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Sample records for prostate tumor growth

  1. Tumor-specific RNA interference targeting Pokemon suppresses tumor growth and induces apoptosis in prostate cancer.

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    Li, Yining; Xu, Shuxiong; Wang, Xiangwei; Shi, Hua; Sun, Zhaolin; Yang, Zhao

    2013-02-01

    To explore the exact mechanism of Pokemon in prostate cancer. Pokemon is a member of the POK family of transcriptional repressors. Its main function is suppression of the p14ARF (alternate reading frame) tumor suppressor gene. Although Pokemon expression has been found to be increased in various types of lymphoma, the exact mechanism of the gene in prostate cancer is not clear. In the present study, prostate cancer cells were transfected with the specific short hairpin ribonucleic acid (RNA) expression vector targeting Pokemon. The expression of Pokemon messenger RNA and its protein was detected by semiquantitative reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The cell growth and cell apoptosis were also examined using the methyl thiazolyl tetrazolium assay and flow cytometry. The results demonstrated that specific RNA interference (RNAi) could decrease the expression levels of Pokemon gene messenger RNA and protein in prostate cancer cells. In addition, that specific RNAi significantly inhibited the cell proliferation and increased the apoptotic rate. In vivo experiments showed that specific RNAi inhibited the tumorigenicity of prostate cancer cells and significantly suppressed tumor growth. Therefore, an RNAi-targeted Pokemon gene strategy could be a potential approach to prostate cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Extratumoral Heme Oxygenase-1 (HO-1 Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

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    Sofia Halin Bergström

    Full Text Available Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1. To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

  3. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

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    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, André; Gnanasekar, Munirathinam

    2012-01-01

    Highlights: ► Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. ► Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. ► Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. ► Knock down of RAGE abrogates prostate tumor growth in vivo. ► Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  4. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique

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    Jie Ni

    2016-02-01

    Full Text Available Prostate cancer (CaP is the most commonly diagnosed and the second leading cause of death from cancer in males in USA. Prostate orthotopic mouse model has been widely used to study human CaP in preclinical settings. Measurement of changes in tumor size obtained from noninvasive diagnostic images is a standard method for monitoring responses to anticancer modalities. This article reports for the first time the usage of a three-dimensional (3D ultrasound system equipped with photoacoustic (PA imaging in monitoring longitudinal prostate tumor growth in a PC-3 orthotopic NODSCID mouse model (n = 8. Two-dimensional and 3D modes of ultrasound show great ability in accurately depicting the size and shape of prostate tumors. PA function on two-dimensional and 3D images showed average oxygen saturation and average hemoglobin concentration of the tumor. Results showed a good fit in representative exponential tumor growth curves (n = 3; r2 = 0.948, 0.955, and 0.953, respectively and a good correlation of tumor volume measurements performed in vivo with autopsy (n = 8, r = 0.95, P < .001. The application of 3D ultrasound imaging proved to be a useful imaging modality in monitoring tumor growth in an orthotopic mouse model, with advantages such as high contrast, uncomplicated protocols, economical equipment, and nonharmfulness to animals. PA mode also enabled display of blood oxygenation surrounding the tumor and tumor vasculature and angiogenesis, making 3D ultrasound imaging an ideal tool for preclinical cancer research.

  5. Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors

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    Tuomela, Johanna; Valta, Maija; Seppänen, Jani; Tarkkonen, Kati; Väänänen, H Kalervo; Härkönen, Pirkko

    2009-01-01

    Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig) and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice. VEGFR3-Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p < 0.05) and inhibited metastasis to iliac and sacral lymph nodes. In addition, tumor volumes were smaller in the VEGFR3-Ig-treated group compared with the control group (p < 0.05). Transfection of PC-3 cells with the VEGF-C gene led to a high level of 29/31 kD VEGF-C expression in PC-3 cells. The size of orthotopic and subcutaneous PC-3/VEGF-C tumors was significantly greater than that of PC-3/mock tumors (both p < 0.001). Interestingly, while most orthotopic PC-3 and PC-3/mock tumors grown for 4 weeks metastasized to prostate-draining lymph nodes, orthotopic PC-3/VEGF-C tumors primarily metastasized to the lungs. PC-3/VEGF-C tumors showed highly angiogenic morphology with an increased density of blood capillaries compared with PC-3/mock tumors (p < 0.001). The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites

  6. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

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    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-07

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo.

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    Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E; Henning, Susanne M; Vadgama, Jaydutt V

    2017-06-01

    The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa , has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo , which provides a high promise in its translation to human application.

  8. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

    Science.gov (United States)

    Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E.; Henning, Susanne M.; Vadgama, Jaydutt V.

    2017-01-01

    The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its translation to human application

  9. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

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    Piwen Wang

    2017-06-01

    Full Text Available The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (<2 μM significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30–50% at 48 h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50 mg/kg (LD or 100 mg/kg (HD b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD and 70% (HD compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its

  10. Inhibiting Vimentin or beta 1-integrin Reverts Prostate Tumor Cells in IrECM and Reduces Tumor Growth

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    Zhang, Xueping; Fournier, Marcia V.; Ware, Joy L.; Bissell, Mina J.; Zehner, Zendra E.

    2009-07-27

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphological changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional (3D) lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the parental prostate epithelial P69 cell line by selection in nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin or {alpha}6-, {beta}4- and {beta}1-integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via siRNA interference or {beta}1-integrin expression by the addition of the blocking antibody, AIIB2, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by subcutaneous injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in 3D lrECM gels. These studies suggest that the levels of vimentin and {beta}1-integrin play a key role in the homeostasis of the normal acini in prostate and that their dysregulation may lead to tumorigenesis.

  11. Selenite Treatment Inhibits LAPC-4 Tumor Growth and Prostate-Specific Antigen Secretion in a Xenograft Model of Human Prostate Cancer

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    Bhattacharyya, Rumi S.; Husbeck, Bryan; Feldman, David; Knox, Susan J.

    2008-01-01

    Purpose: Selenium compounds have known chemopreventive effects on prostate cancer. However selenite, an inorganic form of selenium, has not been extensively studied as a treatment option for prostate cancer. Our previous studies have demonstrated the inhibition of androgen receptor expression and androgen stimulated prostate-specific antigen (PSA) expression by selenite in human prostate cancer cell lines. In this study, we investigated the in vivo effects of selenite as a therapy to treat mice with established LAPC-4 tumors. Methods and Materials: Male mice harboring androgen-dependent LAPC-4 xenograft tumors were treated with selenite (2 mg/kg intraperitoneally three times per week) or vehicle for 42 days. In addition, androgen-independent LAPC-4 xenograft tumors were generated in female mice over 4 to 6 months. Once established, androgen-independent LAPC-4 tumor fragments were passaged into female mice and were treated with selenite or vehicle for 42 days. Changes in tumor volume and serum PSA levels were assessed. Results: Selenite significantly decreased androgen-dependent LAPC-4 tumor growth in male mice over 42 days (p < 0.001). Relative tumor volume was decreased by 41% in selenite-treated animals compared with vehicle-treated animals. The inhibition of LAPC-4 tumor growth corresponded to a marked decrease in serum PSA levels (p < 0.01). In the androgen-independent LAPC-4 tumors in female mice, selenite treatment decreased tumor volume by 58% after 42 days of treatment (p < 0.001). Conclusions: These results suggest that selenite may have potential as a novel therapeutic agent to treat both androgen-dependent and androgen-independent prostate cancer

  12. Selenium, but not lycopene or vitamin E, decreases growth of transplantable dunning R3327-H rat prostate tumors.

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    Brian L Lindshield

    Full Text Available BACKGROUND: Lycopene, selenium, and vitamin E are three micronutrients commonly consumed and supplemented by men diagnosed with prostate cancer. However, it is not clear whether consumption of these compounds, alone or in combination, results in improved outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the effects of dietary lycopene (250 mg/kg diet, selenium (methylselenocysteine, 1 mg/kg diet, and vitamin E (gamma-tocopherol, 200 mg/kg diet alone and in combination on the growth of androgen-dependent Dunning R3327-H rat prostate adenocarcinomas in male, Copenhagen rats. AIN-93G diets containing these micronutrients were prefed for 4 to 6 weeks prior to tumor implantation by subcutaneous injection. Tumors were allowed to grow for approximately 18 weeks. Across diet groups, methylselenocysteine consumption decreased final tumor area (P = 0.003, tumor weight (P = 0.003, and the tumor weight/body weight ratio (P = 0.003, but lycopene and gamma-tocopherol consumption intake did not alter any of these measures. There were no significant interactions among nutrient combinations on tumor growth. Methylselenocysteine consumption also led to small, but significant decreases in body weight (P = 0.007, food intake (P = 0.012, and body weight gain/food intake ratio (P = 0.022. However, neither body weight nor gain/food intake ratio was correlated with tumor weight. Methylselenocysteine, lycopene, and gamma-tocopherol consumed alone and in combination did not alter serum testosterone or dihydrotestosterone concentrations; tumor proliferation or apoptosis rates. In addition, the diets also did not alter tumor or prostate androgen receptor, probasin, selenoprotein 15, selenoprotein P, or selenium binding protein 2 mRNA expression. However, using castration and finasteride-treated tissues from a previous study, we found that androgen ablation altered expression of these selenium-associated proteins. CONCLUSIONS: Of the three micronutrients tested, only

  13. BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer

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    Yusuff, Shamila; Davis, Stephani; Flaherty, Kathleen; Huselid, Eric; Patrizii, Michele; Jones, Daniel; Cao, Liangxian; Sydorenko, Nadiya; Moon, Young-Choon; Zhong, Hua; Medina, Daniel J.; Kerrigan, John; Stein, Mark N.; Kim, Isaac Y.; Davis, Thomas W.; DiPaola, Robert S.; Bertino, Joseph R.; Sabaawy, Hatem E.

    2016-01-01

    Purpose Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment. PMID:27307599

  14. Growth and Progression of TRAMP Prostate Tumors in Relationship to Diet and Obesity

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    Melissa J. L. Bonorden

    2012-01-01

    Full Text Available To clarify effects of diet and body weight on prostate cancer development, three studies were undertaken using the TRAMP mouse model of this disease. In the first experiment, obesity was induced by injection of gold thioglucose (GTG. Age of prostate tumor detection (~33 wk and death (~43 wk was not significantly different among the groups. In the second study, TRAMP-C2 cells were injected into syngeneic C57BL6 mice and tumor progression was evaluated in mice fed either high-fat or low-fat diets. The high fat fed mice had larger tumors than did the low-fat fed mice. In the third study, tumor development was followed in TRAMP mice fed a high fat diet from 6 weeks of age. There were no significant effects of body weight status or diet on tumor development among the groups. When the tumors were examined for the neuroendocrine marker synaptophysin, there was no correlation with either body weight or diet. However, there was a significant correlation of the expression of synaptophysin with earlier age to tumor detection and death. In summary, TRAMP-C2 cells grew faster when the mice were fed a high-fat diet. Further synaptophysin may be a marker of poor prognosis independent of weight and diet.

  15. Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts

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    El-Zawahry, Ahmed; McKillop, John; Voelkel-Johnson, Christina

    2005-01-01

    Prostate cancer is a significant health problem among American men. Treatment strategies for androgen-independent cancer are currently not available. Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, including androgen-independent PC3 prostate carcinoma cells. In vitro, TRAIL-mediated apoptosis of prostate cancer cell lines can be enhanced by doxorubicin and correlates with the downregulation of the anti-apoptotic protein c-FLIP. This study evaluated the effects of doxorubicin on c-FLIP expression and tumor growth in combination with Apo2L/TRAIL in a xenograft model. In vitro cytotoxic effects of TRAIL were measured using a MTS-based viability assay. For in vivo studies, PC3 prostate carcinoma cells were grown subcutaneously in athymic nude mice and tumor growth was measured following treatment with doxorubicin and/or Apo2L/TRAIL. c-FLIP expression was determined by western blot analysis. Apoptosis in xenografts was detected using TUNEL. Statistical analysis was performed using the student t-test. In vitro experiments show that PC3 cells are partially susceptible to Apo2L/TRAIL and that susceptibility is enhanced by doxorubicin. In mice, doxorubicin did not significantly affect the growth of PC3 xenografts but reduced c-FLIP expression in tumors. Expression of c-FLIP in mouse heart was decreased only at the high doxorubicin concentration (8 mg/kg). Combination of doxorubicin with Apo2L/TRAIL resulted in more apoptotic cell death and tumor growth inhibition than Apo2L/TRAIL alone. Combination of doxorubicin and Apo2L/TRAIL is more effective in growth inhibition of PC3 xenografts in vivo than either agent alone and could present a novel treatment strategy against hormone-refractory prostate cancer. The intracellular mechanism by which doxorubicin enhances the effect of Apo2L/TRAIL on PC3 xenografts may be by reducing expression of c-FLIP

  16. Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling

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    Bharadwaj, Alamelu G.; Goodrich, Nathaniel P.; McAtee, Caitlin O.; Haferbier, Katie; Oakley, Gregory G.; Wahl, James K.; Simpson, Melanie A.

    2011-01-01

    Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA-induced suppression of N-cadherin, while E-cadherin expression and β-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition.

  17. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

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    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  18. DEPDC1 promotes cell proliferation and tumor growth via activation of E2F signaling in prostate cancer.

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    Huang, Lin; Chen, Keng; Cai, Zhao-Peng; Chen, Fu-Chao; Shen, Hui-Yong; Zhao, Wei-Hua; Yang, Song-Jie; Chen, Xu-Biao; Tang, Guo-Xue; Lin, Xi

    2017-08-26

    DEP domain containing 1 (DEPDC1) is recently reported to be overexpressed in several types of human cancer; however the role of DEPDC1 in prostate cancer remains to be investigated. Herein, we identified that the DEPDC1 mRNA and protein expression levels were dramatically increased in prostate cancer tissues and cell lines. Overexpression of DEPDC1 promoted, but depletion of DEPDC1 inhibited cell proliferation by regulating the G1-S phase cell cycle transition. Importantly, we found that DEPDC1 was essential for the tumor growth and formation of bone metastases of prostate cancer cells in vivo. Finally, we demonstrated that DEPDC1 interacted with E2F1 and increased its transcriptional activity, leading to hyper-activation of E2F signaling in prostate cancer cells. Our findings reveal an oncogenic role of DEPDC1 in prostate cancer progression via activation of E2F signaling, and suggest DEPDC1 might be a potential therapeutic target against the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. A novel mouse model of human prostate cancer to study intraprostatic tumor growth and the development of lymph node metastases.

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    Linxweiler, Johannes; Körbel, Christina; Müller, Andreas; Hammer, Markus; Veith, Christian; Bohle, Rainer M; Stöckle, Michael; Junker, Kerstin; Menger, Michael D; Saar, Matthias

    2018-06-01

    In this study, we aimed to establish a versatile in vivo model of prostate cancer, which adequately mimics intraprostatic tumor growth, and the natural routes of metastatic spread. In addition, we analyzed the capability of high-resolution ultrasonography (hrUS), in vivo micro-CT (μCT), and 9.4T MRI to monitor tumor growth and the development of lymph node metastases. A total of 5 × 10 5 VCaP cells or 5 × 10 5 cells of LuCaP136- or LuCaP147 spheroids were injected into the prostate of male CB17-SCID mice (n = 8 for each cell type). During 12 weeks of follow-up, orthotopic tumor growth, and metastatic spread were monitored by repetitive serum-PSA measurements and imaging studies including hrUS, μCT, and 9.4T MRI. At autopsy, primary tumors and metastases were harvested and examined by histology and immunohistochemistry (CK5, CK8, AMACR, AR, Ki67, ERG, and PSA). From imaging results and PSA-measurements, tumor volume doubling time, tumor-specific growth rate, and PSA-density were calculated. All 24 mice developed orthotopic tumors. The tumor growth could be reliably monitored by a combination of hrUS, μCT, MRI, and serum-PSA measurements. In most animals, lymph node metastases could be detected after 12 weeks, which could also be well visualized by hrUS, and MRI. Immunohistochemistry showed positive signals for CK8, AMACR, and AR in all xenograft types. CK5 was negative in VCaP- and focally positive in LuCaP136- and LuCaP147-xenografts. ERG was positive in VCaP- and negative in LuCaP136- and LuCaP147-xenografts. Tumor volume doubling times and tumor-specific growth rates were 21.2 days and 3.9 %/day for VCaP-, 27.6 days and 3.1 %/day for LuCaP136- and 16.2 days and 4.5 %/day for LuCaP147-xenografts, respectively. PSA-densities were 433.9 ng/mL per milliliter tumor for VCaP-, 6.5 ng/mL per milliliter tumor for LuCaP136-, and 11.2 ng/mL per milliliter tumor for LuCaP147-xenografts. By using different monolayer and 3D spheroid cell cultures in an

  20. Prostate Tumor Growth Can Be Modulated by Dietarily Targeting the 15-Lipoxygenase-1 and Cyclooxygenase-2 Enzymes

    Directory of Open Access Journals (Sweden)

    Uddhav P. Kelavkar

    2009-07-01

    Full Text Available The main objectives of our study were to determine the bioavailability of omega-3 (ω-3 to the tumor, to understand its mechanisms, and to determine the feasibility of targeting the ω-6 polyunsaturated fatty acids (PUFAs metabolizing 15-lipoxygenase-1 (15-LO-1 and cyclooxygenase-2 (COX-2 pathways. Nude mice injected subcutaneously with LAPC-4 prostate cancer cells were randomly divided into three different isocaloric (and same percent [%] of total fat diet groups: high ω-6 linoleic acid (LA, high ω-3 stearidonic acid (SDA PUFAs, and normal (control diets. Tumor growth and apoptosis were examined as end points after administration of short-term (5 weeks ω-3 and ω-6 fatty acid diets. Tumor tissue membranes were examined for growth, lipids, enzyme activities, apoptosis, and proliferation. Tumors from the LA diet-fed mice exhibited the most rapid growth compared with tumors from the control and SDA diet-fed mice. Moreover, a diet switch from LA to SDA caused a dramatic decrease in the growth of tumors in 5 weeks, whereas tumors grew more aggressively when mice were switched from an SDA to an LA diet. Evaluating tumor proliferation (Ki-67 and apoptosis (caspase-3 in mice fed the LA and SDA diets suggested increased percentage proliferation index from the ω-6 diet-fed mice compared with the tumors from the ω-3 SDA-fed mice. Further, increased apoptosis was observed in tumors from ω-3 SDA diet-fed mice versus tumors from ω-6 diet-fed mice. Levels of membrane phospholipids of red blood cells reflected dietary changes and correlated with the levels observed in tumors. Linoleic or arachidonic acid and metabolites (eicosanoid/prostaglandins were analyzed for 15-LO-1 and COX-2 activities by high-performance liquid chromatography. We also examined the percent unsaturated or saturated fatty acids in the total phospholipids, PUFA ω-6/ω-3 ratios, and other major enzymes (elongase, Delta [Δ]-5-desaturase, and Δ-6-desaturase of ω-6 catabolic

  1. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    International Nuclear Information System (INIS)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen

    2015-01-01

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice

  2. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

    2015-08-14

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

  3. Inhibition of vimentin or B1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xueping; Fournier, Marcia V; Ware, Joy L; Bissell, Mina J; Yacoub, Adly; Zehner, Zendra E

    2008-06-12

    Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the parental, nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to {beta}-catenin, E-cadherin, or {alpha}6 and {beta}1 integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via small interfering RNA interference or the expression of {alpha}6 and {beta}1 integrins by the addition of blocking antibodies, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by s.c. injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in three-dimensional lrECM gels. These studies suggest that the levels of vimentin and {beta}1 integrin play a key role in the homeostasis of the normal acinus in prostate and that their dysregulation may lead to tumorigenesis. [Mol Cancer Ther 2009;8(3):499-508].

  4. Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Kun Li

    Full Text Available The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1, which is a part of nucleosome remodeling and deacetylation (NuRD co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa. In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER, found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.

  5. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    ... (T) and dihydrotestosterone (DHT), and intraprostatic T and DHT in experimental animals. Thus, high fat diet is likely to modulate the ventral prostate weight via an androgen-independent mechanism...

  6. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    .... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

  7. Inhibitory Effect of a γ-Tocopherol-Rich Mixture of Tocopherols on the Formation and Growth of LNCaP Prostate Tumors in Immunodeficient Mice

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Xi, E-mail: xizheng@rci.rutgers.edu [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Cui, Xiao-Xing [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Khor, Tin Oo; Huang, Ying [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); DiPaola, Robert S; Goodin, Susan [Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Lee, Mao-Jung [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Yang, Chung S [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Kong, Ah-Ng [Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States); Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Allan H, Conney [Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854 (United States); Cancer Institute of New Jersey, New Brunswick, NJ 08903 (United States)

    2011-09-28

    In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that γ-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of γ-TmT increased the levels of α-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that γ-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of γ-TmT for prostate cancer in humans.

  8. Inhibitory Effect of a γ-Tocopherol-Rich Mixture of Tocopherols on the Formation and Growth of LNCaP Prostate Tumors in Immunodeficient Mice

    International Nuclear Information System (INIS)

    Zheng, Xi; Cui, Xiao-Xing; Khor, Tin Oo; Huang, Ying; DiPaola, Robert S; Goodin, Susan; Lee, Mao-Jung; Yang, Chung S; Kong, Ah-Ng; Allan H, Conney

    2011-01-01

    In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that γ-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of γ-TmT increased the levels of α-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that γ-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of γ-TmT for prostate cancer in humans

  9. An Embryonic Growth Pathway is Reactivated in Human Prostate Cancer

    National Research Council Canada - National Science Library

    Bushman, Wade

    2005-01-01

    .... This research postulates that prostate cancer cells commandeer this normal epithelial-mesenchymal signaling pathway to recruit stromal cells to support abnormal tumor growth and tests the hypothesis...

  10. An Embryonic Growth Pathway is Reactivated in Human Prostate Cancer

    National Research Council Canada - National Science Library

    Bushman, Wade

    2003-01-01

    .... This research postulates that prostate cancer cells commandeer this normal epithelial-mesenchymal signaling pathway to recruit stromal cells to support abnormal tumor growth and tests the hypothesis...

  11. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

    OpenAIRE

    Piwen Wang; Walter Solorzano; Tanya Diaz; Clara E. Magyar; Susanne M. Henning; Jaydutt V. Vadgama

    2017-01-01

    The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower dos...

  12. Differential oxygen dynamics in two diverse Dunning prostate R3327 rat tumor sublines (MAT-Lu and HI) with respect to growth and respiratory challenge

    International Nuclear Information System (INIS)

    Zhao Dawen; Constantinescu, Anca; Hahn, Eric W.; Mason, Ralph P.

    2002-01-01

    Purpose: Since hypoxia may influence tumor response to therapy and prognosis, we have compared oxygenation of tumors known to exhibit differential growth rate and tissue differentiation. Methods and Materials: Regional tumor oxygen tension was measured using 19 F nuclear magnetic resonance echo planar imaging relaxometry of hexafluorobenzene, which provided dynamic maps with respect to respiratory intervention. Investigations used two Dunning prostate R3327 rat tumor sublines: the fast growing, highly metastatic MAT-Lu and the moderately well-differentiated, slower growing HI. Results: Both sublines showed significantly higher oxygen tension in smaller tumors ( 3 ) than in larger tumors (>3.5 cm 3 ). Pooled data showed that MAT-Lu tumors exhibited greater hypoxia compared with the size-matched HI tumors (p 2 for tumors of both sublines (p 2 , while those in the MAT-Lu tumors showed little response to respiratory intervention. Conclusions: These results concur with hypotheses that hypoxia is related to tumor growth rate and degree of differentiation. Under baseline conditions, the differences were subtle. However, response to respiratory intervention revealed highly significant differences, which, if held valid in the clinic, could have prognostic value

  13. Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6.

