM2C, PC3-siADAM9 demonstrated 100% metastasis activities in PC3-pSM2C, and no any metastasis in mice with PC3-siADAM9. In summary, we notice ADAM9 may associated with the activation/stabilization of integrin complex. Knockdown of ADAM9 demonstrated decreased of cell migration on dish and metastasis when inoculated in mice, suggests hemidesmosome-ADAM9 interaction may involved in cancer migration and metastasis potential. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 425. doi:10.1158/1538-7445.AM2011-425

4504 Introduction and Objective: Prostate cancer (PCa) bone metastasis often present in patients after a long latent period. Dormant cancer cells in contact with bone stromal cells can be reactivated under certain pathophysiologic conditions. We characterized novel molecular pathways leading to PCa bone metastasis in animal models. Methods: Tissue microarrays of normal (4), PIN (13), benign (22), primary (19) PCa and PCa bone metastasis (58) were analyzed by IHC for the expression of β2-microglobulin (β2-M), a novel growth factor and signaling molecule, focal adhesion kinase (FAK), a key cell adhesion molecule, LIV-1, a zinc transporter involved in epithelial to mesenchymal transition, BDNF, a chemokine, and heparanase (HPSE), a heparan sulfate (HS) degrading enzyme. IHC was scored blindly by one pathologist. Data were analyzed by Kruskal-Wallis test for p-value and logistic regression analysis to differentiate Gleason scores. Results: PCa cells with mitochondrial DNA mutations or activated by β2-M provoked consistently higher levels of reactive oxygen species (ROS) production. ROS stimulated HS proteoglycan, perlecan, expression and augmented PCa cell growth in bone microenvironment. Downstream targets of ROS, HS/perlecan and β2-M signaling were identified: FAK, LIV-1, and BDNF. Results showed that β2-M (p

Background Both benign prostatic hyperplasia (BPH) and Type-1 diabetes mellitus (T1DM) share similar epidemiologic features and are all associated with the insulin-like growth factor (IGF)-mediated hormonal imbalance. The purpose of this study is to understand whether exercise (EX) could alleviate DM and DM + BPH. Methods Sprague-Dawley rats were divided into eight groups: normal control, EX, BPH, BPH + EX, DM, DM + EX, BPH + DM, and BPH + DM + EX. T1DM was induced by intraperitoneal (ip) injection of streptozotocin (65 mg/kg) in Week 2, and BPH was induced by successive ip injections of Sustanon® (testosterone, 3.5 mg/head) plus estradiol (0.1 mg/head) from Week 3 to Week 9. Treadmill exercise training (20 m/min, 60 min per time) was performed three times per week for 6 weeks. Results In BPH + EX, EX maintained at a constant body weight (BW); and suppressed stromal layer thickening, collagen deposition, blood glucose (BG), levels of testosterone (Ts), 5α-reductase(5αRd), dihydrotestosterone (DHT), androgen receptor (AR), serum hydrogen peroxide, TBARs, and interleukin-6 (IL-6). EX recovered testes size and substantially increased nitric oxide (NO) levels. In DM + EX group, EX decreased BW, PW, nuclear proliferation, inflammatory cell aggregation, collagen deposition, and BG. As contrast, EX upregulated insulin, IGF, Ts, NO, 5αRd, AR, and DHT, and substantially reduced PSA. In BPH + DM + EX, EX maintained BW at a subnormal level, slightly suppressed prostate stromal inflammation, collagen deposition, and BG, moderately restored sIn and IGF. Although failed to suppress Ts, EX highly upregulated 5αRd and suppressed DHT and AR, together with highly upregulated NO resulting in substantially reduced PSA. Conclusion EX, by remodeling androgen and NO expressions, can effectively alleviate BPH, DM, and BPH + DM.