    Science.gov (United States)

    Tsai, Yuan-Chin; Chen, Wei-Yu; Siu, Man Kit; Tsai, Hong-Yuan; Yin, Juan Juan; Huang, Jiaoti; Liu, Yen-Nien

    2017-01-01

    It has been suggested that ETV6 serves as a tumor suppressor; however, its molecular regulation and cellular functions remain unclear. We used prostate cancer as a model system and demonstrated a molecular mechanism in which ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA-96 (miR-96)-mediated downregulation. In addition, EGFR acts as a transcriptional coactivator that binds to the promoter of primary miR-96 and transcriptionally regulates miR-96 levels. We analyzed two sets of clinical prostate cancer samples, confirmed association patterns that were consistent with the EGFR-miR-96-ETV6 signaling model and demonstrated that the reduced ETV6 levels were associated with malignant prostate cancer. Based on results derived from multiple approaches, we identified the biological functions of ETV6 as a tumor suppressor that inhibits proliferation and metastasis in prostate cancer. We present a molecular mechanism in which EGFR activation leads to the induction of miR-96 expression and suppression of ETV6, which contributes to prostate cancer progression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure inhibit prostate tumor growth in TRAMP mice

    Czech Academy of Sciences Publication Activity Database

    Mikyšková, Romana; Indrová, Marie; Štěpánek, Ivan; Kanchev, Ivan; Bieblová, Jana; Vošahlíková, Š.; Moserová, I.; Truxová, I.; Fučíková, J.; Bartunkova, J.; Spisek, R.; Sedláček, Radislav; Reiniš, Milan

    2017-01-01

    Roč. 6, č. 12 (2017), č. článku e1362528. ISSN 2162-402X R&D Projects: GA MŠk(CZ) LM2015040; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk ED2.1.00/19.0395; GA ČR GA15-24769S Institutional support: RVO:68378050 Keywords : dendritic cells * docetaxel * high hydrostatic pressure * immunotherapy * prostate cancer Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Immunology Impact factor: 7.719, year: 2016

  15. Characterization of Heterogeneous Prostate Tumors in Targeted Pten Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Hanneke Korsten

    Full Text Available Previously, we generated a preclinical mouse prostate tumor model based on PSA-Cre driven inactivation of Pten. In this model homogeneous hyperplastic prostates (4-5m developed at older age (>10m into tumors. Here, we describe the molecular and histological characterization of the tumors in order to better understand the processes that are associated with prostate tumorigenesis in this targeted mouse Pten knockout model. The morphologies of the tumors that developed were very heterogeneous. Different histopathological growth patterns could be identified, including intraductal carcinoma (IDC, adenocarcinoma and undifferentiated carcinoma, all strongly positive for the epithelial cell marker Cytokeratin (CK, and carcinosarcomas, which were negative for CK. IDC pattern was already detected in prostates of 7-8 month old mice, indicating that it could be a precursor stage. At more than 10 months IDC and carcinosarcoma were most frequently observed. Gene expression profiling discriminated essentially two molecular subtypes, denoted tumor class 1 (TC1 and tumor class 2 (TC2. TC1 tumors were characterized by high expression of epithelial markers like Cytokeratin 8 and E-Cadherin whereas TC2 tumors showed high expression of mesenchyme/stroma markers such as Snail and Fibronectin. These molecular subtypes corresponded with histological growth patterns: where TC1 tumors mainly represented adenocarcinoma/intraductal carcinoma, in TC2 tumors carcinosarcoma was the dominant growth pattern. Further molecular characterization of the prostate tumors revealed an increased expression of genes associated with the inflammatory response. Moreover, functional markers for senescence, proliferation, angiogenesis and apoptosis were higher expressed in tumors compared to hyperplasia. The highest expression of proliferation and angiogenesis markers was detected in TC2 tumors. Our data clearly showed that in the genetically well-defined PSA-Cre;Pten-loxP/loxP prostate tumor

  16. A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.

    Science.gov (United States)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2014-10-01

    Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

  17. Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules.

    Science.gov (United States)

    Masoodi, Khalid Z; Xu, Yadong; Dar, Javid A; Eisermann, Kurtis; Pascal, Laura E; Parrinello, Erica; Ai, Junkui; Johnston, Paul A; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. ©2017 AACR . ©2017 American Association for Cancer Research.

  18. Pomegranate-Extract Pill in Preventing Tumor Growth in Patients With Localized Prostate Cancer Undergoing Active Surveillance

    Science.gov (United States)

    2018-03-02

    PSA Level Less Than or Equal to Fifteen; PSA Level Less Than Ten; Stage I Prostate Cancer AJCC v7; Stage II Prostate Cancer AJCC v7; Stage IIA Prostate Cancer AJCC v7; Stage IIB Prostate Cancer AJCC v7

  19. Walnuts lower TRAMP prostate tumor growth by altering IGF-1, energy and cholesterol metabolism and is not due to their fatty acids

    Science.gov (United States)

    Dietary changes could potentially reduce prostate cancer morbidity and mortality. Prostate tumor size, gene expression, metabolite and plasma responses to a 100 g of fat/kg diet (whole walnuts, walnut oil and other oils; balanced for macronutrients, tocopherols (a-and ' ) for 18 weeks were assessed ...

  20. The Downregulation of the Expression of CD147 by Tumor Suppressor REIC/Dkk-3, and Its Implication in Human Prostate Cancer Cell Growth Inhibition.

    Science.gov (United States)

    Mori, Akihiro; Watanabe, Masami; Sadahira, Takuya; Kobayashi, Yasuyuki; Ariyoshi, Yuichi; Ueki, Hideo; Wada, Koichiro; Ochiai, Kazuhiko; Li, Shun-Ai; Nasu, Yasutomo

    2017-04-01

    The cluster of differentiation 147 (CD147), also known as EMMPRIN, is a key molecule that promotes cancer progression. We previously developed an adenoviral vector encoding a tumor suppressor REIC/Dkk-3 gene (Ad-REIC) for cancer gene therapy. The therapeutic effects are based on suppressing the growth of cancer cells, but, the underlying molecular mechanism has not been fully clarified. To elucidate this mechanism, we investigated the effects of Ad-REIC on the expression of CD147 in LNCaP prostate cancer cells. Western blotting revealed that the expression of CD147 was significantly suppressed by Ad-REIC. Ad-REIC also suppressed the cell growth of LNCaP cells. Since other researchers have demonstrated that phosphorylated mitogen-activated protein kinases (MAPKs) and c-Myc protein positively regulate the expression of CD147, we investigated the correlation between the CD147 level and the activation of MAPK and c-Myc expression. Unexpectedly, no positive correlation was observed between CD147 and its possible regulators, suggesting that another signaling pathway was involved in the downregulation of CD147. This is the first study to show the downregulation of CD147 by Ad-REIC in prostate cancer cells. At least some of the therapeutic effects of Ad-REIC may be due to the downregulation of the cancer-progression factor, CD147.

  1. Trimethoxy-resveratrol and piceatannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts

    Science.gov (United States)

    Resveratrol (Res) is recognized as a promising cancer chemoprevention dietary polyphenol with antioxidative, anti-inflammatory and anticancer properties. However, the role of its analogues in prostate cancer (PCa) chemoprevention is still unknown. METHODS. We synthesized natural and synthetic anal...

  2. Circulating Tumor Cells in Prostate Cancer

    International Nuclear Information System (INIS)

    Hu, Brian; Rochefort, Holly; Goldkorn, Amir

    2013-01-01

    Circulating tumor cells (CTCs) can provide a non-invasive, repeatable snapshot of an individual patient’s tumor. In prostate cancer, CTC enumeration has been extensively studied and validated as a prognostic tool and has received FDA clearance for use in monitoring advanced disease. More recently, CTC analysis has been shifting from enumeration to more sophisticated molecular characterization of captured cells, which serve as a “liquid biopsy” of the tumor, reflecting molecular changes in an individual’s malignancy over time. Here we will review the main CTC studies in advanced and localized prostate cancer, highlighting the important gains as well as the challenges posed by various approaches, and their implications for advancing prostate cancer management

  3. Tumor-Associated Antigens for Specific Immunotherapy of Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kiessling, Andrea [Biologics Safety and Disposition, Preclinical Safety, Translational Sciences, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Werk Klybeck, Klybeckstraße 141, Basel CH-4057 (Switzerland); Wehner, Rebekka [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Füssel, Susanne [Department of Urology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Bachmann, Michael [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Wirth, Manfred P. [Department of Urology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Schmitz, Marc, E-mail: marc.schmitz@tu-dresden.de [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany)

    2012-02-22

    Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8{sup +} cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4{sup +} T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy.

  4. Epidermal growth factor in the rat prostate

    DEFF Research Database (Denmark)

    Tørring, Niels; Jørgensen, P E; Poulsen, Steen Seier

    1998-01-01

    Epidermal growth factor (EGF) induces proliferation in prostate epithelial and stromal cells in primary culture. This investigation was set up to characterize the time and spatial expression of EGF in the rat prostate.......Epidermal growth factor (EGF) induces proliferation in prostate epithelial and stromal cells in primary culture. This investigation was set up to characterize the time and spatial expression of EGF in the rat prostate....

  5. Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor

    International Nuclear Information System (INIS)

    Bourke, Vincent A.; Zhao Dawen; Gilio, Joseph; Chang, C.-H.; Jiang Lan; Hahn, Eric W.; Mason, Ralph P.

    2007-01-01

    Purpose: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. Methods and Materials: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by 19 F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. Results: Large tumors (>3.0 cm 3 ) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO 2 ) than their smaller counterparts ( 3 ). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO 2 , and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO 2 > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. Conclusions: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy

  6. Stochastic models for tumoral growth

    OpenAIRE

    Escudero, Carlos

    2006-01-01

    Strong experimental evidence has indicated that tumor growth belongs to the molecular beam epitaxy universality class. This type of growth is characterized by the constraint of cell proliferation to the tumor border, and surface diffusion of cells at the growing edge. Tumor growth is thus conceived as a competition for space between the tumor and the host, and cell diffusion at the tumor border is an optimal strategy adopted for minimizing the pressure and helping tumor development. Two stoch...

  7. Hedgehog pathway activity in the LADY prostate tumor model

    Directory of Open Access Journals (Sweden)

    Kasper Susan

    2007-03-01

    Full Text Available Abstract Background Robust Hedgehog (Hh signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth. The role of Hh signaling has been studied in several xenograft tumor models, however, the role of Hh in tumor development in a transgenic prostate cancer model has never been examined. Results We analyzed expression of Hh pathway components and conserved Hh target genes along with progenitor cell markers and selected markers of epithelial differentiation during tumor development in the LADY transgenic mouse model. Tumor development was associated with a selective increase in Ihh expression. In contrast Shh expression was decreased. Expression of the Hh target Patched (Ptc was significantly decreased while Gli1 expression was not significantly altered. A survey of other relevant genes revealed significant increases in expression of Notch-1 and Nestin together with decreased expression of HNF3a/FoxA1, NPDC-1 and probasin. Conclusion Our study shows no evidence for a generalized increase in Hh signaling during tumor development in the LADY mouse. It does reveal a selective increase in Ihh expression that is associated with increased expression of progenitor cell markers and decreased expression of terminal differentiation markers. These data suggest that Ihh expression may be a feature of a progenitor cell population that is involved in tumor development.

  8. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation

    NARCIS (Netherlands)

    Hamid, A.R.; Verhaegh, G.W.C.T.; Smit, F.P.; RIjt-van de Westerlo, C.; Armandari, I.; Brandt, A.; Sweep, F.C.; Sedelaar, J.P.M.; Schalken, J.A.

    2015-01-01

    PURPOSE: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are

  9. On complexity and homogeneity measures in predicting biological aggressiveness of prostate cancer; Implication of the cellular automata model of tumor growth.

    Science.gov (United States)

    Tanase, Mihai; Waliszewski, Przemyslaw

    2015-12-01

    We propose a novel approach for the quantitative evaluation of aggressiveness in prostate carcinomas. The spatial distribution of cancer cell nuclei was characterized by the global spatial fractal dimensions D0, D1, and D2. Two hundred eighteen prostate carcinomas were stratified into the classes of equivalence using results of ROC analysis. A simulation of the cellular automata mix defined a theoretical frame for a specific geometric representation of the cell nuclei distribution called a local structure correlation diagram (LSCD). The LSCD and dispersion Hd were computed for each carcinoma. Data mining generated some quantitative criteria describing tumor aggressiveness. Alterations in tumor architecture along progression were associated with some changes in both shape and the quantitative characteristics of the LSCD consistent with those in the automata mix model. Low-grade prostate carcinomas with low complexity and very low biological aggressiveness are defined by the condition D0 1.764 and Hd < 38. The novel homogeneity measure Hd identifies carcinomas with very low aggressiveness within the class of complexity C1 or carcinomas with very high aggressiveness in the class C7. © 2015 Wiley Periodicals, Inc.

  10. Stochastic models for tumoral growth

    Science.gov (United States)

    Escudero, Carlos

    2006-02-01

    Strong experimental evidence has indicated that tumor growth belongs to the molecular beam epitaxy universality class. This type of growth is characterized by the constraint of cell proliferation to the tumor border and the surface diffusion of cells at the growing edge. Tumor growth is thus conceived as a competition for space between the tumor and the host, and cell diffusion at the tumor border is an optimal strategy adopted for minimizing the pressure and helping tumor development. Two stochastic partial differential equations are reported in this paper in order to correctly model the physical properties of tumoral growth in (1+1) and (2+1) dimensions. The advantage of these models is that they reproduce the correct geometry of the tumor and are defined in terms of polar variables. An analysis of these models allows us to quantitatively estimate the response of the tumor to an unfavorable perturbation during growth.

  11. Gastrin-releasing peptide receptor (GRPr) promotes EMT, growth, and invasion in canine prostate cancer.

    Science.gov (United States)

    Elshafae, Said M; Hassan, Bardes B; Supsavhad, Wachiraphan; Dirksen, Wessel P; Camiener, Rachael Y; Ding, Haiming; Tweedle, Michael F; Rosol, Thomas J

    2016-06-01

    The gastrin-releasing peptide receptor (GRPr) is upregulated in early and late-stage human prostate cancer (PCa) and other solid tumors of the mammary gland, lung, head and neck, colon, uterus, ovary, and kidney. However, little is known about its role in prostate cancer. This study examined the effects of a heterologous GRPr agonist, bombesin (BBN), on growth, motility, morphology, gene expression, and tumor phenotype of an osteoblastic canine prostate cancer cell line (Ace-1) in vitro and in vivo. The Ace-1 cells were stably transfected with the human GRPr and tumor cells were grown in vitro and as subcutaneous and intratibial tumors in nude mice. The effect of BBN was measured on cell proliferation, cell migration, tumor growth (using bioluminescence), tumor cell morphology, bone tumor phenotype, and epithelial-mesenchymal transition (EMT) and metastasis gene expression (quantitative RT-PCR). GRPr mRNA expression was measured in primary canine prostate cancers and normal prostate glands. Bombesin (BBN) increased tumor cell proliferation and migration in vitro and tumor growth and invasion in vivo. BBN upregulated epithelial-to-mesenchymal transition (EMT) markers (TWIST, SNAIL, and SLUG mRNA) and downregulated epithelial markers (E-cadherin and β-catenin mRNA), and modified tumor cell morphology to a spindle cell phenotype. Blockade of GRPr upregulated E-cadherin and downregulated VIMENTIN and SNAIL mRNA. BBN altered the in vivo tumor phenotype in bone from an osteoblastic to osteolytic phenotype. Primary canine prostate cancers had increased GRPr mRNA expression compared to normal prostates. These data demonstrated that the GRPr is important in prostate cancer growth and progression and targeting GRPr may be a promising strategy for treatment of prostate cancer. Prostate 76:796-809, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

    Science.gov (United States)

    Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

    2012-07-15

    Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

  13. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

    Science.gov (United States)

    Bonkhoff, Helmut

    2018-01-01

    The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

  14. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model.

    Science.gov (United States)

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-03-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer.

  15. Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor

    Energy Technology Data Exchange (ETDEWEB)

    Bourke, Vincent A [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Dawen, Zhao [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Gilio, Joseph [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Chang, C -H [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Lan, Jiang [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Hahn, Eric W [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States); Mason, Ralph P [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX (United States)

    2007-03-15

    Purpose: To investigate the application of pretreatment oxygenation to the AT1 subline of the Dunning R3327 prostate tumor, which is more hypoxic and faster growing than the H1 subline previously studied. Methods and Materials: Dunning prostate R3327-AT1 tumors growing on Copenhagen rats were administered 30 Gy of X-ray radiation either with or without oxygen inhalation. Tumor oxygenation was sampled by {sup 19}F nuclear magnetic resonance echo planar imaging relaxometry of the reporter molecule hexafluorobenzene, no more than 24 h before irradiation. Results: Large tumors (>3.0 cm{sup 3}) exhibited significantly greater hypoxic fractions and lower mean partial pressure of oxygen (pO{sub 2}) than their smaller counterparts (<1.5 cm{sup 3}). However, unlike the R3327-HI subline, large AT1 tumors generally did not respond to oxygen inhalation in terms of altered hypoxic fraction or response to irradiation. Although the tumors did not respond to oxygen inhalation, each tumor had a different pO{sub 2}, and there was a clear trend between level of oxygenation at time of irradiation and tumor growth delay, with considerably better outcome when mean pO{sub 2} > 10 mm Hg. The comparatively small baseline hypoxic fraction in the group of small tumors was virtually eliminated by breathing oxygen, and the growth rate was significantly reduced for tumors on rats breathing oxygen during irradiation. Conclusions: These results further validate the usefulness of nuclear magnetic resonance oximetry as a predictor of response to radiation therapy.

  16. Geometrical approach to tumor growth

    OpenAIRE

    Escudero, Carlos

    2006-01-01

    Tumor growth has a number of features in common with a physical process known as molecular beam epitaxy. Both growth processes are characterized by the constraint of growth development to the body border, and surface diffusion of cells/particles at the growing edge. However, tumor growth implies an approximate spherical symmetry that makes necessary a geometrical treatment of the growth equations. The basic model was introduced in a former article [C. Escudero, Phys. Rev. E 73, 020902(R) (200...

  17. Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

    Science.gov (United States)

    Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

    2010-01-01

    The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

  18. Tumor clone dynamics in lethal prostate cancer.

    Science.gov (United States)

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt

    2014-09-17

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. Copyright © 2014, American Association for the Advancement of Science.

  19. Geometrical approach to tumor growth.

    Science.gov (United States)

    Escudero, Carlos

    2006-08-01

    Tumor growth has a number of features in common with a physical process known as molecular beam epitaxy. Both growth processes are characterized by the constraint of growth development to the body border, and surface diffusion of cells and particles at the growing edge. However, tumor growth implies an approximate spherical symmetry that makes necessary a geometrical treatment of the growth equations. The basic model was introduced in a former paper [C. Escudero, Phys. Rev. E 73, 020902(R) (2006)], and in the present work we extend our analysis and try to shed light on the possible geometrical principles that drive tumor growth. We present two-dimensional models that reproduce the experimental observations, and analyze the unexplored three-dimensional case, for which interesting conclusions on tumor growth are derived.

  20. Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Teresa D. Elo

    2010-11-01

    Full Text Available Expression of fibroblast growth factor 8 (FGF-8 is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

  1. Prostatic Adenocarcinoma with Concurrent Sertoli Cell Tumor in a Dog

    Science.gov (United States)

    Gill, C. W.

    1981-01-01

    A case of metastatic prostatic adenocarcinoma with concurrent Sertoli cell tumor is presented in an old, miniature Schnauzer dog. The prostatic neoplasm was highly anaplastic and had metastasized widely. Clinical signs were compatible with increased estrogen production. It is interesting to note that the prostatic carcinoma, usually considered to be androgen dependent, developed and metastasized, despite the presence of apparently increased estrogen levels. ImagesFigure 1.Figure 2.Figure 3.Figure 4.Figure 5.Figure 6. PMID:7340923

  2. FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

    Science.gov (United States)

    Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

    2012-02-01

    Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  3. Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

    Science.gov (United States)

    2017-12-01

    is associated with androgen receptor (AR). We detected Oct4 protein expression in prostate cancer cells as well as in tumor tissue specimens...unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Identification of genes driving prostate carcinogenesis will lead to new cancer treatment. The human...a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due to the gene expression of POU5F1B

  4. The Addition of Manganese Porphyrins during Radiation Inhibits Prostate Cancer Growth and Simultaneously Protects Normal Prostate Tissue from Radiation Damage

    Directory of Open Access Journals (Sweden)

    Arpita Chatterjee

    2018-01-01

    Full Text Available Radiation therapy is commonly used for prostate cancer treatment; however, normal tissues can be damaged from the reactive oxygen species (ROS produced by radiation. In separate reports, we and others have shown that manganese porphyrins (MnPs, ROS scavengers, protect normal cells from radiation-induced damage but inhibit prostate cancer cell growth. However, there have been no studies demonstrating that MnPs protect normal tissues, while inhibiting tumor growth in the same model. LNCaP or PC3 cells were orthotopically implanted into athymic mice and treated with radiation (2 Gy, for 5 consecutive days in the presence or absence of MnPs. With radiation, MnPs enhanced overall life expectancy and significantly decreased the average tumor volume, as compared to the radiated alone group. MnPs enhanced lipid oxidation in tumor cells but reduced oxidative damage to normal prostate tissue adjacent to the prostate tumor in combination with radiation. Mechanistically, MnPs behave as pro-oxidants or antioxidants depending on the level of oxidative stress inside the treated cell. We found that MnPs act as pro-oxidants in prostate cancer cells, while in normal cells and tissues the MnPs act as antioxidants. For the first time, in the same in vivo model, this study reveals that MnPs enhance the tumoricidal effect of radiation and reduce oxidative damage to normal prostate tissue adjacent to the prostate tumor in the presence of radiation. This study suggests that MnPs are effective radio-protectors for radiation-mediated prostate cancer treatment.

  5. Effects of homeopathic preparations on human prostate cancer growth in cellular and animal models.

    Science.gov (United States)

    MacLaughlin, Brian W; Gutsmuths, Babett; Pretner, Ewald; Jonas, Wayne B; Ives, John; Kulawardane, Don Victor; Amri, Hakima

    2006-12-01

    The use of dietary supplements for various ailments enjoys unprecedented popularity. As part of this trend, Sabal serrulata (saw palmetto) constitutes the complementary treatment of choice with regard to prostate health. In homeopathy, Sabal serrulata is commonly prescribed for prostate problems ranging from benign prostatic hyperplasia to prostate cancer. The authors' work assessed the antiproliferative effects of homeopathic preparations of Sabal serrulata, Thuja occidentalis, and Conium maculatum, in vivo, on nude mouse xenografts, and in vitro, on PC-3 and DU-145 human prostate cancer as well as MDA-MB-231 human breast cancer cell lines. Treatment with Sabal serrulata in vitro resulted in a 33% decrease of PC-3 cell proliferation at 72 hours and a 23% reduction of DU-145 cell proliferation at 24 hours (PConium maculatum did not have any effect on human prostate cancer cell proliferation. In vivo, prostate tumor xenograft size was significantly reduced in Sabal serrulata-treated mice compared to untreated controls (P=.012). No effect was observed on breast tumor growth. Our study clearly demonstrates a biologic response to homeopathic treatment as manifested by cell proliferation and tumor growth. This biologic effect was (i)significantly stronger to Sabal serrulata than to controls and (ii)specific to human prostate cancer. Sabal serrulata should thus be further investigated as a specific homeopathic remedy for prostate pathology.

  6. Molecular differences in transition zone and peripheral zone prostate tumors

    Science.gov (United States)

    Sinnott, Jennifer A.; Rider, Jennifer R.; Carlsson, Jessica; Gerke, Travis; Tyekucheva, Svitlana; Penney, Kathryn L.; Sesso, Howard D.; Loda, Massimo; Fall, Katja; Stampfer, Meir J.; Mucci, Lorelei A.; Pawitan, Yudi; Andersson, Sven-Olof; Andrén, Ove

    2015-01-01

    Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20–30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P zones. Zone of origin may be important to consider in prostate tumor biomarker research. PMID:25870172

  7. Relative biological effectiveness (RBE) of fast neutrons with the Dunning rat prostate tumor R3327-HI

    International Nuclear Information System (INIS)

    Wenz, F.; Lohr, F.; Peschke, P.; Wolber, G.; Hoever, K.H.; Hahn, E.W.

    1993-01-01

    Human prostate tumors are known to be good candidates for neutron therapy. The Dunning rat prostate tumor system R3327 was found in many studies to be an excellent model for human prostate tumors. There is still a paucity of studies on the response of the Dunning tumors to fast neutrons. Tumors of the R3327-HI subline are moderately well differentiated and mucin producing. They show one euploid cell population, a bromodeoxyuridine labelling index of 5%, a potential doubling time of 8.9 days, a volume doubling time of about ten days and a cell loss rate of 10%. Tumors were transplanted s.c. in the distal thigh of Copenhagen rats and treated with 60 Co-photons (10, 20, 30, 40 Gy, 45 cGy/min) and 14-MeV-neutrons (8, 10, 12 Gy, 7 to 11 cGy/min). Tumor volumes were measured twice weekly. Growth delay was defined as time in days until the tumors reached twice their treatment volume. Linear regressions on the median growth delays of the different treatment groups were calculated. The ratio of the neutron- and photon-slopes yielded an RBE of 3.1±0.3. Additionally isoeffect-RBE values between 2.3 and 2.6 were graphically estimated. (orig.) [de

  8. Identification and Reconstruction of Prostate Tumor-Suppressing Exosomes for Therapeutic Applications

    Science.gov (United States)

    2016-03-01

    to the altered contents of exosomes , those from prostate cancer cells (tumor exosomes ) no longer have tumor suppressive functions. If this... cancer . To develop this concept, exosomes will be isolated from normal prostate epithelial cells by differential centrifugations or affinity...purifications and evaluated for tumor suppressing activities against various prostate cancer cells (Aim 1). Then the components of the tumor suppressing exosomes

  9. Response of rat prostate and lung tumors to ionizing radiation combined with the angiogenesis inhibitor AMCA

    Energy Technology Data Exchange (ETDEWEB)

    Kal, H.B. [Dept. of Radiotherapy, Univ. Medical Centre Utrecht (Netherlands); Struikmans, H. [Dept. of Radiotherapy, Univ. Medical Centre Utrecht (Netherlands); Dept. of Radiotherapy, Medical Centre Haaglanden, Westeinde Hospital, The Hague (Netherlands); Gebbink, M.F.B.G.; Voest, E.E. [Dept. of Medical Oncology, Univ. Medical Centre Utrecht (Netherlands)

    2004-12-01

    Aim: to determine whether radiation combined with Trans-4-AminoMethyl cyclohexane carboxylic acid (AMCA, or tranexamic acid, Cyklokapron registered) results in a better tumor response than radiation alone. Materials and methods: we evaluated the responses of the L44 lung tumor in BN rats and R3327-MATLyLu (MLL) prostate tumor in Copenhagen rats, to single and fractionated X-ray doses with and without AMCA (1.5 g/kg). Tumors were grown subcutaneously in the flank of the animal. AMCA was administered subcutaneously twice daily for at least 2 weeks. Response to treatment was evaluated according to excess growth delay and specific growth delay. Results: L44 and MLL tumors treated with AMCA only experienced a non-significant growth delay. L44 tumors treated with 4 daily dose fractions of 2.5 Gy had a significant excess and specific growth delay when treated with AMCA, the enhancement ratio was 1.6-1.7. The enhancement ratio based on the calculated excess biologically effective dose of the linear-quadratic concept was 1.4-1.5. MLL tumors treated with a single dose of 20 Gy and AMCA had no significant excess growth delay. Conclusion: the enhancement ratio of 1.4-1.7 for the L44 tumor, but not for the MLL tumor, due to AMCA treatment, indicates that AMCA may potentiate the anti-tumor effect of ionizing radiation in distinct tumor types. (orig.)

  10. Response of rat prostate and lung tumors to ionizing radiation combined with the angiogenesis inhibitor AMCA

    International Nuclear Information System (INIS)

    Kal, H.B.; Struikmans, H.; Gebbink, M.F.B.G.; Voest, E.E.

    2004-01-01

    Aim: to determine whether radiation combined with Trans-4-AminoMethyl cyclohexane carboxylic acid (AMCA, or tranexamic acid, Cyklokapron registered) results in a better tumor response than radiation alone. Materials and methods: we evaluated the responses of the L44 lung tumor in BN rats and R3327-MATLyLu (MLL) prostate tumor in Copenhagen rats, to single and fractionated X-ray doses with and without AMCA (1.5 g/kg). Tumors were grown subcutaneously in the flank of the animal. AMCA was administered subcutaneously twice daily for at least 2 weeks. Response to treatment was evaluated according to excess growth delay and specific growth delay. Results: L44 and MLL tumors treated with AMCA only experienced a non-significant growth delay. L44 tumors treated with 4 daily dose fractions of 2.5 Gy had a significant excess and specific growth delay when treated with AMCA, the enhancement ratio was 1.6-1.7. The enhancement ratio based on the calculated excess biologically effective dose of the linear-quadratic concept was 1.4-1.5. MLL tumors treated with a single dose of 20 Gy and AMCA had no significant excess growth delay. Conclusion: the enhancement ratio of 1.4-1.7 for the L44 tumor, but not for the MLL tumor, due to AMCA treatment, indicates that AMCA may potentiate the anti-tumor effect of ionizing radiation in distinct tumor types. (orig.)

  11. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Montgomery, Bruce; Nelson, Peter S; Vessella, Robert; Kalhorn, Tom; Hess, David; Corey, Eva

    2010-01-01

    Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm 3 vs. 1195 ± 84 mm 3 , p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

  12. Transcriptome sequencing in prostate cancer identifies inter-tumor heterogeneity

    Directory of Open Access Journals (Sweden)

    Janet Mendonca

    2015-06-01

    Full Text Available Given the dearth of gene mutations in prostate cancer, [1] ,[2] it is likely that genomic rearrangements play a significant role in the evolution of prostate cancer. However, in the search for recurrent genomic alterations, "private alterations" have received less attention. Such alterations may provide insights into the evolution, behavior, and clinical outcome of an individual tumor. In a recent report in "Genome Biology" Wyatt et al. [3] defines unique alterations in a cohort of high-risk prostate cancer patient with a lethal phenotype. Utilizing a transcriptome sequencing approach they observe high inter-tumor heterogeneity; however, the genes altered distill into three distinct cancer-relevant pathways. Their analysis reveals the presence of several non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression.

  13. Naked DNA Immunization for Prevention of Prostate Cancer in a Dunning Rat Prostate Tumor Model

    National Research Council Canada - National Science Library

    Mincheff, Milcho

    2003-01-01

    ...: H-PSMA-T, R-"PSMA"-T, H-PSA, H-PSA-T, H-PAP-T and R"PSMA"-S. Preliminary studies using the Copenhagen rat tumor prostate model showed uniform tumor development in rats that were injected subcutaneously with 100 000 AT3B-lPSMA,PSA cells...

  14. On complex preparation for radiotherapy of prostatic tumor patients

    International Nuclear Information System (INIS)

    Tkachev, S.I.

    1980-01-01

    An experience with the treatment of 62 patients with prostatic gland tumor has contributed to the elaboration of some approaches to the utilization of modern diagnostic facilities in order to define the spread of neoplastic process and select therapeutic tactics. A sequence of methods to be used has been described, including clinical and X-ray, radioisotope and ultrasonic methods of examination. The matter of particular attention is a newly developed method of the prostatic gland cranio-caudal size determination. The latter together with ultrasonic data enable one to detect the size of the tumor and select an adequate physico-technical regime of irradiation for each individual patient

  15. SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer

    DEFF Research Database (Denmark)

    Iglesias Gato, Diego; Chuan, Yin Choy; Wikström, Pernilla

    2014-01-01

    ) as mediator of the cross talk between androgens and GH signals in the prostate and its potential role as tumor suppressor in prostate cancer (PCa). We observed that SOCS2 protein levels assayed by immunohistochemistry are elevated in hormone therapy-naive localized prostatic adenocarcinoma in comparison...... of transcription 5 protein (STAT5) and androgen receptor-dependent transcription. Consequentially, SOCS2 inhibits GH activation of Janus kinase 2, Src and STAT5 as well as both cell invasion and cell proliferation in vitro. In vivo, SOCS2 limits proliferation and production of IGF-1 in the prostate in response......Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2...

  16. Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells.

    Science.gov (United States)

    Wen, Juan; Zhao, Yuan; Li, Jinghe; Weng, Chunyan; Cai, Jingjing; Yang, Kan; Yuan, Hong; Imperato-McGinley, Julianne; Zhu, Yuan-Shan

    2013-07-01

    Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer. Copyright © 2013 Wiley Periodicals, Inc.

  17. Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer-90Y conjugates in treatment of prostate tumors

    International Nuclear Information System (INIS)

    Buckway, Brandon; Frazier, Nick; Gormley, Adam J.; Ray, Abhijit; Ghandehari, Hamidreza

    2014-01-01

    Introduction: The treatment of prostate cancer using a radiotherapeutic 90 Y labeled N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer can be enhanced with localized tumor hyperthermia. An 111 In labeled HPMA copolymer system for single photon emission computerized tomography (SPECT) was developed to observe the biodistribution changes associated with hyperthermia. Efficacy studies were conducted in prostate tumor bearing mice using the 90 Y HPMA copolymer with hyperthermia. Methods: HPMA copolymers containing 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthesized by reversible addition-fragmentation transfer (RAFT) copolymerization and subsequently labeled with either 111 In for imaging or 90 Y for efficacy studies. Radiolabel stability was characterized in vitro with mouse serum. Imaging and efficacy studies were conducted in DU145 prostate tumor bearing mice. Imaging was performed using single photon emission computerized tomography (SPECT). Localized mild tumor hyperthermia was achieved by plasmonic photothermal therapy using gold nanorods. Results: HPMA copolymer-DOTA conjugates demonstrated efficient labeling and stability for both radionuclides. Imaging analysis showed a marked increase of radiolabeled copolymer within the hyperthermia treated prostate tumors, with no significant accumulation in non-targeted tissues. The greatest reduction in tumor growth was observed in the hyperthermia treated tumors with 90 Y HPMA copolymer conjugates. Histological analysis confirmed treatment efficacy and safety. Conclusion: HPMA copolymer-DOTA conjugates radiolabeled with both the imaging and treatment radioisotopes, when combined with hyperthermia can serve as an image guided approach for efficacious treatment of prostate tumors

  18. Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter-Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth.

    Directory of Open Access Journals (Sweden)

    Shian-Ying Sung

    Full Text Available Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.

  19. Evaluation of the effect of prostate volume change on tumor control probability in LDR brachytherapy

    Directory of Open Access Journals (Sweden)

    Courtney Knaup

    2011-09-01

    Full Text Available Purpose: This study evaluates low dose-rate brachytherapy (LDR prostate plans to determine the biological effectof dose degradation due to prostate volume changes. Material and methods: In this study, 39 patients were evaluated. Pre-implant prostate volume was determinedusing ultrasound. These images were used with the treatment planning system (Nucletron Spot Pro 3.1® to create treatmentplans using 103Pd seeds. Following the implant, patients were imaged using CT for post-implant dosimetry. Fromthe pre and post-implant DVHs, the biologically equivalent dose and the tumor control probability (TCP were determinedusing the biologically effective uniform dose. The model used RBE = 1.75 and α/β = 2 Gy. Results: The prostate volume changed between pre and post implant image sets ranged from –8% to 110%. TCP andthe mean dose were reduced up to 21% and 56%, respectively. TCP is observed to decrease as the mean dose decreasesto the prostate. The post-implant tumor dose was generally observed to decrease, compared to the planned dose.A critical uniform dose of 130 Gy was established. Below this dose, TCP begins to fall-off. It was also determined thatpatients with a small prostates were more likely to suffer TCP decrease. Conclusions: The biological effect of post operative prostate growth due to operative trauma in LDR was evaluatedusing the concept. The post-implant dose was lower than the planned dose due to an increase of prostate volumepost-implant. A critical uniform dose of 130 Gy was determined, below which TCP begun to decline.

  20. Evaluation of the effect of prostate volume change on tumor control probability in LDR brachytherapy.

    Science.gov (United States)

    Knaup, Courtney; Mavroidis, Panayiotis; Stathakis, Sotirios; Smith, Mark; Swanson, Gregory; Papanikolaou, Niko

    2011-09-01

    This study evaluates low dose-rate brachytherapy (LDR) prostate plans to determine the biological effect of dose degradation due to prostate volume changes. In this study, 39 patients were evaluated. Pre-implant prostate volume was determined using ultrasound. These images were used with the treatment planning system (Nucletron Spot Pro 3.1(®)) to create treatment plans using (103)Pd seeds. Following the implant, patients were imaged using CT for post-implant dosimetry. From the pre and post-implant DVHs, the biologically equivalent dose and the tumor control probability (TCP) were determined using the biologically effective uniform dose. The model used RBE = 1.75 and α/β = 2 Gy. The prostate volume changed between pre and post implant image sets ranged from -8% to 110%. TCP and the mean dose were reduced up to 21% and 56%, respectively. TCP is observed to decrease as the mean dose decreases to the prostate. The post-implant tumor dose was generally observed to decrease, compared to the planned dose. A critical uniform dose of 130 Gy was established. Below this dose, TCP begins to fall-off. It was also determined that patients with a small prostates were more likely to suffer TCP decrease. The biological effect of post operative prostate growth due to operative trauma in LDR was evaluated using the concept. The post-implant dose was lower than the planned dose due to an increase of prostate volume post-implant. A critical uniform dose of 130 Gy was determined, below which TCP begun to decline.

  1. Sonic Hedgehog Signaling Promotes Tumor Growth

    National Research Council Canada - National Science Library

    Bushman, Wade

    2007-01-01

    ... of the DOD New Investigator award indicate that Shh signaling promotes tumor growth. This proposal addresses the hypothesis that Sonic hedgehog signaling promotes tumor growth by activating stromal cell gene expression...

  2. Quantification of tumor extension in prostate biopsies: importance in the identification of confined tumors

    Directory of Open Access Journals (Sweden)

    Leite Kátia R.M.

    2003-01-01

    Full Text Available OBJECTIVE: To assess the importance of quantifying the adenocarcinoma in prostate biopsies when determining the tumor's final stage in patients who undergo radical prostatectomy. To identify the best methodology for obtaining such data. PATIENTS AND METHODS: Prostate biopsies from 132 patients were examined, with determination of Gleason histological grade and tumor volume in number of involved fragments, tumor extent of the fragment mostly affected by the tumor and the total percentage of tumor in the specimen. Theses parameters were statistically correlated with the neoplasia's final stage following the evaluation of radical prostatectomy specimens. RESULTS: An average of 12 and a median of 14 biopsy fragments were evaluated per patient. In the univariate analysis the Gleason histological grade, the largest tumor extent in one fragment and the total percentage of tumor in the specimen were correlated with tumor stage of the surgical specimen. In the multivariate analysis, the Gleason histological grade and the total percentage of tumor were strongly correlated with the neoplasia's final stage. The risk of the tumor not being confined was 3 for Gleason 7 tumors and 10.6 for Gleason 8 tumors or above. In cases where the tumor involved more than 60% of the specimen, the risk of non-confined disease was 4.4 times. Among 19 patients with unfavorable histological parameters, Gleason > 7 and extension greater than 60% the tumor final stage was pT3 in 95%. CONCLUSION: When associated to the Gleason histological grade, tumor quantification in prostate biopsies is an important factor for determining organ-confined disease, and among the methods, total percentage of tumor is the most informative one. Such data should be included in the pathological report and must be incorporated in future nomograms.

  3. S100A9 interaction with TLR4 promotes tumor growth.

    Directory of Open Access Journals (Sweden)

    Eva Källberg

    Full Text Available By breeding TRAMP mice with S100A9 knock-out (S100A9(-/- animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/- and TLR4(-/-, but not in RAGE(-/- animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b(+ cells. Lastly, treatment of mice with a small molecule (ABR-215050 that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.

  4. Vascular endothelial growth factor (VEGF and prostate pathology

    Directory of Open Access Journals (Sweden)

    Francisco Botelho

    2010-08-01

    Full Text Available PURPOSE: Previous studies suggest that vascular endothelial growth factor (VEGF circulating levels might improve identification of patients with prostate cancer but results are conflicting. Our aim was to compare serum VEGF levels across different prostate pathologies (including benign prostatic hyperplasia, prostatitis, high grade prostate intraepithelial neoplasia and prostate cancer in patients at high risk of prostate cancer. MATERIALS AND METHODS: We consecutively enrolled 186 subjects with abnormal digital rectal examination and/or total PSA (tPSA = 2.5 ng/mL. Blood was collected before diagnostic ultrasound guided trans-rectal prostate biopsy, or any prostate oncology treatment, to measure PSA isoforms and VEGF. Unconditional logistic regression was used to compute age-, tPSA- and free/total PSA-adjusted odds ratios (OR and respective 95% confidence intervals (95% CI for the association between serum VEGF and different prostatic pathologies. RESULTS: Prostate biopsy main diagnoses were normal or benign prostatic hyperplasia (27.3%, prostatitis (16.6%, and prostatic cancer (55.0%. The median VEGF levels (ng/mL in these groups were 178.2, 261.3 and 266.4 (p = 0.029, respectively, but no significant differences were observed for benign vs. malignant pathologies (215.2 vs. 266.4, p = 0.551. No independent association was observed between VEGF (3rd vs. 1st third and prostate cancer, when compared to benign conditions (adjusted OR = 1.44; CI 95%: 0.64-3.26. CONCLUSIONS: In patients at high risk of prostate cancer, circulating VEGF levels have no clinical role in deciding which patients should be submitted to prostate biopsy. Prostatitis patients, often with higher PSA levels, also present high serum levels of VEGF, and their inclusion in control groups might explain the heterogeneous results in previous studies.

  5. Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes.

    Science.gov (United States)

    Yan, Lisa; Da Silva, Diane M; Verma, Bhavna; Gray, Andrew; Brand, Heike E; Skeate, Joseph G; Porras, Tania B; Kanodia, Shreya; Kast, W Martin

    2015-02-15

    LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown to activate immune cells and result in tumor regression in a virally-induced tumor model, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration toward an anti-tumoral milieu, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors. Real Time PCR was used to evaluate expression of forced LIGHT and other immunoregulatory genes in prostate tumors samples. For in vivo studies, adenovirus encoding murine LIGHT was injected intratumorally into TRAMP-C2 prostate cancer cell tumor bearing mice. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor-specific lymphocytes were quantified via ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment. LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. LIGHT expression peaked within 48 hr of infection, recruited effector T cells that recognized mouse prostate stem cell antigen (PSCA) into the tumor microenvironment, and inhibited infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment. Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated

  6. Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

    National Research Council Canada - National Science Library

    Pasquale, Elena B

    2007-01-01

    Mutations have been recently identified in the EphB2 receptor gene in prostate cancer suggesting that EphB2, a member of the large Eph receptor tyrosine kinase family, is a tumor suppressor in prostate cancer...

  7. Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

    National Research Council Canada - National Science Library

    Pasquale, Elena B

    2006-01-01

    Mutations have been recently identified in the EphB2 receptor gene in prostate cancer suggesting that EphB2, a member of the large Eph receptor tyrosine kinase family, is a tumor suppressor in prostate cancer...

  8. Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Dietmar Abraham

    2013-09-01

    Full Text Available The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF. PlGF is a member of the vascular endothelial growth factor (VEGF family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer.

  9. The Effect of Tumor-Prostate Ratio on Biochemical Recurrence after Radical Prostatectomy

    Directory of Open Access Journals (Sweden)

    Sung Yong Cho

    2016-08-01

    Full Text Available Purpose: Prostate tumor volume calculated after surgery using pathologic tissue has been shown to be an independent risk factor for biochemical recurrence. Nonetheless, prostate size varies among individuals, regardless of the presence or absence of cancer. We assumed to be lower margin positive rate in the surgical operation, when the prostate volume is larger and the tumor lesion is same. Thus, we defined the tumor-prostate ratio in the ratio of tumor volume to prostate volume. In order to compensate the prostate tumor volume, the effect of tumor-prostate ratio on biochemical recurrence was examined. Materials and Methods: This study included 251 patients who underwent open retropubic radical prostatectomy for prostate cancer in a single hospital. We analyzed the effects of tumor volume and tumor-prostate ratio, as well as the effects of known risk factors for biochemical recurrence, on the duration of disease-free survival. Results: In the univariate analysis, the risk factors that significantly impacted disease-free survival time were found to be a prostate-specific antigen level ≥10 ng/mL, a tumor volume ≥5 mL, tumor-prostate ratio ≥10%, tumor capsular invasion, lymph node invasion, positive surgical margins, and seminal vesicle invasion. In the multivariate analysis performed to evaluate the risk factors found to be significant in the univariate analysis, positive surgical margins (hazard ratio=3.066 and a tumor density ≥10% (hazard ratio=1.991 were shown to be significant risk factors for biochemical recurrence. Conclusions: Tumor-prostate ratio, rather than tumor volume, should be regarded as a significant risk factor for biochemical recurrence.

  10. Molecular imaging of tumor blood vessels in prostate cancer.

    Science.gov (United States)

    Tilki, Derya; Seitz, Michael; Singer, Bernhard B; Irmak, Ster; Stief, Christian G; Reich, Oliver; Ergün, Süleyman

    2009-05-01

    In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of tumor vascular remodelling. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not necessarily result in the reduction of tumor diameter. The basis for the molecular imaging of tumor blood vessels is the remodelling of the tumor vessels under anti-angiogenic therapy which obviously occurs at an early stage and seems to be a convincing parameter. Beside the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodelling of the micro tumor vessels. New imaging approaches combining specific molecular markers for tumor vessels with the different imaging techniques are needed to overcome this issue as exemplarily discussed for prostate cancer in this review. Molecular contrast agents targeting the vasculature will allow clinicians the visualization of vascular remodelling processes taking place under anti-angiogenic therapy and improve tumor diagnosis and follow-up.

  11. Apoptosis and Tumor Progressionin Prostate Cancer

    National Research Council Canada - National Science Library

    Tenniswood, Martin P

    2005-01-01

    ... (as measured by BrdU incorporation) and apoptosis as measured by TUNEL staining. We have standardized an efficient methodologies for isolating cells from primary tumors expressing REP by fluorescence activated cell sorting (FACS...

  12. Chronic treatment with epidermal growth factor induces growth of the rat ventral prostate

    DEFF Research Database (Denmark)

    Tørring, N; Jensen, L V; Wen, J G

    2001-01-01

    of the prostate epithelium, the stroma and the lumen following EGF treatment, in a pattern resembling physiological growth of the ventral prostate. A significant correlation (r = 0.78, p testosterone...

  13. Osteopontin is a tumor autoantigen in prostate cancer patients

    Science.gov (United States)

    TILLI, TATIANA M.; SILVA, ELOÍSIO A.; MATOS, LÍVIA C.; FAGET, DOUGLAS V.; DIAS, BIANCA F.P.; VASCONCELOS, JULIANA S.P.; YOKOSAKI, YASUYUKI; GIMBA, ETEL R.P.

    2011-01-01

    Anti-tumor antibodies act as biomarkers for the early diagnosis of prostate cancer (PCa). Osteopontin (OPN) is overexpressed in PCa cells and contributes to the progression of the disease. This study aimed to evaluate whether OPN evokes a humoral immune response in PCa patients and whether the reactivity levels of anti-OPN antibodies may be used to better differentiate PCa from benign and healthy donor plasma samples. Plasma samples from biopsy-proven PCa patients (29), benign prostate hyperplasia (BPH) (18) and control healthy donors (HD) (30) were tested by immunoblots using the recombinant human OPN. The frequency of anti-OPN antibodies was significantly higher in PCa (66%) plasma samples as compared to BPH (33%) and HD controls (10%). Anti-OPN antibodies were detected in a high proportion of plasma samples from patients with a Gleason score of less than 6 (57%), prostate-specific antigen levels lower than 10 ng/ml (67%) and pT2 organ-confined disease (70%), suggesting that anti-OPN antibodies may be used as an early serum marker for PCa. To the best of our knowledge, this is the first description of OPN as a tumor autoantigen and one of the most reactive individual autoantigens described thus far. These data support the inclusion of OPN in a multiplex of tumor antigens in order to perform antibody profiling in PCa as well as in other malignancies overexpressing OPN. PMID:22870138

  14. Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

    Science.gov (United States)

    Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

    2008-07-01

    Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

  15. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2016-10-01

    cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression...impact of pharmacological inhibition of Cxcl5 and Cxcr2 on MDSCs using the transwell migration assay 26 . First, anti-Cxcl5 neutralizing antibody...and MRI . (B) Generation of the CPPSML chimera model. (C) Fluorescence microscopy and H&E image of snap frozen prostate tumor from chimera showing that

  16. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

    Science.gov (United States)

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-11-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

  17. Perioperative Search for Circulating Tumor Cells in Patients Undergoing Prostate Brachytherapy for Clinically Nonmetastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Hideyasu Tsumura

    2017-01-01

    Full Text Available Despite the absence of local prostate cancer recurrence, some patients develop distant metastases after prostate brachytherapy. We evaluate whether prostate brachytherapy procedures have a potential risk for hematogenous spillage of prostate cancer cells. Fifty-nine patients who were undergoing high-dose-rate (HDR or low-dose-rate (LDR brachytherapy participated in this prospective study. Thirty patients with high-risk or locally advanced cancer were treated with HDR brachytherapy after neoadjuvant androgen deprivation therapy (ADT. Twenty-nine patients with clinically localized cancer were treated with LDR brachytherapy without neoadjuvant ADT. Samples of peripheral blood were drawn in the operating room before insertion of needles (preoperative and again immediately after the surgical manipulation (intraoperative. Blood samples of 7.5 mL were analyzed for circulating tumor cells (CTCs using the CellSearch System. While no preoperative samples showed CTCs (0%, they were detected in intraoperative samples in 7 of the 59 patients (11.8%; preoperative vs. intraoperative, p = 0.012. Positive CTC status did not correlate with perioperative variables, including prostate-specific antigen (PSA at diagnosis, use of neoadjuvant ADT, type of brachytherapy, Gleason score, and biopsy positive core rate. We detected CTCs from samples immediately after the surgical manipulation. Further study is needed to evaluate whether those CTCs actually can survive and proliferate at distant sites.

  18. S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells

    International Nuclear Information System (INIS)

    Amaral, Camila L.; Freitas, Lidia B.; Tamura, Rodrigo E.; Tavares, Mariana R.; Pavan, Isadora C. B.; Bajgelman, Marcio C.; Simabuco, Fernando M.

    2016-01-01

    The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms–p70-S6K1, p85-S6K1 and p54-S6K2–in prostate cancer, as well as their potential as therapeutic targets. In this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro. S6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF-4708671 was particularly effective for reducing migration and proliferation of PC3 cell line. These findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment. The online version of this article (doi:10.1186/s12885-016-2629-y) contains supplementary material, which is available to authorized users

  19. Biochemomechanical poroelastic theory of avascular tumor growth

    Science.gov (United States)

    Xue, Shi-Lei; Li, Bo; Feng, Xi-Qiao; Gao, Huajian

    2016-09-01

    Tumor growth is a complex process involving genetic mutations, biochemical regulations, and mechanical deformations. In this paper, a thermodynamics-based nonlinear poroelastic theory is established to model the coupling among the mechanical, chemical, and biological mechanisms governing avascular tumor growth. A volumetric growth law accounting for mechano-chemo-biological coupled effects is proposed to describe the development of solid tumors. The regulating roles of stresses and nutrient transport in the tumor growth are revealed under different environmental constraints. We show that the mechano-chemo-biological coupling triggers anisotropic and heterogeneous growth, leading to the formation of layered structures in a growing tumor. There exists a steady state in which tumor growth is balanced by resorption. The influence of external confinements on tumor growth is also examined. A phase diagram is constructed to illustrate how the elastic modulus and thickness of the confinements jointly dictate the steady state of tumor volume. Qualitative and quantitative agreements with experimental observations indicate the developed model is capable of capturing the essential features of avascular tumor growth in various environments.

  20. FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer.

    Science.gov (United States)

    Davidsson, Sabina; Andren, Ove; Ohlson, Anna-Lena; Carlsson, Jessica; Andersson, Swen-Olof; Giunchi, Francesca; Rider, Jennifer R; Fiorentino, Michelangelo

    2018-01-01

    The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (T regs ). In the present study we evaluated the prevalence of T reg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4 + T regs and CD8 + T regs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of T regs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. In men with prostate cancer, similarly high numbers of stromal CD4 + T regs were identified in PAH and tumor, but CD4 + T regs were less common in PIN. Greater numbers of epithelial CD4+ T regs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4 + T regs in the normal prostatic tissue counterpart. Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4 + T regs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established. © 2017 The Authors. The Prostate Published by Wiley Periodicals Inc.

  1. Chronic treatment with epidermal growth factor induces growth of the rat ventral prostate

    DEFF Research Database (Denmark)

    Tørring, N; Jensen, L V; Wen, J G

    2001-01-01

    the hyperplastic growth phase of the prostate in newborn rats.MATERIAL AND METHODS: Newborn rats were treated for 8 weeks with EGF (150 microg/kg body weight per day), administered as daily subcutaneous injections. Sections of the prostate tissue were examined by a stereological technique to determine tissue......OBJECTIVE: The epidermal growth factor (EGF) system is expressed in the rat prostate, and growth factors from this system induce proliferation in prostate epithelial and stromal cell cultures. The aim of the study was to investigate the possible growth-promoting effects of the system during...... of the prostate epithelium, the stroma and the lumen following EGF treatment, in a pattern resembling physiological growth of the ventral prostate. A significant correlation (r = 0.78, p

  2. Lemur Tyrosine Kinase-3 Suppresses Growth of Prostate Cancer Via the AKT and MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Pengcheng Sun

    2017-08-01

    Full Text Available Background/Aims: Lemur tyrosine kinase (LMTK-3 is a member of the receptor tyrosine kinase (RTK family. Abnormal expression of LMTK-3 exists in various types of cancers, especially in endocrine-resistant breast cancers; however, the precise level of expression and the biological function in prostate cancer are poorly understood. Methods: In the present study, we determined the expression of LMTK-3 in prostate cancer using immunohistochemistry and Western blotting. We infected PC3 and LNCaP cells with lentivirus-LMTK-3 and observed the biologic characteristics of the PC3 and LNCaP cells in vitro with TUNEL, and migration and invasion assays, respectively. We also established a transplant tumor model of human prostate cancer with infected cells in 15 BALB/c-nu/nu nude mice. Results: LMTK-3 was expressed in prostate epithelial cells. There was a significant decline in the level of LMTK-3 expression in prostate cancers compared to normal tissues. LMTK-3 inhibited PC3 and LNCaP cell growth, migration, and invasion, and induced cell apoptosis in vitro. We also observed that LMTK-3 induced PC3 cell apoptosis in vivo. Further study showed that LMTK-3 inhibited phosphorylation of AKT and ERK, and promoted phosphorylation and activation of p38 kinase and Jun kinase (JNK. Conclusion: Recombinant lentivirus with enhanced expression of LMTK-3 inhibited prostate cancer cell growth and induced apoptosis in vitro and in vivo. AKT and MAPK signaling pathways may contribute to the process.

  3. Rapid ex vivo imaging of PAIII prostate to bone tumor with SWIFT-MRI.

    Science.gov (United States)

    Luhach, Ihor; Idiyatullin, Djaudat; Lynch, Conor C; Corum, Curt; Martinez, Gary V; Garwood, Michael; Gillies, Robert J

    2014-09-01

    The limiting factor for MRI of skeletal/mineralized tissue is fast transverse relaxation. A recent advancement in MRI technology, SWIFT (Sweep Imaging with Fourier Transform), is emerging as a new approach to overcome this difficulty. Among other techniques like UTE, ZTE, and WASPI, the application of SWIFT technology has the strong potential to impact preclinical and clinical imaging, particularly in the context of primary or metastatic bone cancers because it has the added advantage of imaging water in mineralized tissues of bone allowing MRI images to be obtained of tissues previously visible only with modalities such as computed tomography (CT). The goal of the current study is to examine the feasibility of SWIFT for the assessment of the prostate cancer induced changes in bone formation (osteogenesis) and destruction (osteolysis) in ex vivo specimens. A luciferase expressing prostate cancer cell line (PAIII) or saline control was inoculated directly into the tibia of 6-week-old immunocompromised male mice. Tumor growth was assessed weekly for 3 weeks before euthanasia and dissection of the tumor bearing and sham tibias. The ex vivo mouse tibia specimens were imaged with a 9.4 Tesla (T) and 7T MRI systems. SWIFT images are compared with traditional gradient-echo and spin-echo MRI images as well as CT and histological sections. SWIFT images with nominal resolution of 78 μm are obtained with the tumor and different bone structures identified. Prostate cancer induced changes in the bone microstructure are visible in SWIFT images, which is supported by spin-echo, high resolution CT and histological analysis. SWIFT MRI is capable of high-quality high-resolution ex vivo imaging of bone tumor and surrounding bone and soft tissues. Furthermore, SWIFT MRI shows promise for in vivo bone tumor imaging, with the added benefits of nonexposure to ionizing radiation, quietness, and speed. Copyright © 2013 Wiley Periodicals, Inc.

  4. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

  5. ERF is a Potential ERK Modulated Tumor Suppressor in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    6/27/2016 - 6/27/2019 1.20 calendar Prostate Cancer Foundation (formerly CaP CURE) $ 75,000 Epigenetic ...AWARD NUMBER: W81XWH-15-1-0277 TITLE: ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Rohit...4. TITLE AND SUBTITLE ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0277

  6. Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation

    DEFF Research Database (Denmark)

    Sugiyama, Nami; Varjosalo, Markku; Meller, Pipsa

    2010-01-01

    /stroma border and tumor invasion front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with poor cancer prognosis, increased MT1-MMP-dependent collagen invasion......Aberrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to tumor progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response...... to membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk variant. Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas, where they were partially coexpressed at the tumor...

  7. Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression

    International Nuclear Information System (INIS)

    Sanità, Patrizia; Capulli, Mattia; Teti, Anna; Galatioto, Giuseppe Paradiso; Vicentini, Carlo; Chiarugi, Paola; Bologna, Mauro; Angelucci, Adriano

    2014-01-01

    Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism. Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression. Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive

  8. Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Iván González-Chavarría

    Full Text Available Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.

  9. ING3 promotes prostate cancer growth by activating the androgen receptor.

    Science.gov (United States)

    Nabbi, Arash; McClurg, Urszula L; Thalappilly, Subhash; Almami, Amal; Mobahat, Mahsa; Bismar, Tarek A; Binda, Olivier; Riabowol, Karl T

    2017-05-16

    The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development. Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3. We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more

  10. Simulating tumor growth in confined heterogeneous environments

    International Nuclear Information System (INIS)

    Gevertz, Jana L; Torquato, Salvatore; Gillies, George T

    2008-01-01

    The holy grail of computational tumor modeling is to develop a simulation tool that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies. In order to develop such a predictive model, one must account for many of the complex processes involved in tumor growth. One interaction that has not been incorporated into computational models of neoplastic progression is the impact that organ-imposed physical confinement and heterogeneity have on tumor growth. For this reason, we have taken a cellular automaton algorithm that was originally designed to simulate spherically symmetric tumor growth and generalized the algorithm to incorporate the effects of tissue shape and structure. We show that models that do not account for organ/tissue geometry and topology lead to false conclusions about tumor spread, shape and size. The impact that confinement has on tumor growth is more pronounced when a neoplasm is growing close to, versus far from, the confining boundary. Thus, any clinical simulation tool of cancer progression must not only consider the shape and structure of the organ in which a tumor is growing, but must also consider the location of the tumor within the organ if it is to accurately predict neoplastic growth dynamics

  11. Non-invasive pre-clinical MR imaging of prostate tumor hypoxia for radiation therapy prognosis

    Directory of Open Access Journals (Sweden)

    Derek White

    2014-03-01

    Full Text Available Purpose: To investigate the usefulness of Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI changes in signal intensity related to oxygen challenge for predicting tumor response to radiation therapy.Methods: Dynamic MR signal changes were acquired using Varian 4.7T small animal MR scanner prior to image-guided radiation therapy (IGRT of small (n = 6 and large subcutaneous (n = 5 prostate tumors in adult male rats. An interleaved blood-oxygen level dependent (BOLD and tissue-oxygen level dependent (TOLD data acquisition or (IBT was performed using a baseline of medical air as positive control and using medical oxygen as a breathing challenge. BOLD used a 2-D multi-slice spoiled gradient-echo with multi-echo sequence. TOLD used a 2-D multi-slice spoiled gradient-echo sequence. Voxel changes in signal intensity were determined by a correlation coefficient mapping technique. Irradiation technique planned consisted of 1F × 15 Gy AP/PA or 2F × 7.5 Gy AP/PA to the gross tumor volume (GTV. Tumor growth measurements were recorded over time to assess the response to IGRT.Results: BOLD and TOLD signals variously illustrated positive or negative impulse responses in the tumor ROI due to inhaling medical oxygen. Correlation coefficient mapping demonstrated heterogeneity in tumors after inhaling medical oxygen. BOLD and TOLD signals exhibited increased changes in signal intensities after the first fraction of dose. Multi-fractionation had minimum effect until the second fraction of dose was applied. Tumor growth delays were observed when inhaling medical oxygen during IGRT.Conclusion: OE-MRI is a non-invasive imaging modality that can provide insight to the oxygen status of tumors. Observed increase percent changes in BOLD and TOLD signal intensities after the first fraction of dose suggest tumors experienced reoxygenation. OE-MRI could be used for predicting tumor response to IGRT when using medical oxygen for increasing GTV radiosensitivity, suggesting

  12. Quantitation and gompertzian analysis of tumor growth

    DEFF Research Database (Denmark)

    Rygaard, K; Spang-Thomsen, M

    1998-01-01

    to transform the experimental data into useful growth curves. A transformed Gompertz function is used as the basis for calculating relevant parameters pertaining to tumor growth and response to therapy. The calculations are facilitated by use of a computer program which performs the necessary calculations...... and presents the growth data in graphic form....

  13. Role of Growth Hormone in Prostate Cancer

    National Research Council Canada - National Science Library

    Swanson, Steven M

    2007-01-01

    We have established a GH-deficient prostate cancer model (Tag/Ghdr/dr rat) indicating that a reduction in GH and/or IGF-I can significantly inhibit prostate carcinogenesis in this model in contrast to GH wild-type controls...

  14. beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Udi Gluschnaider

    2010-02-01

    Full Text Available Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. beta-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis.Here we show that beta-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against beta-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that beta-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium.Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining beta-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.

  15. Tumor cell proliferation kinetics and tumor growth rate

    Energy Technology Data Exchange (ETDEWEB)

    Tubiana, M

    1989-01-01

    The present knowledge on the growth rate and the proliferation kinetics of human tumor is based on the measurement of the tumor doubling times (DT) in several hundred patients and on the determination of the proportion of proliferating cells with radioactive thymidine or by flow cytometry in large numbers of patients. The results show that the DT of human tumor varies widely, from less than one week to over one year with a median value of approximately 2 months. The DTs are significantly correlated with the histological type. They depend upon (1) the duration of the cell cycle whose mean duration is 2 days with small variations from tumor to tumor, (2) the proportion of proliferating cells and consequently the cell birth rate which varies widely among tumors and which is significantly correlated to the DT, (3) the cell loss factors which also vary widely and which are the greatest when proliferation is most intensive. These studies have several clinical implications: (a) they have further increased our understanding of the natural history of human tumor, (b) they have therapeutic implications since tumor responsiveness and curability by radiation and drugs are strongly influenced by the cell kinetic parameters of the tumor, (c) the proportion of proliferating cells is of great prognostic value in several types of human cancers. The investigation of the molecular defects, which are correlated with the perturbation of control of cell proliferation, should lead to significant fundamental and therapeutic advances. (orig.).

  16. Solitary Fibrous Tumor of the Prostate: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Laurence Moureau-Zabotto

    2012-01-01

    Full Text Available Solitary fibrous tumor (SFT, usually described in the pleura, is exceedingly rare in the prostate. We report a 60-year-old man with prostatic SFT revealed by obstructive urinary symptoms, and detected by ultrasonography. Computed tomography (CT and magnetic resonance imaging suggested a prostatic origin. CT-guided tumor biopsy diagnosed a SFT. A cystoprostatectomy was performed. Pathologic examination showed a 15-cm tumor arising from the prostate and showing histological criteria suggestive of aggressiveness. The surgical resection margins were tumor-free. The patient was then regularly monitored and is still alive in complete remission, 28 months after surgery. In conclusion, we report a new exceptional case of prostatic SFT. We review the literature and discuss the challenging issues of misdiagnosis, prognosis and treatment.

  17. Solitary fibrous tumor of the prostate: case report and review of the literature.

    Science.gov (United States)

    Moureau-Zabotto, Laurence; Chetaille, Bruno; Bladou, Franck; Dauvergne, Pierre-Yves; Marcy, Myriam; Perrot, Delphine; Guiramand, Jérôme; Sarran, Anthony; Bertucci, François

    2012-01-01

    Solitary fibrous tumor (SFT), usually described in the pleura, is exceedingly rare in the prostate. We report a 60-year-old man with prostatic SFT revealed by obstructive urinary symptoms, and detected by ultrasonography. Computed tomography (CT) and magnetic resonance imaging suggested a prostatic origin. CT-guided tumor biopsy diagnosed a SFT. A cystoprostatectomy was performed. Pathologic examination showed a 15-cm tumor arising from the prostate and showing histological criteria suggestive of aggressiveness. The surgical resection margins were tumor-free. The patient was then regularly monitored and is still alive in complete remission, 28 months after surgery. In conclusion, we report a new exceptional case of prostatic SFT. We review the literature and discuss the challenging issues of misdiagnosis, prognosis and treatment.

  18. S100A9 Interaction with TLR4 Promotes Tumor Growth

    Science.gov (United States)

    Källberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Björk, Per; Wikström, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas

    2012-01-01

    By breeding TRAMP mice with S100A9 knock-out (S100A9−/−) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9−/− and TLR4−/−, but not in RAGE−/− animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies. PMID:22470535

  19. BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone

    Science.gov (United States)

    2013-07-01

    of NDRG1 is correlated with tumor progression and poor prog- nosis in patients with esophageal squamous cell carcinoma. Dis. Esophagus . 19:454–458...Dormancy of Prostatic Tumor Stem Cell in Bone PRINCIPAL INVESTIGATOR: Fei Xing, Ph.D...BMP7 Induces Dormancy of Prostatic Tumor Stem Cell in Bone 5b. GRANT NUMBER W81XWH-10-1-0666 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Fei

  20. Self-scaling tumor growth

    DEFF Research Database (Denmark)

    Schmiegel, Jürgen

    We study the statistical properties of the star-shaped approximation of in vitro tumor profiles. The emphasis is on the two-point correlation structure of the radii of the tumor as a function of time and angle. In particular, we show that spatial two-point correlators follow a cosine law. Further......We study the statistical properties of the star-shaped approximation of in vitro tumor profiles. The emphasis is on the two-point correlation structure of the radii of the tumor as a function of time and angle. In particular, we show that spatial two-point correlators follow a cosine law....... Furthermore, we observe self-scaling behaviour of two-point correlators of different orders, i.e. correlators of a given order are a power law of the correlators of some other order. This power-law dependence is similar to what has been observed for the statistics of the energy-dissipation in a turbulent flow....... Based on this similarity, we provide a Lévy based model that captures the correlation structure of the radii of the star-shaped tumor profiles....

  1. Skeletal metastases of carcinomas of prostate in dependence on tumor size and tumor differentiation

    International Nuclear Information System (INIS)

    Krause, U.

    1981-01-01

    153 patients with carcinoma of the prostate underwent holebody skeletal scintiscanning. It resulted that the tendency to the development of skeletal metastases increases with increasing dedifferentiation of the tumor. Also the tumor size correlated with the metastase identification. The tumor dedifferentiation also increased with the tumor size. The findings proved that the early diagnosis of a carcinoma of the prostate is a necessary prerequisite, because a radical total removal can only be curative when any metastases are absent. The comparative evaluation of the diagnostic methods proved the superiority of the nuclear medical examination. In 68% of the cases the roentgenologic examination led to correctly positive results. This investigation showed with 98% a high diagnostic specificity and therefore it should be applied in addition to scintiscanning in order to obtain supplementary information. The alkaline and the acid phosphatase offering an almost identical informative value resulted to be not useful for establishing an early diagnosis of skeletal metastases. It was found that the determination of the blood sedimentation rate and of the lactate dehydrogenase do also not render possible the early diagnosis of skeletal metastases. (orig./MG) [de

  2. Carcinoid tumor of the verumontanum (colliculus seminalis of the prostatic urethra with a coexisting prostatic adenocarcinoma: a case report

    Directory of Open Access Journals (Sweden)

    Werahera Priya N

    2010-01-01

    Full Text Available Abstract Introduction Urethral carcinoid tumors are very rare tumors with only four cases described in the literature. Case presentation We present the case of a 61-year-old man with a primary carcinoid tumor of the verumontanum (colliculis seminalis portion of the prostatic urethra with a coexisting prostatic adenocarcinoma. In addition to whole mount hematoxylin and eosin staining, special immunoperoxidase staining specific for chromogranin A, neuron specific enolase, synaptophysin, pan-cytokeratin and PSA, and a special combined staining for racemase (α-methyl CoA antigen and p63 antigen were performed. A review of the literature is included. A single focus of invasive prostatic adenocarcinoma was identified in the periphery of the mid-left, posterior quadrant of the prostate. Approximately 17 mm from this adenocarcinoma, within the verumontanum of the prostatic urethra, there was a 3 mm maximal dimension carcinoid tumor. Conclusion Based on different histological features and antigenic profiles, we concluded that the two tumors were distinct.

  3. Resveratrol Reduces Prostate Cancer Growth and Metastasis by Inhibiting the Akt/MicroRNA-21 Pathway

    Science.gov (United States)

    Sheth, Sandeep; Jajoo, Sarvesh; Kaur, Tejbeer; Mukherjea, Debashree; Sheehan, Kelly; Rybak, Leonard P.; Ramkumar, Vickram

    2012-01-01

    The consumption of foods containing resveratrol produces significant health benefits. Resveratrol inhibits cancer by reducing cell proliferation and metastasis and by inducing apoptosis. These actions could be explained by its ability to inhibit (ERK-1/2), Akt and suppressing the levels of estrogen and insulin growth factor -1 (IGF-1) receptor. How these processes are manifested into the antitumor actions of resveratrol is not clear. Using microarray studies, we show that resveratrol reduced the expression of various prostate-tumor associated microRNAs (miRs) including miR-21 in androgen-receptor negative and highly aggressive human prostate cancer cells, PC-3M-MM2. This effect of resveratrol was associated with reduced cell viability, migration and invasiveness. Additionally, resveratrol increased the expression of tumor suppressors, PDCD4 and maspin, which are negatively regulated by miR-21. Short interfering (si) RNA against PDCD4 attenuated resveratrol’s effect on prostate cancer cells, and similar effects were observed following over expression of miR-21 with pre-miR-21 oligonucleotides. PC-3M-MM2 cells also exhibited high levels of phospho-Akt (pAkt), which were reduced by both resveratrol and LY294002 (a PI3-kinase inhibitor). MiR-21 expression in these cells appeared to be dependent on Akt, as LY294002 reduced the levels of miR-21 along with a concurrent increase in PDCD4 expression. These in vitro findings were further corroborated in a severe combined immunodeficient (SCID) mouse xenograft model of prostate cancer. Oral administration of resveratrol not only inhibited the tumor growth but also decreased the incidence and number of metastatic lung lesions. These tumor- and metastatic-suppressive effects of resveratrol were associated with reduced miR-21 and pAkt, and elevated PDCD4 levels. Similar anti-tumor effects of resveratrol were observed in DU145 and LNCaP prostate cancer cells which were associated with suppression of Akt and PDCD4, but

  4. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

    DEFF Research Database (Denmark)

    Jiang, Nan; Hjorth-Jensen, Kim; Hekmat, Omid

    2015-01-01

    Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic app...

  5. Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer

    NARCIS (Netherlands)

    Oort, van I.M.; Witjes, J.A.; Kok, D.E.G.; Kiemeney, L.A.; Hulsbergen-van de Kaa, C.A.

    2008-01-01

    Previous studies suggest that maximum tumor diameter (MTD) is a predictor of recurrence in prostate cancer (PC). This study investigates the prognostic value of MTD for biochemical recurrence (BCR) in patients with PC, after radical prostatectomy (RP), with emphasis on high-risk localized prostate

  6. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

    International Nuclear Information System (INIS)

    Echchgadda, Ibtissam; Chang, Te-Hung; Sabbah, Ahmed; Bakri, Imad; Ikeno, Yuji; Hubbard, Gene B; Chatterjee, Bandana; Bose, Santanu

    2011-01-01

    Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further

  7. Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression.

    Directory of Open Access Journals (Sweden)

    Nitin Patel

    Full Text Available Prostate cancer (PCa is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT. Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC, a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC.

  8. Impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    Science.gov (United States)

    Chen, Zhe (Jay); Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-01-01

    Previous studies have shown that the procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations depends strongly on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al. (Int. J. Radiat. Oncol. Biol. Phys. 41, 1069–1077–1998) was used to characterize the edema evolutions observed previously during clinical PIB for prostate cancer. The concept of biologically effective dose (BED), taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not taken into account appropriately, can increase the cell survival and decrease the probability of local control of PIB. The edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life for radioactive decay and decreasing energy of the photons energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days

  9. The impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    International Nuclear Information System (INIS)

    Chen Zhe; Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-01-01

    Previous studies have shown that procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations strongly depends on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131 Cs, 125 I and 103 Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al (1998 Int. J. Radiat. Oncol. Biol. Phys. 41 1069-77) was used to characterize the edema evolutions previously observed during clinical PIB for prostate cancer. The concept of biologically effective dose, taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not appropriately taken into account, can increase the cell survival and decrease the probability of local control of PIB. The magnitude of an edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life of radioactive decay and decreasing photon energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125 I sources was less affected by edema than PIB using 131 Cs or 103 Pd sources due to the long radioactive decay half-life of 125 I. The effect of edema on PIB using 131 Cs or 103 Pd was similar. The effect of edema on 103 Pd PIB was slightly greater, even though the decay half-life of 103 Pd (17 days) is

  10. The promotion on cell growth of androgen-dependent prostate cancer by antimony via mimicking androgen activity.

    Science.gov (United States)

    Zhang, Changwen; Li, Penghao; Wen, Yingwu; Feng, Guowei; Liu, Yu; Zhang, Yangyi; Xu, Yong; Zhang, Zhihong

    2018-05-15

    Antimony is a widely used heavier pnictogens in industry, and its toxicity has been a matter of concern. Although previous studies have suggested that antimony may have the function as either a tumor suppressor or an oncogene in several cancers, the molecular basis underlying antimony-mediated transformation is still unclear. In the current study, we attempt to elucidate the potential role of antimony in the development of prostate cancer. Our results showed that the concentration of antimony was much higher in serum of prostate cancer patients, and was closely associated with poor outcome of patients who underwent radical prostatectomy. Additionally, low dose of antimony could promote proliferation and invasion of androgen-dependent prostate cancer cell line LNCaP cells in vitro and in vivo. The mechanistic studies demonstrated that exposure to antimony triggered the phosphorylation of androgen receptor (AR), which transcriptionally regulates the expression of androgen-related targets, including PSA and NKX3.1. Overall, our results unearthed that antimony could promote tumor growth by mimicking androgen activity in androgen-dependent prostate cancer cells. Therefore, these findings expanded our understanding on the molecular mechanism of antimony in tumorigenesis and tumor progression of prostate cancer, and it appears to be an inspiring strategy to restrain prostate cancer by inhibiting antimony-induced androgen-like effects. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Characterizing components of the Saw Palmetto Berry Extract (SPBE) on prostate cancer cell growth and traction

    International Nuclear Information System (INIS)

    Scholtysek, Carina; Krukiewicz, Aleksandra A.; Alonso, Jose-Luis; Sharma, Karan P.; Sharma, Pal C.; Goldmann, Wolfgang H.

    2009-01-01

    Saw Palmetto Berry Extract (SPBE) is applied for prostate health and treatment of urinary tract infections, nonbacterial prostitis and Benign Prostatic Hyperplasia (BPH) in man. An assumption is that SPBE affects tumor cell progression and migration in breast and prostate tissue. In this work, DU-145 cells were used to demonstrate that SPBE and its sterol components, β-sitosterol and stigmasterol, inhibit prostate cancer growth by increasing p53 protein expression and also inhibit carcinoma development by decreasing p21 and p27 protein expression. In the presence of cholesterol, these features are not only reversed but increased significantly. The results show for the first time the potential of SPBE, β-sitosterol and stigmasterol as potential anti-tumor agents. Since the protein p53 is also regarded as nuclear matrix protein facilitating actin cytoskeletal binding, 2D tractions were measured. The cell adhesion strength in the presence of SPBE, β-sitosterol and cholesterol and the observation was that the increase in p53 expression triggered an increase in the intracellular force generation. The results suggest a dual function of p53 in cells.

  12. Characterizing components of the Saw Palmetto Berry Extract (SPBE) on prostate cancer cell growth and traction.

    Science.gov (United States)

    Scholtysek, Carina; Krukiewicz, Aleksandra A; Alonso, José-Luis; Sharma, Karan P; Sharma, Pal C; Goldmann, Wolfgang H

    2009-02-13

    Saw Palmetto Berry Extract (SPBE) is applied for prostate health and treatment of urinary tract infections, nonbacterial prostitis and Benign Prostatic Hyperplasia (BPH) in man. An assumption is that SPBE affects tumor cell progression and migration in breast and prostate tissue. In this work, DU-145 cells were used to demonstrate that SPBE and its sterol components, beta-sitosterol and stigmasterol, inhibit prostate cancer growth by increasing p53 protein expression and also inhibit carcinoma development by decreasing p21 and p27 protein expression. In the presence of cholesterol, these features are not only reversed but increased significantly. The results show for the first time the potential of SPBE, beta-sitosterol and stigmasterol as potential anti-tumor agents. Since the protein p53 is also regarded as nuclear matrix protein facilitating actin cytoskeletal binding, 2D tractions were measured. The cell adhesion strength in the presence of SPBE, beta-sitosterol and cholesterol and the observation was that the increase in p53 expression triggered an increase in the intracellular force generation. The results suggest a dual function of p53 in cells.

  13. In silico modeling for tumor growth visualization.

    Science.gov (United States)

    Jeanquartier, Fleur; Jean-Quartier, Claire; Cemernek, David; Holzinger, Andreas

    2016-08-08

    Cancer is a complex disease. Fundamental cellular based studies as well as modeling provides insight into cancer biology and strategies to treatment of the disease. In silico models complement in vivo models. Research on tumor growth involves a plethora of models each emphasizing isolated aspects of benign and malignant neoplasms. Biologists and clinical scientists are often overwhelmed by the mathematical background knowledge necessary to grasp and to apply a model to their own research. We aim to provide a comprehensive and expandable simulation tool to visualizing tumor growth. This novel Web-based application offers the advantage of a user-friendly graphical interface with several manipulable input variables to correlate different aspects of tumor growth. By refining model parameters we highlight the significance of heterogeneous intercellular interactions on tumor progression. Within this paper we present the implementation of the Cellular Potts Model graphically presented through Cytoscape.js within a Web application. The tool is available under the MIT license at https://github.com/davcem/cpm-cytoscape and http://styx.cgv.tugraz.at:8080/cpm-cytoscape/ . In-silico methods overcome the lack of wet experimental possibilities and as dry method succeed in terms of reduction, refinement and replacement of animal experimentation, also known as the 3R principles. Our visualization approach to simulation allows for more flexible usage and easy extension to facilitate understanding and gain novel insight. We believe that biomedical research in general and research on tumor growth in particular will benefit from the systems biology perspective.

  14. ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0277 TITLE: ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr...Rohit Bose CONTRACTING ORGANIZATION: Sloan Kettering Institute for Cancer Research New York NY 10065 REPORT DATE: October 2017 TYPE OF REPORT...4. TITLE AND SUBTITLE ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0277 5c

  15. Vector-based RNA interference against vascular endothelial growth factor-A significantly limits vascularization and growth of prostate cancer in vivo.

    Science.gov (United States)

    Wannenes, Francesca; Ciafré, Silvia Anna; Niola, Francesco; Frajese, Gaetano; Farace, Maria Giulia

    2005-12-01

    RNA interference technology is emerging as a very potent tool to obtain a cellular knockdown of a desired gene. In this work we used vector-based RNA interference to inhibit vascular endothelial growth factor (VEGF) expression in prostate cancer in vitro and in vivo. We demonstrated that transduction with a plasmid carrying a small interfering RNA targeting all isoforms of VEGF, dramatically impairs the expression of this growth factor in the human prostate cancer cell line PC3. As a consequence, PC3 cells loose their ability to induce one of the fundamental steps of angiogenesis, namely the formation of a tube-like network in vitro. Most importantly, our "therapeutic" vector is able to impair tumor growth rate and vascularization in vivo. We show that a single injection of naked plasmid in developing neoplastic mass significantly decreases microvessel density in an androgen-refractory prostate xenograft and is able to sustain a long-term slowing down of tumor growth. In conclusion, our results confirm the basic role of VEGF in the angiogenic development of prostate carcinoma, and suggest that the use of our vector-based RNA interference approach to inhibit angiogenesis could be an effective tool in view of future gene therapy applications for prostate cancer.

  16. Triparanol suppresses human tumor growth in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Bi, Xinyu [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China); Han, Xingpeng [Department of Pathology, Tianjin Chest Hospital, Tianjin 300051 (China); Zhang, Fang [Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, Zhejiang (China); He, Miao [Life Sciences School, Sun Yat-sen University, Guangzhou 510275 (China); Zhang, Yi [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhi, Xiu-Yi, E-mail: xiuyizhi@yahoo.com.cn [Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhao, Hong, E-mail: zhaohong9@sina.com [Department of Abdominal Surgical Oncology, Lab of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021 (China)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Demonstrate Triparanol can block proliferation in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrate Triparanol can induce apoptosis in multiple cancer cells. Black-Right-Pointing-Pointer Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. Black-Right-Pointing-Pointer Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  17. Triparanol suppresses human tumor growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Bi, Xinyu; Han, Xingpeng; Zhang, Fang; He, Miao; Zhang, Yi; Zhi, Xiu-Yi; Zhao, Hong

    2012-01-01

    Highlights: ► Demonstrate Triparanol can block proliferation in multiple cancer cells. ► Demonstrate Triparanol can induce apoptosis in multiple cancer cells. ► Proved Triparanol can inhibit Hedgehog signaling in multiple cancer cells. ► Demonstrated Triparanol can impede tumor growth in vivo in mouse xenograft model. -- Abstract: Despite the improved contemporary multidisciplinary regimens treating cancer, majority of cancer patients still suffer from adverse effects and relapse, therefore posing a significant challenge to uncover more efficacious molecular therapeutics targeting signaling pathways central to tumorigenesis. Here, our study have demonstrated that Triparanol, a cholesterol synthesis inhibitor, can block proliferation and induce apoptosis in multiple human cancer cells including lung, breast, liver, pancreatic, prostate cancer and melanoma cells, and growth inhibition can be rescued by exogenous addition of cholesterol. Remarkably, we have proved Triparanol can significantly repress Hedgehog pathway signaling in these human cancer cells. Furthermore, study in a mouse xenograft model of human lung cancer has validated that Triparanol can impede tumor growth in vivo. We have therefore uncovered Triparanol as potential new cancer therapeutic in treating multiple types of human cancers with deregulated Hedgehog signaling.

  18. The expression of receptors for estrogen and epithelial growth factor in the male rabbit prostate and prostatic urethra following castration

    DEFF Research Database (Denmark)

    Bødker, A; Balslev, E; Iversen, H G

    1997-01-01

    In the lower urinary tract of the male rabbit, estrogen receptors (ERs) are restricted to the urethra and the prostatic stroma. At present, the function of ERs in these tissues is not known. Epithelial growth factor (EGF) stimulates proliferation of epidermal and epithelial tissues, and several...... were included as controls. In the control group, ERs were found in the urothelial lining and lamina propria of the prostatic urethra, and in the prostatic stroma. EGF receptors were demonstrated in the epithelial lining of the prostatic urethra and the glandular epithelium of the prostate. Following...... castration, the expression of ERs, assessed as the increase in the number of positively stained specimens, increased significantly in the lamina propria of the prostatic urethra and the prostatic stroma. EGF receptor expression increased significantly in the epithelial lining of the prostatic urethra...

  19. Correlation of bone scintigraphy findings and tumor markers during follow-up prostate cancer

    International Nuclear Information System (INIS)

    Aizawa, Taku

    1996-01-01

    In the last 9 years, 217 patients with prostate cancer were treated at our department. Of these patients 153 cases treated by estrogen therapy were followed up by bone scintigraphy and tumor marker examinations (prostate specific antigen [PSA], prostate acid phosphatase [PAP], gamma-seminoprotein [γ-SM) . The correlation between changes on bone scintigrams and synchronous changes in tumor markers was evaluated retrospectively. In cases in which bone metastasis was not recognized on bone scintigrams before treatment, changes of tumor markers corresponded with subsequent changes on bone scintigrams in more than 90%. However, in cases with bone metastasis on bone scintigrams before treatment, changes of bone scintigrams and changes of tumor markers corresponded in only 55% of cases. Changes of bone scintigrams do not always correspond with changes of tumor markers. However, by taking into consideration physical examination parameters such as bone pain, in addition to changes of tumor markers, most changes on bone scintigrams can be anticipated. The reasons for lack of correspondence between changes of bone scintigrams and changes of tumor markers may be, changes of tumor markers are more rapid than the changes on bone scintigram, some poorly differentiated cancers do not have increased tumor marker levels and bone scintigrams do not demonstrate soft tissue involvement. In the follow-up of patients with prostate cancer, it is not necessary to perform bone scintigraphy regularly at 3-month intervals. Bone scintigraphy should only be performed when serum levels of tumor markers increase or bone pain appears. (author)

  20. Information dynamics in carcinogenesis and tumor growth.

    Science.gov (United States)

    Gatenby, Robert A; Frieden, B Roy

    2004-12-21

    The storage and transmission of information is vital to the function of normal and transformed cells. We use methods from information theory and Monte Carlo theory to analyze the role of information in carcinogenesis. Our analysis demonstrates that, during somatic evolution of the malignant phenotype, the accumulation of genomic mutations degrades intracellular information. However, the degradation is constrained by the Darwinian somatic ecology in which mutant clones proliferate only when the mutation confers a selective growth advantage. In that environment, genes that normally decrease cellular proliferation, such as tumor suppressor or differentiation genes, suffer maximum information degradation. Conversely, those that increase proliferation, such as oncogenes, are conserved or exhibit only gain of function mutations. These constraints shield most cellular populations from catastrophic mutator-induced loss of the transmembrane entropy gradient and, therefore, cell death. The dynamics of constrained information degradation during carcinogenesis cause the tumor genome to asymptotically approach a minimum information state that is manifested clinically as dedifferentiation and unconstrained proliferation. Extreme physical information (EPI) theory demonstrates that altered information flow from cancer cells to their environment will manifest in-vivo as power law tumor growth with an exponent of size 1.62. This prediction is based only on the assumption that tumor cells are at an absolute information minimum and are capable of "free field" growth that is, they are unconstrained by external biological parameters. The prediction agrees remarkably well with several studies demonstrating power law growth in small human breast cancers with an exponent of 1.72+/-0.24. This successful derivation of an analytic expression for cancer growth from EPI alone supports the conceptual model that carcinogenesis is a process of constrained information degradation and that malignant

  1. Molecular Ultrasound Imaging of Early Vascular Response in Prostate Tumors Irradiated with Carbon Ions

    Directory of Open Access Journals (Sweden)

    Moritz Palmowski

    2009-09-01

    Full Text Available Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1 and of αvβ3-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of αvβ3-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of αvβ3-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and αvβ3-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.

  2. The Histone Deacetylase Inhibitor, Vorinostat, Reduces Tumor Growth at the Metastatic Bone Site and Associated Osteolysis, but Promotes Normal Bone Loss

    OpenAIRE

    Pratap, Jitesh; Akech, Jacqueline; Wixted, John J.; Szabo, Gabriela; Hussain, Sadiq; McGee-Lawrence, Meghan E.; Li, Xiaodong; Bedard, Krystin; Dhillon, Robinder J.; van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.; Westendorf, Jennifer J.; Lian, Jane B.

    2010-01-01

    Vorinostat, an oral histone deacetylase inhibitor with anti-tumor activity, is in clinical trials for hematological and solid tumors that metastasize and compromise bone structure. Consequently, there is a requirement to establish the effects of vorinostat on tumor growth within bone. Breast (MDA-231) and prostate (PC3) cancer cells were injected into tibias of SCID/NCr mice and the effects of vorinostat on tumor growth and osteolytic disease were assessed by radiography, μCT, histological an...

  3. Prostate tumor DNA methylation is associated with cigarette smoking and adverse prostate cancer outcomes.

    Science.gov (United States)

    Shui, Irene M; Wong, Chao-Jen; Zhao, Shanshan; Kolb, Suzanne; Ebot, Ericka M; Geybels, Milan S; Rubicz, Rohina; Wright, Jonathan L; Lin, Daniel W; Klotzle, Brandy; Bibikova, Marina; Fan, Jian-Bing; Ostrander, Elaine A; Feng, Ziding; Stanford, Janet L

    2016-07-15

    DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies

  4. Cells competition in tumor growth poroelasticity

    Science.gov (United States)

    Fraldi, Massimiliano; Carotenuto, Angelo R.

    2018-03-01

    Growth of biological tissues has been recently treated within the framework of Continuum Mechanics, by adopting heterogeneous poroelastic models where the interaction between soft matrix and interstitial fluid flow is coupled with inelastic effects ad hoc introduced to simulate the macroscopic volumetric growth determined by cells division, cells growth and extracellular matrix changes occurring at the micro-scale level. These continuum models seem to overcome some limitations intrinsically associated to other alternative approaches based on mass balances in multiphase systems, because the crucial role played by residual stresses accompanying growth and nutrients walkway is preserved. Nevertheless, when these strategies are applied to analyze solid tumors, mass growth is usually assigned in a prescribed form that essentially copies the in vitro measured intrinsic growth rates of the cell species. As a consequence, some important cell-cell dynamics governing mass evolution and invasion rates of cancer cells, as well as their coupling with feedback mechanisms associated to in situ stresses, are inevitably lost and thus the spatial distribution and the evolution with time of the growth inside the tumor -which would be results rather than inputs- are forced to enter in the model simply as data. In order to solve this paradox, it is here proposed an enhanced multi-scale poroelastic model undergoing large deformations and embodying inelastic growth, where the net growth terms directly result from the "interspecific" predator-prey (Volterra/Lotka-like) competition occurring at the micro-scale level between healthy and abnormal cell species. In this way, a system of fully-coupled non-linear PDEs is derived to describe how the fight among cell species to grab the available common resources, stress field, pressure gradients, interstitial fluid flows driving nutrients and inhomogeneous growth all simultaneously interact to decide the tumor fate.

  5. Big Bang Tumor Growth and Clonal Evolution.

    Science.gov (United States)

    Sun, Ruping; Hu, Zheng; Curtis, Christina

    2018-05-01

    The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

  6. Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression.

    Science.gov (United States)

    Ahearn, Thomas U; Tchrakian, Nairi; Wilson, Kathryn M; Lis, Rosina; Nuttall, Elizabeth; Sesso, Howard D; Loda, Massimo; Giovannucci, Edward; Mucci, Lorelei A; Finn, Stephen; Shui, Irene M

    2016-06-01

    Prostate cancer metastases preferentially target bone, and the calcium-sensing receptor (CaSR) may play a role in promoting this metastatic progression. We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer. A validated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer. The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study. We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009. Participants were followed up or cancer-specific mortality or development of metastatic disease. On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0). Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.

  7. Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.

    Science.gov (United States)

    Deng, X; Shao, G; Zhang, H-T; Li, C; Zhang, D; Cheng, L; Elzey, B D; Pili, R; Ratliff, T L; Huang, J; Hu, C-D

    2017-03-02

    Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

  8. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mayu O Frank

    2010-09-01

    Full Text Available Studies of patients with paraneoplastic neurologic disorders (PND have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC vaccine.We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002, decrease in prostate specific antigen (PSA slope (p = 0.016, and a two-fold increase in PSA doubling time (p = 0.003 were identified when we compared data before and after vaccination.An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.ClinicalTrials.gov NCT00289341.

  9. Interleukin-30: A novel microenvironmental hallmark of prostate cancer progression.

    Science.gov (United States)

    Di Carlo, Emma

    2014-01-01

    Metastatic prostate cancer is a leading cause of cancer-related death in men worldwide. We have recently discovered that IL-30 shapes the microenvironment of prostate cancer and tumor-draining lymph nodes to favor tumor progression. IL-30 supports tumor growth in vitro, and IL-30 expression in prostate cancer patients is associated with high tumor grade and metastatic stage of disease. Thus, IL-30 may constitute a valuable target for modern therapeutic approaches to hamper prostate cancer progression.

  10. Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment

    Directory of Open Access Journals (Sweden)

    Vessella Robert L

    2006-01-01

    Full Text Available Abstract Background After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL, a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment. Methods Intra-tibial injections of LuCaP 23.1 cells were used to generate tumors in the bone environment, and animals were treated with ZOL, docetaxel, or a combination of these. Effects on bone and tumor were evaluated by measurements of bone mineral density and histomorphometrical analysis. Results ZOL decreased proliferation of LuCaP 23.1 in the bone environment, while docetaxel at a dose that effectively inhibited growth of subcutaneous tumors did not show any effects in the bone environment. The combination of the drugs significantly inhibited the growth of LuCaP 23.1 tumors in the bone. Conclusion In conclusion, the use of the osteolysis-inhibitory agent ZOL in combination with docetaxel inhibits growth of prostate tumors in bone and represents a potential treatment option.

  11. Evaluation of Tumor Heterogeneity of Prostate Carcinoma by Flow- and Image DNA Cytometry and Histopathological Grading

    Directory of Open Access Journals (Sweden)

    Naining Wang

    2000-01-01

    Full Text Available Background. Heterogeneity of prostate carcinoma is one of the reasons for pretreatment underestimation of tumor aggressiveness. We studied tumor heterogeneity and the probability of finding the highest tumor grade and DNA aneuploidy with relation to the number of biopsies. Material and methods. Specimens simulating core biopsies from five randomly selected tumor areas from each of 16 Böcking’s grade II and 23 grade III prostate carcinomas were analyzed for tumor grade and DNA ploidy by flow‐ and fluorescence image cytometry (FCM, FICM. Cell cycle composition was measured by FCM. Results. By determination of ploidy and cell cycle composition, morphologically defined tumors can further be subdivided. Heterogeneity of tumor grade and DNA ploidy (FCM was 54% and 50%. Coexistence of diploid tumor cells in aneuploid specimens represents another form of tumor heterogeneity. The proportion of diploid tumor cells decreased significantly with tumor grade and with increase in the fraction of proliferating cell of the aneuploid tumor part. The probability of estimating the highest tumor grade or aneuploidy increased from 40% for one biopsy to 95% for 5 biopsies studied. By combining the tumor grade with DNA ploidy, the probability of detecting a highly aggressive tumor increased from 40% to 70% and 90% for one and two biopsies, respectively. Conclusion. Specimens of the size of core biopsies can be used for evaluation of DNA ploidy and cell cycle composition. Underestimation of aggressiveness of prostate carcinoma due to tumor heterogeneity is minimized by simultaneous study of the tumor grade and DNA ploidy more than by increasing the number of biopsies. The biological significance of coexistent diploid tumor cell in aneuploid lesions remains to be evaluated.

  12. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Liang Y

    2016-05-01

    growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells. Our findings suggest that cholesterol biosynthesis inhibitors such as RO, when used in combination with commonly used chemotherapeutic drugs or ERβ specific ligands, could represent a novel therapeutic approach to prevent the growth of prostate cancer tumors. Keywords: prostate cancer, cholesterol biosynthesis inhibitor, cell viability, xenograft, castration resistant

  13. Rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel.

    Science.gov (United States)

    Bhardwaj, Sharonlin; Varma, Seema

    2018-03-01

    Tumor lysis syndrome is a serious and sometimes lethal complication of cancer treatment that is comprised of a set of metabolic disturbances along with clinical manifestations. Initiating chemotherapy in bulky, rapidly proliferating tumors causes rapid cell turnover that in turn releases metabolites into circulation that give rise to metabolic derangements that can be dangerous. This syndrome is usually seen in high-grade hematological malignancies. Less commonly, tumor lysis syndrome can present in solid tumors and even rarely in genitourinary tumors. In this report, the authors describe a specific case of tumor lysis syndrome in a patient with metastatic prostate cancer following treatment with docetaxel.

  14. Differential splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities

    Science.gov (United States)

    2017-12-01

    populations: contributing factor in prostate cancer disparities? PRINCIPAL INVESTIGATOR: Norman H Lee, PhD CONTRACTING ORGANIZATION: George Washington...splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities? 5b...American (AA) versus Caucasian American (CA) prostate cancer (PCa). We focused our efforts on two oncogenes, phosphatidylinositol-4,5-bisphosphate 3

  15. Combination of α-Tomatine and Curcumin Inhibits Growth and Induces Apoptosis in Human Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Huarong Huang

    Full Text Available α-Tomatine is a glycoalkaloid found in tomatoes and curcumin is a major yellow pigment of turmeric. In the present study, the combined effect of these two compounds on prostate cancer cells was studied. Treatment of different prostate cancer cells with curcumin or α-tomatine alone resulted in growth inhibition and apoptosis in a concentration-dependent manner. Combinations of α-tomatine and curcumin synergistically inhibited the growth and induced apoptosis in prostate cancer PC-3 cells. Effects of the α-tomatine and curcumin combination were associated with synergistic inhibition of NF-κB activity and a potent decrease in the expression of its downstream gene Bcl-2 in the cells. Moreover, strong decreases in the levels of phospho-Akt and phosphor-ERK1/2 were found in PC-3 cells treated with α-tomatine and curcumin in combination. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with α-tomatine and curcumin. Combination of α-tomatine and curcumin more potently inhibited the growth of PC-3 tumors than either agent alone. Results from the present study indicate that α-tomatine in combination with curcumin may be an effective strategy for inhibiting the growth of prostate cancer.

  16. Essential contribution of tumor-derived perlecan to epidermal tumor growth and angiogenesis

    DEFF Research Database (Denmark)

    Jiang, Xinnong; Multhaupt, Hinke; Chan, En

    2004-01-01

    As a major heparan sulfate proteoglycan (PG) in basement membranes, perlecan has been linked to tumor invasion, metastasis, and angiogenesis. Here we produced epidermal tumors in immunocompromised rats by injection of mouse RT101 tumor cells. Tumor sections stained with species-specific perlecan...... factor. In vivo, antisense perlecan-transfected cells generated no tumors, whereas untransfected and vector-transfected cells formed tumors with obvious neovascularization, suggesting that tumor perlecan rather than host perlecan controls tumor growth and angiogenesis....

  17. A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats.

    Science.gov (United States)

    Allan, George; Lai, Muh-Tsann; Sbriscia, Tifanie; Linton, Olivia; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Dodds, Robert; Fiordeliso, James; Lanter, James; Sui, Zhihua; Lundeen, Scott

    2007-01-01

    The pharmacological activity of JNJ-26146900 is described. JNJ-26146900 is a nonsteroidal androgen receptor (AR) ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the androgen antagonist bicalutamide (Casodex). In intact rats, JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of bicalutamide. JNJ-26146900 prevented prostate tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed tumor growth significantly in a CWR22-LD1 mouse xenograft model of human prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg, JNJ-26146900 significantly reduced castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of hydroxyapatite to 166+/-26mg/cm(3) following orchidectomy, and was maintained at 194+/-20mg/cm(3) with JNJ-26146900 treatment (Pselective androgen receptor modulators (SARMs) have the potential for anabolic effects on bone and muscle while maintaining therapeutic efficacy in prostate cancer.

  18. Cellular Angiofibroma of the Prostate: A Rare Tumor in an Unusual Location

    Directory of Open Access Journals (Sweden)

    Inez Wyn

    2014-01-01

    Full Text Available We report the unusual occurrence of a cellular angiofibroma in prostatic tissue. In this case, a 84-year-old man presented in the emergency room with urinary retention. Ultrasound revealed an enlarged prostate, which was suggestive for benign prostatic hyperplasia. The patient was treated with a Millin retropubic prostatectomy. Macroscopically the prostate contained multiple circumscribed nodules. Microscopic examination of the tumor showed the appearance of cellular angiofibroma, consisting of bland spindle cells and prominent, hyalinized vessels. The diagnosis was supported by FISH, which revealed monoallelic loss of RB1/13q14 region, as seen in spindle cell lipoma, (extra- mammary myofibroblastoma, and cellular angiofibroma. Cellular angiofibromas are rare, benign soft tissue tumours and were never reported in the prostatic gland.

  19. HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling

    Directory of Open Access Journals (Sweden)

    Choi Chan

    2010-05-01

    Full Text Available Abstract Background Androgen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained. Results In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling. Conclusions Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.

  20. Building a high-resolution T2-weighted MR-based probabilistic model of tumor occurrence in the prostate.

    Science.gov (United States)

    Nagarajan, Mahesh B; Raman, Steven S; Lo, Pechin; Lin, Wei-Chan; Khoshnoodi, Pooria; Sayre, James W; Ramakrishna, Bharath; Ahuja, Preeti; Huang, Jiaoti; Margolis, Daniel J A; Lu, David S K; Reiter, Robert E; Goldin, Jonathan G; Brown, Matthew S; Enzmann, Dieter R

    2018-02-19

    We present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer. In our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space. Probabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate. We present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies.

  1. Targeting MEK5 Enhances Radiosensitivity of Human Prostate Cancer and Impairs Tumor-Associated Angiogenesis

    Science.gov (United States)

    2016-09-01

    analysis of tumor necrosis factor - alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype...AWARD NUMBER: W81XWH-15-1-0296 TITLE: Targeting MEK5 Enhances Radiosensitivity of Human Prostate Cancer and Impairs Tumor - Associated...Cancer and Impairs Tumor -Associated Angiogenesis 5b. GRANT NUMBER W81XWH-15-1-0296 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER

  2. Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice

    International Nuclear Information System (INIS)

    Hillerdal, Victoria; Ramachandran, Mohanraj; Leja, Justyna; Essand, Magnus

    2014-01-01

    Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer. We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves). PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice. Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer

  3. Adenovirus E2F1 Overexpression Sensitizes LNCaP and PC3 Prostate Tumor Cells to Radiation In Vivo

    International Nuclear Information System (INIS)

    Udayakumar, Thirupandiyur S.; Stoyanova, Radka; Hachem, Paul; Ahmed, Mansoor M.; Pollack, Alan

    2011-01-01

    Purpose: We previously showed that E2F1 overexpression radiosensitizes prostate cancer cells in vitro. Here, we demonstrate the radiosensitization efficacy of adenovirus (Ad)-E2F1 infection in growing (orthotopic) LNCaP and (subcutaneous) PC3 nude mice xenograft tumors. Methods and Materials: Ad-E2F1 was injected intratumorally in LNCaP (3 x 10 8 plaque-forming units [PFU]) and PC3 (5 x 10 8 PFU) tumors treated with or without radiation. LNCaP tumor volumes (TV) were measured by magnetic resonance imaging, caliper were used to measure PC3 tumors, and serum prostate-specific antigen (PSA) levels were determined by enzyme-linked immunosorbent assay. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, and key proteins involved in cell death signaling were analyzed by Western blotting. Results: Intracellular overexpression of Ad-E2F1 had a significant effect on the regression of TV and reduction of PSA levels relative to that of adenoviral luciferase (Ad-Luc)-infected control. The in vivo regressing effect of Ad-E2F1 on LNCaP tumor growth was significant (PSA, 34 ng/ml; TV, 142 mm 3 ) compared to that of Ad-Luc control (PSA, 59 ng/ml; TV, 218 mm 3 ; p 3 to Ad-Luc+RT/PSA, 42 ng/ml, and TV, 174 mm 3 , respectively; p <0.05). For PC3 tumors, the greatest effect was observed with Ad-E2F1 infection alone; there was little or no effect when radiotherapy (RT) was combined. However, addition of RT enhanced the level of in situ apoptosis in PC3 tumors. Molecularly, addition of Ad-E2F1 in a combination treatment abrogated radiation-induced BCL-2 protein expression and was associated with an increase in activated BAX, and together they caused a potent radiosensitizing effect, irrespective of p53 and androgen receptor functional status. Conclusions: We show here for the first time that ectopic overexpression of E2F1 in vivo, using an adenoviral vector, significantly inhibits orthotopic p53 wild-type LNCaP tumors and subcutaneous

  4. Detection of Tumor Markers in Prostate Cancer and Comparison of Sensitivity between Real Time and Nested PCR

    OpenAIRE

    Matsuoka, Takayuki; Shigemura, Katsumi; Yamamichi, Fukashi; Fujisawa, Masato; Kawabata, Masato; Shirakawa, Toshiro

    2012-01-01

    The objective of this study is to investigate and compare the sensitivity in conventional PCR, quantitative real time PCR, nested PCR and western blots for detection of prostate cancer tumor markers using prostate cancer (PCa) cells. We performed conventional PCR, quantitative real time PCR, nested PCR, and western blots using 5 kinds of PCa cells. Prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), and androgen receptor (AR) were compared for their detection sensitivi...

  5. Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer.

    Science.gov (United States)

    Hadaschik, Boris; Su, Yun; Huter, Eva; Ge, Yingzi; Hohenfellner, Markus; Beckhove, Philipp

    2012-04-01

    Immunotherapy is a promising approach in an effort to control castration resistant prostate cancer. We characterized tumor antigen reactive T cells in patients with prostate cancer and analyzed the suppression of antitumor responses by regulatory T cells. Peripheral blood samples were collected from 57 patients with histologically confirmed prostate cancer, 8 patients with benign prostatic hyperplasia and 16 healthy donors. Peripheral blood mononuclear cells were isolated and antigen specific interferon-γ secretion of isolated T cells was analyzed by enzyme-linked immunospot assay. T cells were functionally characterized and T-cell responses before and after regulatory T-cell depletion were compared. As test tumor antigens, a panel of 11 long synthetic peptides derived from a total of 8 tumor antigens was used, including prostate specific antigen and prostatic acid phosphatase. In patients with prostate cancer we noted a 74.5% effector T-cell response rate compared with only 25% in patients with benign prostatic hyperplasia and 31% in healthy donors. In most patients 2 or 3 tumor antigens were recognized. Comparing various disease stages there was a clear increase in the immune response against prostate specific antigens from intermediate to high risk tumors and castration resistant disease. Regulatory T-cell depletion led to a significant boost in effector T-cell responses against prostate specific antigen and prostatic acid phosphatase. Tumor specific effector T cells were detected in most patients with prostate cancer, especially those with castration resistant prostate cancer. Since effector T-cell responses against prostate specific antigens strongly increased after regulatory T-cell depletion, our results indicate that immunotherapy efficacy could be enhanced by decreasing regulatory T cells. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  6. Impact of pneumoperitoneum on tumor growth.

    Science.gov (United States)

    Lécuru, F; Agostini, A; Camatte, S; Robin, F; Aggerbeck, M; Jaïs, J P; Vilde, F; Taurelle, R

    2002-08-01

    To compare intraperitoneal tumor growth after CO2 laparoscopy (L), gasless laparoscopy (GL), midline laparotomy (ML), and general anesthesia (GA) as a control. A prospective randomized trial was carried out in nude rats. A carcinomatosis was obtained by intraperitoneal injection of either one of the two human ovarian cancer cell lines IGR-OV1 or NIH:OVCAR-3. Rats secondly underwent randomly different kind of procedures: CO2 L (8 mmHg, 60 min), GL (traction by a balloon for 60 min), ML (bowel removed and let on a mesh for 60 min), or GA. The rats were finally killed 10 or 35 days after surgery (respectively in IGR-OV1, or NIH:OVCAR-3 models). Tumor growth was assessed by the weight of the omental metastasis and MIB1 immunostaining. Peritoneal dissemination as well as abdominal wall metastases were assessed by pathological examination. Statistical analysis used the chi-square test (or Fisher exact test) and Bonferroni method for multiple comparison between groups. Fifteen rats were included in each group. Mean omental weight was significantly increased after surgery (3.1 to 5.6 g), when compared to control (2.4 g), but no significant difference was recorded between the three surgical accesses. MIB1 immunostaining was poor in the PNP group (37%), whereas it was higher after midline laparotomy (51%), but the difference was not significant (p = 0.07). Similarly, no significant variation was recorded in the NIH:OVCAR-3 model for omental weight or MIB1 staining. CO2 pneumoperitoneum significantly increased right diaphragmatic dome involvement in the NIH:OVCAR-3 model. Abdominal wall metastases were significantly more frequent after surgery when compared to the control group, but no significant difference could be demonstrated between surgical groups in each model. In these solid tumor models, CO2 pneumoperitoneum had no deleterious effect on tumor growth when compared to gasless laparoscopy or midline laparotomy.

  7. Imaging of bioluminescent LNCaP-luc-M6 tumors: a new animal model for the study of metastatic human prostate cancer.

    Science.gov (United States)

    Scatena, Caroline D; Hepner, Mischa A; Oei, Yoko A; Dusich, Joan M; Yu, Shang-Fan; Purchio, Tony; Contag, Pamela R; Jenkins, Darlene E

    2004-05-15

    Animal experiments examining hormone-sensitive metastatic prostate cancer using the human LNCaP cell line have been limited to endpoint analyses. To permit longitudinal studies, we generated a luciferase-expressing cell line and used bioluminescent imaging (BLI) to non-invasively monitor the in vivo growth of primary LNCaP tumors and metastasis. LNCaP.FGC cells were transfected to constitutively express firefly luciferase. LNCaP-luc-M6 cells were tested for bioluminescent signal intensity and hormone responsiveness in vitro. The cells were implanted in subcutaneous and orthotopic sites in SCID-bg mice and imaged over time. The LNCaP-luc-M6 cells formed subcutaneous and orthotopic tumors in SCID-bg mice, and nearly all tumor-bearing animals developed pulmonary metastases. Early detection and temporal growth of primary tumors and metastatic lesions was successfully monitored by BLI. The LNCaP-luc-M6 cell line is a bioluminescent, hormone-sensitive prostate cancer cell line applicable for BLI studies to non-invasively monitor subcutaneous and orthotopic prostate tumor growth and metastasis in vivo. Copyright 2004 Wiley-Liss, Inc.

  8. Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Pedersen, S B

    1997-01-01

    PURPOSE: To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate.MA...

  9. Differential Patterns of Large Tumor Antigen-Specific Immune Responsiveness in Patients with BK Polyomavirus-Positive Prostate Cancer or Benign Prostatic Hyperplasia

    Science.gov (United States)

    Sais, Giovanni; Wyler, Stephen; Hudolin, Tvrtko; Banzola, Irina; Mengus, Chantal; Bubendorf, Lukas; Wild, Peter J.; Hirsch, Hans H.; Sulser, Tullio; Spagnoli, Giulio C.

    2012-01-01

    The role of the polyomavirus BK (BKV) large tumor antigen (L-Tag) as a target of immune response in patients with prostate cancer (PCa) has not been investigated thus far. In this study, we comparatively analyzed humoral and cellular L-Tag-specific responsiveness in age-matched patients bearing PCa or benign prostatic hyperplasia, expressing or not expressing BKV L-Tag-specific sequences in their tissue specimens, and in non-age-matched healthy individuals. Furthermore, results from patients with PCa were correlated to 5-year follow-up clinical data focusing on evidence of biochemical recurrence (BR) after surgery (prostate specific antigen level of ≥0.2 ng/ml). In peripheral blood mononuclear cells (PBMC) from patients with PCa with evidence of BR and BKV L-Tag-positive tumors, stimulation with peptides derived from the BKV L-Tag but not those derived from Epstein-Barr virus, influenza virus, or cytomegalovirus induced a peculiar cytokine gene expression profile, characterized by high expression of interleukin-10 (IL-10) and transforming growth factor β1 and low expression of gamma interferon genes. This pattern was confirmed by protein secretion data and correlated with high levels of anti-BKV L-Tag IgG. Furthermore, in PBMC from these PCa-bearing patients, L-Tag-derived peptides significantly expanded an IL-10-secreting CD4+ CD25+(high) CD127− FoxP3+ T cell population with an effector memory phenotype (CD103+) capable of inhibiting proliferation of autologous anti-CD3/CD28-triggered CD4+ CD25− T cells. Collectively, our findings indicate that potentially tolerogenic features of L-Tag-specific immune response are significantly associated with tumor progression in patients with BKV+ PCa. PMID:22647697

  10. Focal degeneration of basal cells and the resultant auto-immunoreactions: a novel mechanism for prostate tumor progression and invasion.

    Science.gov (United States)

    Man, Yan-Gao; Gardner, William A

    2008-01-01

    ) significantly lower p63 expression; (3) significantly higher apoptosis; and (4) significantly higher leukocyte infiltration and stromal reactions. Compared to their counterparts distant from focal disruptions or overlying non-disrupted basal cell layers, epithelial cells overlying focal basal cell layer disruptions showed the following unique features: (1) significantly higher proliferation; (2) significantly higher expression of cell cycle control-, cell growth-, and stem cell-related genes; and (3) physical continuity with adjacent invasive lesions. Together, these findings suggest that focal basal cell layer disruptions could substantially impact the molecular profile and biological presentations of the overlying epithelial cells. Based on these and other findings, we have proposed that prostate tumor invasion is triggered by a localized degeneration of aged or injured basal cells and the resultant auto-immunoreactions. Our hypothesized steps for prostate tumor invasion include the following: (1) due to inherited or environmental factors, some patients contained cell cycle control- and renewal-related defects in the basal cell population that cause elevated basal cell degenerations; (2) the degradation products of degenerated basal cells or diffusible molecules of the overlying epithelial cells attract leukocyte infiltration; (3) leukocytes discharge their digestive enzymes upon the direct physical contact, resulting in a focal disruption in the basal cell layer, which leads to several focal alterations: (a) a focal loss of tumor suppressors and paracrine inhibitory function; (b) a focal increase of the permeability for growth-required nutrients and oxygen; (c) a focal increase of growth factors; (d) direct physical contact between epithelial and stromal cells; and (e) the exposure of the overlying epithelial cells directly to the stromal tissue fluid. These alterations individually or collectively stimulate or favor a clonal proliferation and stromal invasion of tumor

  11. Identification of Different Classes of Luminal Progenitor Cells within Prostate Tumors

    Directory of Open Access Journals (Sweden)

    Supreet Agarwal

    2015-12-01

    Full Text Available Primary prostate cancer almost always has a luminal phenotype. However, little is known about the stem/progenitor properties of transformed cells within tumors. Using the aggressive Pten/Tp53-null mouse model of prostate cancer, we show that two classes of luminal progenitors exist within a tumor. Not only did tumors contain previously described multipotent progenitors, but also a major population of committed luminal progenitors. Luminal cells, sorted directly from tumors or grown as organoids, initiated tumors of adenocarcinoma or multilineage histological phenotypes, which is consistent with luminal and multipotent differentiation potentials, respectively. Moreover, using organoids we show that the ability of luminal-committed progenitors to self-renew is a tumor-specific property, absent in benign luminal cells. Finally, a significant fraction of luminal progenitors survived in vivo castration. In all, these data reveal two luminal tumor populations with different stem/progenitor cell capacities, providing insight into prostate cancer cells that initiate tumors and can influence treatment response.

  12. Quercetin inhibits angiogenesis through thrombospondin-1 upregulation to antagonize human prostate cancer PC-3 cell growth in vitro and in vivo.

    Science.gov (United States)

    Yang, Feiya; Jiang, Xian; Song, Liming; Wang, Huiping; Mei, Zhu; Xu, Zhiqing; Xing, Nianzeng

    2016-03-01

    The rapid growth, morbidity and mortality of prostate cancer, and the lack of effective treatment have attracted great interests of researchers to find novel cancer therapies aiming to inhibit angiogenesis and tumor growth. Quercetin is a flavonoid compound that widely exists in the nature. Our previous study preliminarily demonstrated that quercetin effectively inhibited human prostate cancer cell xenograft tumor growth by inhibiting angiogenesis. Thrombospondin-1 (TSP-1) is the first reported endogenous anti-angiogenic factor that can inhibit angiogenesis and tumorigenesis. However, the relationship between quercetin inhibiting angiogenesis and TSP-1 upregulation in prostate cancer has not been determined. Thus, we explored the important role of TSP-1 upregulation in reducing angiogenesis and anti-prostate cancer effect of quercetin both in vitro and in vivo for the first time. After the selected doses were used for a certain time, quercetin i) significantly inhibited PC-3 and human umbilical vein endothelial cells (HUVECs) proliferation, migration and invasion in a dose-dependent manner; ⅱ) effectively inhibited prostate cancer PC-3 cell xenograft tumor growth by 37.5% with 75 mg/kg as compared to vehicle control group, more effective than 25 (22.85%) and 50 mg/kg (29.6%); ⅲ) was well tolerated by BALB/c mice and no obvious toxic reactions were observed; ⅳ) greatly reduced angiogenesis and led to higher TSP-1 protein and mRNA expression both in vitro and in vivo in a dose-dependent manner. Therefore, quercetin could increase TSP-1 expression to inhibit angiogenesis resulting in antagonizing prostate cancer PC-3 cell and xenograft tumor growth. The present study can lay a good basis for the subsequent concrete mechanism study and raise the possibility of applying quercetin to clinical for human prostate cancer in the near future.

  13. Prostate tumor progression in the TRAMP mouse. Protective effects of the aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Fritz, W.; Lin, T.M.; Peterson, R. [Wisconsin Univ., Madison, WI (United States)

    2004-09-15

    The developing male reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD binds to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, to produce sustained alterations in gene expression. Mice lacking the AhR (AhRKO, Ahr{sup -/-}) have permitted further characterization of the role of the AhR in mediating TCDD effects and revealed a physiological role for the AhR in normal development. We previously demonstrated that in utero and lactational TCDD exposure significantly reduced ventral, dorsolateral and anterior prostate weights, and that these effects were dependent on the AhR5. However, reductions in prostate lobe weights in untreated, AhRKO mice compared to wild-type counterparts at various ages demonstrated that the AhR signaling pathway is involved in normal development of the dorsolateral and anterior prostates, but apparently not the ventral prostate. Unaltered serum testosterone concentrations and modest reduction in serum 5{alpha}-androstane-3{alpha},17{beta}a-diol concentrations could not account for reductions in prostate weights in mice lacking AhR (Ahr{sup -/-}). Normal histology and lack of alteration in androgen receptor mRNA levels further indicate that the reduction in prostate weights is not a result of reduced androgen action in AhRKO mice. The observation that regulation of early prostate growth in mice occurs following AhR activation by TCDD, as well as by loss of AhR, suggests that the AhR may also regulate aberrant prostate growth that results from ''reawakening'' of the prostate growth regulatory signals later in life. Our objective was to determine if the AhR signaling pathway has an effect on prostate cancer development.

  14. Preclinical Evaluation of a Novel 177Lu- Radiopharmaceutical Based on Bombesin Structure for Prostate Tumor Diagnosis and Radionuclide Therapy

    International Nuclear Information System (INIS)

    Pujatti, P.B.; Santos, J.S.; Mengatti, J.; Araujo, E.B. de; Suzuki, M.F.; Soares, C.R.J.

    2009-01-01

    Prostate cancer is the most frequently diagnosed cancer in men in Brazil. Treatment options have varied, but once the tumor has metastasized, treatment become less effective and the cancer can progresses to a hormone refractory state characterized by high morbidity and mortality. Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor - have been shown to be massively overexpressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel peptide based on bombesin structure - DOTA-X-BBN(6-14), where X is a spacer of six aminoacids. - with lutetium-177, a β- emitter with optimal physical characteristics for RNT of small tumors and metastases, and to evaluate its in vitro and in vivo properties in Balb-c and Nude mice bearing prostate tumor (PC-3) xenografts. Preliminary studies were done to determine the best labeling conditions of BBNp6 and both ITLC and HPLC were applied to evaluate the radiochemical purity of the preparations. The stability of the radiolabeled peptide was assayed either after storing at 4 o C or incubation in human plasma at 37 deg. C. Biodistribution, pharmacokinetics, whole body and scintigraphic studies were performed in both healthy Balb-c and xenografted Nude mice, in order to characterize the biological properties of labeled peptide. In addition, the specificity of labeled bombesin derivative targeting to PC-3 tumor cells was analysed by in vivo competition assays. In vitro studies involved the

  15. The discovery of putative urine markers for the specific detection of prostate tumor by integrative mining of public genomic profiles.

    Directory of Open Access Journals (Sweden)

    Min Chen

    Full Text Available Urine has emerged as an attractive biofluid for the noninvasive detection of prostate cancer (PCa. There is a strong imperative to discover candidate urinary markers for the clinical diagnosis and prognosis of PCa. The rising flood of various omics profiles presents immense opportunities for the identification of prospective biomarkers. Here we present a simple and efficient strategy to derive candidate urine markers for prostate tumor by mining cancer genomic profiles from public databases. Prostate, bladder and kidney are three major tissues from which cellular matters could be released into urine. To identify urinary markers specific for PCa, upregulated entities that might be shed in exosomes of bladder cancer and kidney cancer are first excluded. Through the ontology-based filtering and further assessment, a reduced list of 19 entities encoding urinary proteins was derived as putative PCa markers. Among them, we have found 10 entities closely associated with the process of tumor cell growth and development by pathway enrichment analysis. Further, using the 10 entities as seeds, we have constructed a protein-protein interaction (PPI subnetwork and suggested a few urine markers as preferred prognostic markers to monitor the invasion and progression of PCa. Our approach is amenable to discover and prioritize potential markers present in a variety of body fluids for a spectrum of human diseases.

  16. Possible application of tumor marker radioimmunoassay in diagnosis of testicular and prostatic carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Kausitz, J

    1988-10-01

    Determinations of alpha fetoprotein and chorionic gonadotropin levels by radioimmunoassay in 340 patients with germ cell tumors of the testes have confirmed that tumor markers are suitable prognostic parameters, facilitate assessment of the clinical stage, are sensitive parameters of the efficacy of chemotherapy and enable early detection of relapses. In a group of 71 patients with prostate cancer, systematic determination of prostate specific antigen levels proved to be a reliable method of monitoring and a sensitive method of detecting remote metastases. (author). 5 figs., 13 tabs., 23 refs.

  17. RNAi-mediated knockdown of pituitary tumor-transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells

    International Nuclear Information System (INIS)

    Huang, S.Q.; Liao, Q.J.; Wang, X.W.; Xin, D.Q.; Chen, S.X.; Wu, Q.J.; Ye, G.

    2012-01-01

    Pituitary tumor-transforming gene-1 (PTTG1) is a proto-oncogene that promotes tumorigenesis and metastasis in numerous cell types and is overexpressed in a variety of human tumors. We have demonstrated that PTTG1 expression was up-regulated in both human prostate cancer specimens and prostate cancer cell lines. For a more direct assessment of the function of PTTG1 in prostate tumorigenesis, RNAi-mediated knockdown was used to selectively decrease PTTG1 expression in PC3 human prostate tumor cells. After three weeks of selection, colonies stably transfected with PTTG1-targeted RNAi (the knockdown PC3 cell line) or empty vector (the control PC3 cell line) were selected and expanded to investigate the role of PTTG1 expression in PC3 cell growth and invasion. Cell proliferation rate was significantly slower (28%) in the PTTG1 knockdown line after 6 days of growth as indicated by an MTT cell viability assay (P < 0.05). Similarly, a soft agar colony formation assay revealed significantly fewer (66.7%) PTTG1 knockdown PC3 cell colonies than control colonies after three weeks of growth. In addition, PTTG1 knockdown resulted in cell cycle arrest at G1 as indicated by fluorescence-activated cell sorting. The PTTG1 knockdown PC3 cell line also exhibited significantly reduced migration through Matrigel in a transwell assay of invasive potential, and down-regulation of PTTG1 could lead to increased sensitivity of these prostate cancer cells to a commonly used anticancer drug, taxol. Thus, PTTG1 expression is crucial for PC3 cell proliferation and invasion, and could be a promising new target for prostate cancer therapy

  18. Insulin-like growth factor II mRNA binding protein 3 (IMP3 is overexpressed in prostate cancer and correlates with higher Gleason scores

    Directory of Open Access Journals (Sweden)

    Mortezavi Ashkan

    2010-06-01

    Full Text Available Abstract Background The oncofetal protein insulin-like growth factor II mRNA binding protein 3 (IMP3 is an important factor for cell-migration and adhesion in malignancies. Recent studies have shown a remarkable overexpression of IMP3 in different human malignant neoplasms and also revealed it as an important prognostic marker in some tumor entities. To our knowledge, IMP3 expression has not been investigated in prostate carcinomas so far. Methods Immunohistochemical stainings for IMP3 were performed on tissue microarray (TMA organized samples from 507 patients: 31 normal prostate tissues, 425 primary carcinomas and 51 prostate cancer metastases or castration-resistant prostate cancers (CRPC. IMP3 immunoreactivity was semiquantitatively scored and correlated with clinical-pathologic parameters including survival. Results IMP3 is significantly stronger expressed in prostate carcinomas compared to normal prostate tissues (p Conclusions Although IMP3 is overexpressed in a significant proportion of prostate cancer cases, which might be of importance for novel therapeutic approaches, it does not appear to possess any immediate diagnostic or prognostic value, limiting its potential as a tissue biomarker for prostate cancer. These results might be corroborated by the fact, that two independent tumor cohorts were separately reviewed.

  19. Insulin-like growth factor II mRNA binding protein 3 (IMP3) is overexpressed in prostate cancer and correlates with higher Gleason scores

    International Nuclear Information System (INIS)

    Ikenberg, Kristian; Behnke, Silvia; Gerhardt, Josefine; Mortezavi, Ashkan; Wild, Peter; Hofstädter, Ferdinand; Burger, Maximilian; Moch, Holger; Kristiansen, Glen; Fritzsche, Florian R; Zuerrer-Haerdi, Ursina; Hofmann, Irina; Hermanns, Thomas; Seifert, Helge; Müntener, Michael; Provenzano, Maurizio; Sulser, Tullio

    2010-01-01

    The oncofetal protein insulin-like growth factor II mRNA binding protein 3 (IMP3) is an important factor for cell-migration and adhesion in malignancies. Recent studies have shown a remarkable overexpression of IMP3 in different human malignant neoplasms and also revealed it as an important prognostic marker in some tumor entities. To our knowledge, IMP3 expression has not been investigated in prostate carcinomas so far. Immunohistochemical stainings for IMP3 were performed on tissue microarray (TMA) organized samples from 507 patients: 31 normal prostate tissues, 425 primary carcinomas and 51 prostate cancer metastases or castration-resistant prostate cancers (CRPC). IMP3 immunoreactivity was semiquantitatively scored and correlated with clinical-pathologic parameters including survival. IMP3 is significantly stronger expressed in prostate carcinomas compared to normal prostate tissues (p < 0.0001), but did not show significant correlation with the pT-stage, the proliferation index (MIB1), preoperative serum PSA level and the margin status. Only a weak and slightly significant correlation was found with the Gleason score and IMP3 expression failed to show prognostic significance in clinico-pathological correlation-analyses. Although IMP3 is overexpressed in a significant proportion of prostate cancer cases, which might be of importance for novel therapeutic approaches, it does not appear to possess any immediate diagnostic or prognostic value, limiting its potential as a tissue biomarker for prostate cancer. These results might be corroborated by the fact, that two independent tumor cohorts were separately reviewed

  20. Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation

    Directory of Open Access Journals (Sweden)

    Piergiuseppe Colombo

    2010-10-01

    Full Text Available Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR revealed a high-grade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histo­logical findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered.

  1. Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

    Directory of Open Access Journals (Sweden)

    Nicosia Alfredo

    2010-04-01

    Full Text Available Abstract Background Prostate stem cell antigen (PSCA is a glycosylphosphatidylinositol (GPI anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth. Methods A bladder cell line was engineered to express a doxycycline (dox regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR Results Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor. Conclusions These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response.

  2. Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

    International Nuclear Information System (INIS)

    Marra, Emanuele; Ciliberto, Gennaro; Palombo, Fabio; Uva, Paolo; Viti, Valentina; Simonelli, Valeria; Dogliotti, Eugenia; De Rinaldis, Emanuele; Lahm, Armin; La Monica, Nicola; Nicosia, Alfredo

    2010-01-01

    Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth. A bladder cell line was engineered to express a doxycycline (dox) regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor. These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response

  3. Multiple gingival pregnancy tumors with rapid growth

    Directory of Open Access Journals (Sweden)

    Wei-Lian Sun

    2014-09-01

    Full Text Available Pregnancy gingivitis is an acute form of gingivitis that affects pregnant women, with a prevalence of 30%, possibly ranging up to 100%. Sometimes, pregnancy gingivitis shows a tendency toward a localized hyperplasia called gingival pyogenic granuloma. Pregnancy tumor is a benign gingival hyperplasia with the gingiva as the most commonly involved site, but rarely it involves almost the entire gingiva. A 22-year-old woman was referred to our clinic with a chief complaint of gingival swelling that had lasted for 2 days. The lesions progressed rapidly and extensively, and almost all the gingiva was involved a week later. Generalized erythema, edema, hyperplasia, a hemorrhagic tendency, and several typical hemangiomatous masses were noted. Pregnancy was denied by the patient at the first and second visits, but was confirmed 2 weeks after the primary visit. The patient was given oral hygiene instructions. She recovered well, and the mass gradually regressed and had disappeared completely at the end of 12 weeks of pregnancy, without recurrence. The gingival lesions were finally diagnosed as multiple gingival pregnancy tumors. The patient delivered a healthy infant. An extensive and rapid growth of gingival pregnancy tumors during the early first month of pregnancy is a rare occurrence that is not familiar to dentists, gynecologists, and obstetricians. Those practitioners engaged in oral medicine and periodontology, primary care obstetrics, and gynecology should be aware of such gingival lesions to avoid misdiagnosis and overtreatment.

  4. Elevated insulin and reduced insulin like growth factor binding protein-3/prostate specific antigen ratio with increase in prostate size in Benign Prostatic Hyperplasia.

    Science.gov (United States)

    Sreenivasulu, Karli; Nandeesha, Hanumanthappa; Dorairajan, Lalgudi Narayanan; Rajappa, Medha; Vinayagam, Vickneshwaran

    2017-06-01

    Insulin and insulin like growth factor-1 (IGF-1) have growth promoting effects, while insulin like growth factor binding protein-3 (IGFBP-3) has growth inhibitory effects. The present study was designed to assess the concentrations of insulin, IGF-1, IGFBP-3 and their association with prostate size in patients with BPH. Ninety 90 BPH cases and 90 controls were enrolled in the study. Insulin, IGF-1, IGFBP-3, PSA, testosterone and estradiol were estimated in both the groups. Insulin, IGF-1 and estradiol were increased and IGFBP-3/PSA was decreased in BPH cases when compared with controls. Insulin (r=0.64, p=0.001) and IGF-1 (r=0.22, p=0.03) were positively correlated and IGFBP-3/PSA (r=-0.316, p=0.002) were negatively correlated with prostate size in BPH. Multivariate analysis showed that insulin (p=0.001) and IGFBP-3/PSA (p=0.004) predicts the prostate size in patients with BPH. Insulin was increased and IGFBP-3/PSA was reduced in BPH patients with increased prostate size. At a cutoff concentration of 527.52, IGFBP-3/PSA ratio was found to differentiate benign growth of prostate from normal prostate with 96% sensitivity and 96% specificity. Insulin is elevated and IGFBP-3/PSA is reduced with increase prostate size in BPH cases. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

    Science.gov (United States)

    Chua, Chee Wai; Epsi, Nusrat J; Leung, Eva Y; Xuan, Shouhong; Lei, Ming; Li, Bo I; Bergren, Sarah K; Hibshoosh, Hanina; Mitrofanova, Antonina

    2018-01-01

    Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. PMID:29334357

  6. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of withaferin A on tumor growth and metastasis in liver in a nude mouse model. Methods: Withaferin A was injected through a portal vein to the orthotopic liver tumor in a nude mice model. Xenogen in vivo imaging system was used to monitor tumor growth and metastasis. The effect of ...

  7. Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone

    Science.gov (United States)

    Kolonin, Mikhail G.; Sergeeva, Anna; Staquicini, Daniela I.; Smith, Tracey L.; Tarleton, Christy A.; Molldrem, Jeffrey J.; Sidman, Richard L.; Marchiò, Serena; Pasqualini, Renata; Arap, Wadih

    2017-01-01

    Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. PMID:28428279

  8. Prostate resonance imaging: morphology and metabolism

    International Nuclear Information System (INIS)

    Ocantos, Jorge A.; Pietrani, Marcelo A.; Paganini, Lisandro

    2007-01-01

    The cancer of prostate is the most frequent neoplasms and the third cause of death in men, although the average of survival of patients it improved, the cancer of prostate is an important problem in health. The majority of these tumors are of slow growth and the early detection allows high probabilities of definitive treatment. The neoplasms of prostate detected at present are smaller than the detected ones 20 years ago behind, nevertheless exist big differences in the aggressiveness of these tumors. The images are very important in the management of prostate cancer, and the magnetic resonance imaging of the prostate is a new tool in the evaluation of prostate cancer [es

  9. Numerical simulation of avascular tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Slezak, D Fernandez; Suarez, C; Soba, A; Risk, M; Marshall, G [Laboratorio de Sistemas Complejos, Departamento de Computacion, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (C1428EGA) Buenos Aires (Argentina)

    2007-11-15

    A mathematical and numerical model for the description of different aspects of microtumor development is presented. The model is based in the solution of a system of partial differential equations describing an avascular tumor growth. A detailed second-order numeric algorithm for solving this system is described. Parameters are swiped to cover a range of feasible physiological values. While previous published works used a single set of parameters values, here we present a wide range of feasible solutions for tumor growth, covering a more realistic scenario. The model is validated by experimental data obtained with a multicellular spheroid model, a specific type of in vitro biological model which is at present considered to be optimum for the study of complex aspects of avascular microtumor physiology. Moreover, a dynamical analysis and local behaviour of the system is presented, showing chaotic situations for particular sets of parameter values at some fixed points. Further biological experiments related to those specific points may give potentially interesting results.

  10. Intravital imaging of plasticity during tumor growth and metastasis

    NARCIS (Netherlands)

    Zomer, Anoek

    2015-01-01

    Most tumors consist of a heterogeneous mixture of genetically and epigenetically distinct tumor cells. In addition, tumors display regional differences in the tumor microenvironment comprising non-transformed cell types such as immune cells and non-cellular factors including growth factors and the

  11. Role of Growth Hormone in Prostate Cancer

    Science.gov (United States)

    2007-02-01

    syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci USA 94:13215... Laron mouse, in which the gene coding for both GHR and GH binding protein has been disrupted or knocked out, with the C3(1)/Tag mouse, which develops...the Laron mouse). Nevertheless, the new model presented here demonstrates that the loss of GHR produced a significant reduction in the level of PIN in

  12. Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

    Directory of Open Access Journals (Sweden)

    Samantha Morley

    2014-08-01

    Full Text Available Prostate cancer (PCa remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, 'amoeboid' phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

  13. Scoparone exerts anti-tumor activity against DU145 prostate cancer cells via inhibition of STAT3 activity.

    Directory of Open Access Journals (Sweden)

    Jeong-Kook Kim

    Full Text Available Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3 contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2 or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.

  14. Prostatitis

    Science.gov (United States)

    Prostatitis Overview Prostatitis is swelling and inflammation of the prostate gland, a walnut-sized gland situated directly below the bladder in ... produces fluid (semen) that nourishes and transports sperm. Prostatitis often causes painful or difficult urination. Other symptoms ...

  15. PC-3 prostate carcinoma cells release signal substances that influence the migratory activity of cells in the tumor's microenvironment

    Directory of Open Access Journals (Sweden)

    Zänker Kurt S

    2010-07-01

    Full Text Available Abstract Background Tumor cells interact with the cells of the microenvironment not only by cell-cell-contacts but also by the release of signal substances. These substances are known to induce tumor vascularization, especially under hypoxic conditions, but are also supposed to provoke other processes such as tumor innervation and inflammatory conditions. Inflammation is mediated by two organ systems, the neuroendocrine system and the immune system. Therefore, we investigated the influence of substances released by PC-3 human prostate carcinoma cells on SH-SY5Y neuroblastoma cells as well as neutrophil granulocytes and cytotoxic T lymphocytes, especially with regard to their migratory activity. Results PC-3 cells express several cytokines and growth factors including vascular endothelial growth factors, fibroblast growth factors, interleukins and neurotrophic factors. SH-SY5Y cells are impaired in their migratory activity by PC-3 cell culture supernatant, but orientate chemotactically towards the source. Neutrophil granulocytes increase their locomotory activity only in response to cell culture supernantant of hypoxic but not of normoxic PC-3 cells. In contrast, cytotoxic T lymphocytes do not change their migratory activity in response to either culture supernatant, but increase their cytotoxicity, whereas supernatant of normoxic PC-3 cells leads to a stronger increase than that of hypoxic PC-3 cells. Conclusions PC-3 cells release several signal substances that influence the behavior of the cells in the tumor's microenvironment, whereas no clear pattern towards proinflammatory or immunosuppressive conditions can be seen.

  16. CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eunjung; Son, Joe Eun; Byun, Sanguine; Lee, Seung Joon; Kim, Yeong A [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Liu, Kangdong [The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912 (United States); Kim, Jiyoung [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Lim, Soon Sung; Park, Jung Han Yoon [Department of Food Science and Nutrition, College of Natural Science, Hallym University, Chuncheon, 200-702 (Korea, Republic of); Dong, Zigang [The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912 (United States); Lee, Ki Won, E-mail: kiwon@snu.ac.kr [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Korea, Republic of); Lee, Hyong Joo, E-mail: leehyjo@snu.ac.kr [WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921 (Korea, Republic of); Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270 (Korea, Republic of)

    2013-10-01

    Licorice extract which is used as a natural sweetener has been shown to possess inhibitory effects against prostate cancer, but the mechanisms responsible are poorly understood. Here, we report a compound, isoangustone A (IAA) in licorice that potently suppresses the growth of aggressive prostate cancer and sought to clarify its mechanism of action. We analyzed its inhibitory effects on the growth of PTEN-deleted human prostate cancer cells, in vitro and in vivo. Administration of IAA significantly attenuated the growth of prostate cancer cell cultures and xenograft tumors. These effects were found to be attributable to inhibition of the G1/S phase cell cycle transition and the accumulation of p27{sup kip1}. The elevated p27{sup kip1} expression levels were concurrent with the decrease of its phosphorylation at threonine 187 through suppression of CDK2 kinase activity and the reduced phosphorylation of Akt at Serine 473 by diminishing the kinase activity of the mammalian target of rapamycin (mTOR). Further analysis using recombinant proteins and immunoprecipitated cell lysates determined that IAA exerts suppressive effects against CDK2 and mTOR kinase activity by direct binding with both proteins. These findings suggested that the licorice compound IAA is a potent molecular inhibitor of CDK2 and mTOR, with strong implications for the treatment of prostate cancer. Thus, licorice-derived extracts with high IAA content warrant further clinical investigation for nutritional sources for prostate cancer patients. - Highlights: • Isoangustone A suppresses growth of PC3 and LNCaP prostate cancer cells. • Administration of isoangustone A inhibits tumor growth in mice. • Treatment of isoangustone A induces cell cycle arrest and accumulation of p27{sup kip1}. • Isoangustone A inhibits CDK2 and mTOR activity. • Isoangustone A directly binds with CDK2 and mTOR complex in prostate cancer cells.

  17. Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter.

    Science.gov (United States)

    Ahn, M; Lee, S-J; Li, X; Jiménez, J A; Zhang, Y-P; Bae, K-H; Mohammadi, Y; Kao, C; Gardner, T A

    2009-01-01

    Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.

  18. 1H-MRSI of prostate cancer: The relationship between metabolite ratio and tumor proliferation

    International Nuclear Information System (INIS)

    Wang Xizhen; Wang Bin; Gao Zhiqin; Liu Jingang; Liu Zuoqin; Niu Qingliang; Sun Zhenkui; Yuan Yuxiao

    2010-01-01

    Purpose: To investigate whether 1H-MRSI can be used to predict the proliferative activity of prostate cancer. Materials and methods: Thirty-eight patients with prostate cancer (PCa) and thirty-three patients with benign prostate hyperplasia (BPH) were included in this study. Patients were examined in supine position using a 1.5 T superconducting magnetic scanner equipped with a pelvic phased-array multi-coil and CSI-3D-PROSTATE sequence. Commercial software was used to acquire and process MR spectroscopic imaging data. Mean (Cho + Cr)/Cit ratios of PCa, BPH, and peripheral zone (PZ) were calculated. Cellularity of PCa was recorded based on hematoxylin and eosin staining. PCNA was detected using immunohistochemical techniques. Results: The mean (Cho + Cr)/Cit ratio of the peripheral zone (0.38 ± 0.09) was lower than that of BPH (0.51 ± 0.19) (P < 0.05). The average value of (Cho + Cr)/Cit ratio of prostate cancer was 3.98 ± 0.12. The (Cho + Cr)/Cit ratio of prostate cancer was higher than that of the peripheral zone and BPH (P < 0.05). The cellularity and PCNA LI of prostate cancer were 12.90 ± 4.07% and 72.1 ± 19.01%, respectively. The (Cho + Cr)/Cit ratio of prostate cancer positively correlated with tumor cellularity (r = 0.582, P = 0.027) and PCNA LI (r = 0.495, P = 0.022). Conclusion: The (Cho + Cr)/Cit ratio of PCa can reveal the differences in proliferative activity between PCa and BPH. MRSIs are therefore able to predict the proliferative rate of variously differentiated prostate cancers.

  19. Molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood

    Directory of Open Access Journals (Sweden)

    Kinnunen Martin

    2010-07-01

    Full Text Available Abstract Background Prostate cancer is the second leading cause of cancer mortality in American men. Although serum PSA testing is widely used for early detection, more specific prognostic tests are needed to guide treatment decisions. Recently, the enumeration of circulating prostate epithelial cells has been shown to correlate with disease recurrence and metastasis following definitive treatment. The purpose of our study was to investigate an immunomagnetic fractionation procedure to enrich circulating prostate tumor cells (CTCs from peripheral blood specimens, and to apply amplified molecular assays for the detection of prostate-specific markers (PSA, PCA3 and TMPRSS2:ERG gene fusion mRNAs. Results As few as five prostate cancer cells were detected per 5 mL of whole blood in model system experiments using anti-EpCAM magnetic particles alone or in combination with anti-PSMA magnetic particles. In our experiments, anti-EpCAM magnetic particles alone exhibited equivalent or better analytical performance with patient samples compared to a combination of anti-EpCAM + anti-PSMA magnetic particles. Up to 39% of men with advanced prostate cancer tested positive with one or more of the molecular assays tested, whereas control samples from men with benign prostate hyperplasia gave consistently negative results as expected. Interestingly, for the vast majority of men who tested positive for PSA mRNA following CTC enrichment, their matched plasma samples also tested positive, although CTC enrichment gave higher overall mRNA copy numbers. Conclusion CTCs were successfully enriched and detected in men with advanced prostate cancer using an immunomagnetic enrichment procedure coupled with amplified molecular assays for PSA, PCA3, and TMPRSS2:ERG gene fusion mRNAs. Our results indicate that men who test positive following CTC enrichment also exhibit higher detectable levels of non-cellular, circulating prostate-specific mRNAs.

  20. Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity.

    Science.gov (United States)

    Riemann, Anne; Güttler, Antje; Haupt, Verena; Wichmann, Henri; Reime, Sarah; Bache, Matthias; Vordermark, Dirk; Thews, Oliver

    2018-03-05

    Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications. CA IX was upregulated by hypoxia as well as acidosis in prostate cancer cells. This induction did not modulate intracellular pH but led to extracellular acidification. Pharmacological inhibition of CA IX activity by U104 (SLC-0111) resulted in a reduction in tumor cell growth and an increase in apoptotic cell death. Intracellular pH was reduced under normoxic and even more so under hypoxic conditions when CA IX level was high. However, although intracellular pH regulation was disturbed, targeting CA IX in combination with daunorubicin or cisplatin did not intensify apoptotic tumor cell death. Hence, targeting CA IX in prostate cancer cells can lead to intracellular pH dysregulation and, consequently, can reduce cellular growth and elevate apoptotic cell death. Attenuation of extracellular acidification by blocking CA IX might additionally impede tumor progression and metastasis. However, no beneficial effect was seen when targeting CA IX in combination with chemotherapeutic drugs.

  1. [Markers of angiogenesis in tumor growth].

    Science.gov (United States)

    Nefedova, N A; Kharlova, O A; Danilova, N V; Malkov, P G; Gaifullin, N M

    2016-01-01

    Angiogenesis is a process of new blood vessels formation. The role of angiogenesis in growth, invasion and metastasis of malignant tumours is nowdays universally recognized. Though, investigation of mechanisms of blood vessels formation and elaboration methods for assessment of tumour angiogenesis are still up-dated. Another important concern are different aspects of usage of immunohistochemical markers of blood vessels endothelium (CD31 and CD34) for assessment of tumour aggressiveness and prognosis. The problems of malignant lymphangiogenesis are also up-to-date. The focus is on methods of immunohistochemical visualization of forming lymphatic vessels, role of podoplanin, the most reliable marker of lymphatic vessels, in their identification, and formulization of the main criteria for lymphangiogenesis estimation, its correlation with metastatic activity and prognostic potential. Studying of angiogenesis and lymph angiogenesis in malignant tumors is important and challenging direction for researching tumour progression and invention of antiangiogenic therapy.

  2. Role of Androgen Receptor in Growth of Androgen Independent Prostate Cancer

    National Research Council Canada - National Science Library

    Chen, Charlie

    2003-01-01

    ...) overexpression is the only consistent change in the progression of prostate cancer. In the last grand period, I confirmed by western blot analysis that androgen receptor protein is higher in HR than HS tumors...

  3. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.

    Science.gov (United States)

    Bennewith, Kevin L; Huang, Xin; Ham, Christine M; Graves, Edward E; Erler, Janine T; Kambham, Neeraja; Feazell, Jonathan; Yang, George P; Koong, Albert; Giaccia, Amato J

    2009-02-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer.

  4. Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

    Science.gov (United States)

    Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

    1991-02-01

    Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]LH-RH (SB-75) on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 micrograms of antagonist SB-75 per day were compared with microcapsules of agonist [D-Trp6]LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate carcinoma. During 8 weeks of treatment, tumor growth was decreased by [D-Trp6]LH-RH and all three doses of SB-75 as compared to untreated controls. The highest dose of SB-75 (71.4 micrograms/day) caused a greater inhibition of prostate cancer growth than [D-Trp6]LH-RH as based on measurement of tumor volume and percentage change in tumor volume. Doses of 23.8 and 47.6 micrograms of SB-75 per day induced a partial and submaximal decrease, respectively, in tumor weight and volume. Tumor doubling time was the longest (50 days) with the high dose of SB-75 vs. 15 days for controls. The body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received SB-75, and testosterone levels were decreased to nondetectable values in the case of the two higher doses of SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of SB-75. Therapy with microgranules of SB-75 significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The results indicate that antagonist SB-75, released from sustained delivery systems, can produce a state of chemical castration and effectively

  5. Elemental mapping by synchrotron radiation X-Ray microfluorescence in cellular spheroid of prostate tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Leitao, R.G.; Anjos, M.J.; Lopes, R.T., E-mail: roberta@lin.ufrj.br [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Instrumentacao Nuclear; Santos, C.A.N. [Instituto Nacional de Metrologia, Qualidade e Tecnologia (INMETRO), Duque de Caxias, RJ (Brazil). Lab. de Biotecnologia; Palumbo Junior, A.; Souza, P.A.V.R.; Nasciutti, L.E. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Instituto de Ciencias Biomedicas; Pereira, G.R. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Lab. de Ensaios Nao Destrutivos, Corrosao e Soldagem

    2013-08-15

    Prostate cancer is the sixth most common type of cancer and the third most common in males in Western industrialized countries. Cellular spheroid serves as excellent physiologic tumor models as they mimic avascular tumors and micrometastases. Trace elements play a significant role in biological processes. They are capable of affecting human health by competing with essential elements for available binding sites and by the activation or inhibition of reactions between metabolic enzymes. It is well known that zinc levels in the peripheral zone of dorsal and lateral lobes of the prostate are almost 10 times higher than in other soft tissues. Prostate tumor cells were isolated of the prostate tissue samples that were collected from patients submitted to surgery. The measurements were performed in XRF beam line at the Synchrotron Light National Laboratory (LNLS) in Campinas, Brazil. The results showed that all elements were heterogeneously distributed in different areas of the spheroids analyzed. P, S and Cl showed similar elemental distribution in all the samples analyzed while K, Ca, Fe, and Cu showed different elemental distribution. In all spheroids analyzed, Zn presented more intense distributions in the central region of the spheroid. The relationship between the function of Zn in the secretory epithelial cells and the carcinogenic process suggests that more studies on elemental mapping in spheroids are necessary. (author)

  6. Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

    Directory of Open Access Journals (Sweden)

    Wendy J. Huss

    2007-11-01

    Full Text Available Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR. Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

  7. Elemental mapping by synchrotron radiation X-Ray microfluorescence in cellular spheroid of prostate tumor cells

    International Nuclear Information System (INIS)

    Leitao, R.G.; Anjos, M.J.; Lopes, R.T.; Santos, C.A.N.; Palumbo Junior, A.; Souza, P.A.V.R.; Nasciutti, L.E.; Pereira, G.R.

    2013-01-01

    Prostate cancer is the sixth most common type of cancer and the third most common in males in Western industrialized countries. Cellular spheroid serves as excellent physiologic tumor models as they mimic avascular tumors and micrometastases. Trace elements play a significant role in biological processes. They are capable of affecting human health by competing with essential elements for available binding sites and by the activation or inhibition of reactions between metabolic enzymes. It is well known that zinc levels in the peripheral zone of dorsal and lateral lobes of the prostate are almost 10 times higher than in other soft tissues. Prostate tumor cells were isolated of the prostate tissue samples that were collected from patients submitted to surgery. The measurements were performed in XRF beam line at the Synchrotron Light National Laboratory (LNLS) in Campinas, Brazil. The results showed that all elements were heterogeneously distributed in different areas of the spheroids analyzed. P, S and Cl showed similar elemental distribution in all the samples analyzed while K, Ca, Fe, and Cu showed different elemental distribution. In all spheroids analyzed, Zn presented more intense distributions in the central region of the spheroid. The relationship between the function of Zn in the secretory epithelial cells and the carcinogenic process suggests that more studies on elemental mapping in spheroids are necessary. (author)

  8. Comprehensive Evaluation of the Role of EZH2 in the Growth, Invasion, and Aggression of a Panel of Prostate Cancer Cell Lines

    Science.gov (United States)

    Karanikolas, Breanne D.W.; Figueiredo, Marxa L.; Wu, Lily

    2010-01-01

    Background Although most prostate cancers respond well to initial treatments, a fraction of prostate cancers are more aggressive and will recur and metastasize. At that point, there are few treatment options available. Significant efforts have been made to identify biomarkers that will identify these more aggressive cancers to tailor a more vigorous treatment in order to improve outcome. Polycomb Group protein Enhancer of Zeste 2 (EZH2) was found to be overexpressed in metastatic prostate tumors, and is considered an excellent candidate for such a biomarker. Scattered studies have found that EZH2 overexpression causes neoplastic transformation, invasion, and growth of prostate cells. However, these studies utilized different systems and cell lines, and so are difficult to correlate with one another. Methods In this study, a comprehensive evaluation of the phenotypic effects of EZH2 in a panel of five prostate cancer cell lines was performed. By using multiple cell lines, and examining overexpression and knockdown of EZH2 concurrently, a broad view of EZH2's role in prostate cancer was achieved. Results Overexpression of EZH2 led to more aggressive behaviors in all prostate cell lines tested. In contrast, downregulation of EZH2 reduced invasion and tumorigenicity of androgen-independent cell lines CWR22Rv1, PC3, and DU145, but not of androgen-dependent cell lines LAPC4 and LNCaP. Conclusions Findings from this study suggest androgen-independent prostate tumors are more dependent on EZH2 expression than androgen-dependent tumors. Our observations provide an explanation for the strong correlation between EZH2 overexpression and advanced stage, aggressive prostate cancers. PMID:20087897

  9. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy

    DEFF Research Database (Denmark)

    Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc

    2012-01-01

    adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment...... of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host...

  10. [Epigenetics of prostate cancer].

    Science.gov (United States)

    Yi, Xiao-Ming; Zhou, Wen-Quan

    2010-07-01

    Prostate cancer is one of the most common malignant tumors in males, and its etiology and pathogenesis remain unclear. Epigenesis is involved in prostate cancer at all stages of the process, and closely related with its growth and metastasis. DNA methylation and histone modification are the most important manifestations of epigenetics in prostate cancer. The mechanisms of carcinogenesis of DNA methylation include whole-genome hypomethylation, aberrant local hypermethylation of promoters and genomic instability. DNA methylation is closely related to the process of prostate cancer, as in DNA damage repair, hormone response, tumor cell invasion/metastasis, cell cycle regulation, and so on. Histone modification causes corresponding changes in chromosome structure and the level of gene transcription, and it may affect the cycle, differentiation and apoptosis of cells, resulting in prostate cancer. Some therapies have been developed targeting the epigenetic changes in prostate cancer, including DNA methyltransferases and histone deacetylase inhibitors, and have achieved certain desirable results.

  11. A new ODE tumor growth modeling based on tumor population dynamics

    International Nuclear Information System (INIS)

    Oroji, Amin; Omar, Mohd bin; Yarahmadian, Shantia

    2015-01-01

    In this paper a new mathematical model for the population of tumor growth treated by radiation is proposed. The cells dynamics population in each state and the dynamics of whole tumor population are studied. Furthermore, a new definition of tumor lifespan is presented. Finally, the effects of two main parameters, treatment parameter (q), and repair mechanism parameter (r) on tumor lifespan are probed, and it is showed that the change in treatment parameter (q) highly affects the tumor lifespan

  12. A new ODE tumor growth modeling based on tumor population dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Oroji, Amin; Omar, Mohd bin [Institute of Mathematical Sciences, Faculty of Science University of Malaya, 50603 Kuala Lumpur, Malaysia amin.oroji@siswa.um.edu.my, mohd@um.edu.my (Malaysia); Yarahmadian, Shantia [Mathematics Department Mississippi State University, USA Syarahmadian@math.msstate.edu (United States)

    2015-10-22

    In this paper a new mathematical model for the population of tumor growth treated by radiation is proposed. The cells dynamics population in each state and the dynamics of whole tumor population are studied. Furthermore, a new definition of tumor lifespan is presented. Finally, the effects of two main parameters, treatment parameter (q), and repair mechanism parameter (r) on tumor lifespan are probed, and it is showed that the change in treatment parameter (q) highly affects the tumor lifespan.

  13. Growth Factors and Breast Tumors, Comparison of Selected Growth Factors with Traditional Tumor Markers

    Czech Academy of Sciences Publication Activity Database

    Kučera, R.; Černá, M.; Ňaršanská, A.; Svobodová, Š.; Straková, M.; Vrzalová, J.; Fuchsová, R.; Třešková, I.; Kydlíček, T.; Třeška, V.; Pecen, Ladislav; Topolčan, O.; Padziora, P.

    2011-01-01

    Roč. 31, č. 12 (2011), s. 4653-4656 ISSN 0250-7005 Grant - others:GA MZd(CZ) NS9727; GA MZd(CZ) NS10238; GA MZd(CZ) NS10253 Institutional research plan: CEZ:AV0Z10300504 Keywords : growth factor * breast cancer * tumor markers * CA 15-3 * CEA * IGF1 * EGF * HGF Subject RIV: FD - Oncology ; Hematology Impact factor: 1.725, year: 2011

  14. Tasquinimod (ABR-215050, a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors

    Directory of Open Access Journals (Sweden)

    Isaacs John T

    2010-05-01

    Full Text Available Abstract Background The orally active quinoline-3-carboxamide tasquinimod [ABR-215050; CAS number 254964-60-8, which currently is in a phase II-clinical trial in patients against metastatic prostate cancer, exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of tasquinimod, in vitro and in vivo experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time semiquantitative reversed transcriptase polymerase chain reaction (sqRT-PCR and protein expression techniques. Results One of the most significant differentially expressed genes both in vitro and in vivo after exposure to tasquinimod, was thrombospondin-1 (TSP1. The up-regulation of TSP1 mRNA in LNCaP tumor cells both in vitro and in vivo correlated with an increased expression and extra cellular secretion of TSP1 protein. When nude mice bearing CWR-22RH human prostate tumors were treated with oral tasquinimod, there was a profound growth inhibition, associated with an up-regulation of TSP1 and a down- regulation of HIF-1 alpha protein, androgen receptor protein (AR and glucose transporter-1 protein within the tumor tissue. Changes in TSP1 expression were paralleled by an anti-angiogenic response, as documented by decreased or unchanged tumor tissue levels of VEGF (a HIF-1 alpha down stream target in the tumors from tasquinimod treated mice. Conclusions We conclude that tasquinimod-induced up-regulation of TSP1 is part of a mechanism involving down-regulation of HIF1α and VEGF, which in turn leads to reduced angiogenesis via inhibition of the "angiogenic switch", that could explain tasquinimods therapeutic potential.

  15. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines

    International Nuclear Information System (INIS)

    Gu Yongpeng; Li Hongzhen; Miki, Jun; Kim, Kee-Hong; Furusato, Bungo; Sesterhenn, Isabell A.; Chu, Wei-Sing; McLeod, David G.; Srivastava, Shiv; Ewing, Charles M.; Isaacs, William B.; Rhim, Johng S.

    2006-01-01

    In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents

  16. Interleukin-Driven Insulin-Like Growth Factor Promotes Prostatic Inflammatory Hyperplasia

    Science.gov (United States)

    Hahn, Alana M.; Myers, Jason D.; McFarland, Eliza K.; Lee, Sanghee

    2014-01-01

    Prostatic inflammation is of considerable importance to urologic research because of its association with benign prostatic hyperplasia and prostate cancer. However, the mechanisms by which inflammation leads to proliferation and growth remain obscure. Here, we show that insulin-like growth factors (IGFs), previously known as critical developmental growth factors during prostate organogenesis, are induced by inflammation as part of the proliferative recovery to inflammation. Using genetic models and in vivo IGF receptor blockade, we demonstrate that the hyperplastic response to inflammation depends on interleukin-1–driven IGF signaling. We show that human prostatic hyperplasia is associated with IGF pathway activation specifically localized to foci of inflammation. This demonstrates that mechanisms of inflammation-induced epithelial proliferation and hyperplasia involve the induction of developmental growth factors, further establishing a link between inflammatory and developmental signals and providing a mechanistic basis for the management of proliferative diseases by IGF pathway modulation. PMID:25292180

  17. PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer.

    Science.gov (United States)

    Rogers, Oliver C; Anthony, Lizamma; Rosen, D Marc; Brennen, W Nathaniel; Denmeade, Samuel R

    2018-04-27

    Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers.

  18. Towards an integrative computational model for simulating tumor growth and response to radiation therapy

    Science.gov (United States)

    Marrero, Carlos Sosa; Aubert, Vivien; Ciferri, Nicolas; Hernández, Alfredo; de Crevoisier, Renaud; Acosta, Oscar

    2017-11-01

    Understanding the response to irradiation in cancer radiotherapy (RT) may help devising new strategies with improved tumor local control. Computational models may allow to unravel the underlying radiosensitive mechanisms intervening in the dose-response relationship. By using extensive simulations a wide range of parameters may be evaluated providing insights on tumor response thus generating useful data to plan modified treatments. We propose in this paper a computational model of tumor growth and radiation response which allows to simulate a whole RT protocol. Proliferation of tumor cells, cell life-cycle, oxygen diffusion, radiosensitivity, RT response and resorption of killed cells were implemented in a multiscale framework. The model was developed in C++, using the Multi-formalism Modeling and Simulation Library (M2SL). Radiosensitivity parameters extracted from literature enabled us to simulate in a regular grid (voxel-wise) a prostate cell tissue. Histopathological specimens with different aggressiveness levels extracted from patients after prostatectomy were used to initialize in silico simulations. Results on tumor growth exhibit a good agreement with data from in vitro studies. Moreover, standard fractionation of 2 Gy/fraction, with a total dose of 80 Gy as a real RT treatment was applied with varying radiosensitivity and oxygen diffusion parameters. As expected, the high influence of these parameters was observed by measuring the percentage of survival tumor cell after RT. This work paves the way to further models allowing to simulate increased doses in modified hypofractionated schemes and to develop new patient-specific combined therapies.

  19. Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

    Science.gov (United States)

    Deep, Gagan; Panigrahi, Gati K.

    2017-01-01

    Prostate cancer (PCA) is the leading malignancy in men and the second leading cause of cancer-related deaths. Hypoxia (low O2 condition) is considered an early event in prostate carcinogenesis associated with an aggressive phenotype. In fact, clinically, hypoxia and hypoxia-related biomarkers are associated with treatment failure and disease progression. Hypoxia-inducible factor 1 (HIF-1) is the key factor that is activated under hypoxia, and mediates adaptation of cells to hypoxic conditions through regulating the expression of genes associated with angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, survival, proliferation, metabolism, stemness, hormone-refractory progression, and therapeutic resistance. Besides HIF-1, several other signaling pathways including PI3K/Akt/mTOR, NADPH oxidase (NOX), Wnt/β-catenin, and Hedgehog are activated in cancer cells under hypoxic conditions, and also contribute in hypoxia-induced biological effects in HIF-1-dependent and -independent manners. Hypoxic cancer cells cause extensive changes in the tumor microenvironment both local and distant, and recent studies have provided ample evidence supporting the crucial role of nanosized vesicles “exosomes” in mediating hypoxia-induced tumor microenvironment remodeling. Exosomes’ role has been reported in hypoxia-induced angiogenesis, stemness, activation of cancer-associated fibroblasts (CAFs), and EMT. Together, existing literature suggests that hypoxia plays a predominant role in PCA growth and progression, and PCA could be effectively prevented and treated via targeting hypoxia/hypoxia-related signaling pathways. PMID:27279239

  20. Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Pedersen, S B

    1997-01-01

    -I after 3 days of treatment, and administration of IGF-I concomitantly with DFMO significantly inhibited ODC activity and the weight increase of the prostate. Stereological examination of the prostate in the IGF-I-treated animals showed growth of the epithelial component of the gland. Systemic treatment...

  1. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy.

    Science.gov (United States)

    Denmeade, Samuel R; Mhaka, Annastasiah M; Rosen, D Marc; Brennen, W Nathaniel; Dalrymple, Susan; Dach, Ingrid; Olesen, Claus; Gurel, Bora; Demarzo, Angelo M; Wilding, George; Carducci, Michael A; Dionne, Craig A; Møller, Jesper V; Nissen, Poul; Christensen, S Brøgger; Isaacs, John T

    2012-06-27

    Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.

  2. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    International Nuclear Information System (INIS)

    Guo, Jia; Liu, Xiuheng; Wang, Min

    2015-01-01

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo

  3. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

    2015-09-04

    Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cell proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.

  4. [Large benign prostatic hiperplasia].

    Science.gov (United States)

    Soria-Fernández, Guillermo René; Jungfermann-Guzman, José René; Lomelín-Ramos, José Pedro; Jaspersen-Gastelum, Jorge; Rosas-Nava, Jesús Emmanuel

    2012-01-01

    the term prostatic hyperplasia is most frequently used to describe the benign prostatic growth, this being a widely prevalent disorder associated with age that affects most men as they age. The association between prostate growth and urinary obstruction in older adults is well documented. large benign prostatic hyperplasia is rare and few cases have been published and should be taken into account during the study of tumors of the pelvic cavity. we report the case of an 81-year-old who had significant symptoms relating to storage and bladder emptying, with no significant elevation of prostate specific antigen. this is a rare condition but it is still important to diagnose and treat as it may be related to severe obstructive uropathy and chronic renal failure. In our institution, cases of large prostatic hyperplasia that are solved by suprapubic adenomectomy are less than 3%.

  5. Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Hao, Jun; Ci, Xinpei; Xue, Hui; Wu, Rebecca; Dong, Xin; Choi, Stephen Yiu Chuen; He, Haiqing; Wang, Yu; Zhang, Fang; Qu, Sifeng; Zhang, Fan; Haegert, Anne M; Gout, Peter W; Zoubeidi, Amina; Collins, Colin; Gleave, Martin E; Lin, Dong; Wang, Yuzhuo

    2018-06-01

    Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a

  6. Assessment of nucleosides as putative tumor biomarkers in prostate cancer screening by CE-UV.

    Science.gov (United States)

    Buzatto, Adriana Zardini; de Oliveira Silva, Mariana; Poppi, Ronei Jesus; Simionato, Ana Valéria Colnaghi

    2017-05-01

    Cancer is responsible for millions of deaths worldwide, but most base diseases may be cured if detected early. Screening tests may be used to identify early-stage malignant neoplasms. However, the major screening tool for prostate cancer, the prostate-specific antigen test, has unsuitable sensitivity. Since cancer cells may affect the pattern of consumption and excretion of nucleosides, such biomolecules are putative biomarkers that can be used for diagnosis and treatment evaluation. Using a previously validated method for the analysis of nucleosides in blood serum by capillary electrophoresis with UV-vis spectroscopy detection, we investigated 60 samples from healthy individuals and 42 samples from prostate cancer patients. The concentrations of nucleosides in both groups were compared and a multivariate partial least squares-discriminant analysis classification model was optimized for prediction of prostate cancer. The validation of the model with an independent sample set resulted in the correct classification of 82.4% of the samples, with sensitivity of 90.5% and specificity of 76.7%. A significant downregulation of 5-methyluridine and inosine was observed, which can be indicative of the carcinogenic process. Therefore, such analytes are potential candidates for prostate cancer screening. Graphical Abstract Separation of the studied nucleosides and the internal standard 8-Bromoguanosine by CE-UV (a); classification of the external validation samples (30 from healthy volunteers and 21 from prostate cancer patients) by the developed Partial Least Square - Discriminant Analysis (PLS-DA) model with accuracy of 82.4% (b); Receiver Operating Characteristics (ROC) curve (c); and Variable Importance in the Projection (VIP) values for the studied nucleosides (d). A significant down-regulation of 5- methyluridine (5mU) and inosine (I) was observed, which can be indicative of the presence of prostate tumors.

  7. Quantitation of circulating tumor cells in blood samples from ovarian and prostate cancer patients using tumor-specific fluorescent ligands.

    Science.gov (United States)

    He, Wei; Kularatne, Sumith A; Kalli, Kimberly R; Prendergast, Franklyn G; Amato, Robert J; Klee, George G; Hartmann, Lynn C; Low, Philip S

    2008-10-15

    Quantitation of circulating tumor cells (CTCs) can provide information on the stage of a malignancy, onset of disease progression and response to therapy. In an effort to more accurately quantitate CTCs, we have synthesized fluorescent conjugates of 2 high-affinity tumor-specific ligands (folate-AlexaFluor 488 and DUPA-FITC) that bind tumor cells >20-fold more efficiently than fluorescent antibodies. Here we determine whether these tumor-specific dyes can be exploited for quantitation of CTCs in peripheral blood samples from cancer patients. A CTC-enriched fraction was isolated from the peripheral blood of ovarian and prostate cancer patients by an optimized density gradient centrifugation protocol and labeled with the aforementioned fluorescent ligands. CTCs were then quantitated by flow cytometry. CTCs were detected in 18 of 20 ovarian cancer patients (mean 222 CTCs/ml; median 15 CTCs/ml; maximum 3,118 CTCs/ml), whereas CTC numbers in 16 gender-matched normal volunteers were negligible (mean 0.4 CTCs/ml; median 0.3 CTCs/ml; maximum 1.5 CTCs/ml; p < 0.001, chi(2)). CTCs were also detected in 10 of 13 prostate cancer patients (mean 26 CTCs/ml, median 14 CTCs/ml, maximum 94 CTCs/ml) but not in 18 gender-matched healthy donors (mean 0.8 CTCs/ml, median 1, maximum 3 CTC/ml; p < 0.0026, chi(2)). Tumor-specific fluorescent antibodies were much less efficient in quantitating CTCs because of their lower CTC labeling efficiency. Use of tumor-specific fluorescent ligands to label CTCs in peripheral blood can provide a simple, accurate and sensitive method for determining the number of cancer cells circulating in the bloodstream.

  8. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2003-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  9. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2004-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  10. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas S

    2005-01-01

    ...). The novelty in our approach is our ability to enhance the selectivity of VSV-induced killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  11. Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

    Directory of Open Access Journals (Sweden)

    Yingjen Jeffrey Wu

    2009-02-01

    Full Text Available The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally 24 hours before human ovarian carcinoma (SKOV3, small cell lung carcinoma (LX-1 SCLC, and glioma (UW28, U87MG, and U251 tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0% of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

  12. Inhibition of prostate cancer growth using doxorubicin assisted by ultrasound-targeted nanobubble destruction

    Directory of Open Access Journals (Sweden)

    Fan X

    2016-07-01

    Full Text Available Xiaozhou Fan,1,* Luofu Wang,2,* Yanli Guo,1 Xingyu Xiong,1 Lianhua Zhu,1 Kejing Fang1 1Department of Ultrasound, Southwest Hospital, 2Department of Urology, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China *These authors contributed equally to this work Abstract: Ultrasound (US-targeted microbubble destruction has been widely used as an effective drug-delivery system. However, nanobubbles (NBs have better stability and stronger penetration than microbubbles, and drug delivery assisted by US-targeted NB destruction (UTND still needs to be investigated. Our aim was to investigate the effect of doxorubicin (DOX on the inhibition of prostate cancer growth under UTND. Contrast-enhanced US imaging of transplanted PC3 prostate cancer in mice showed that under a combination of 1 W/cm2 US power and a 100 Hz intermittent pulse with a “5 seconds on, 5 seconds off” mode, NBs with an average size of (485.7±33 nm were effectively destroyed within 15 minutes in the tumor location. PC3 cells and 20 tumor-bearing mice were divided into four groups: a DOX group, a DOX + NB group, a DOX + US group, and a DOX + NB + US group. The cell growth-inhibition rate and DOX concentration of xenografts in the DOX + NB + US group were highest. Based on another control group and these four groups, another 25 tumor-bearing mice were used to observe the treatment effect of nine DOX injections under UTND. The xenografts in the DOX + NB + US group decreased more obviously and had more cellular apoptosis than other groups. Finally, electron microscopy was used to estimate the cavitation effect of NBs under US irradiation in the control group, NB group, US group, and NB + US group. The results of scanning electron microscopy showed that PC3 cells in the DOX + NB + US group had more holes and significantly increased cell-surface folds. Meanwhile, transmission electric microscopy confirmed that more lanthanum nitrate particles entered

  13. MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model

    Energy Technology Data Exchange (ETDEWEB)

    Oyama, Nobuyuki; Kim, Joonyoung; Jones, Lynne A.; Mercer, Nicole M.; Engelbach, John A.; Sharp, Terry L.; Welch, Michael J. E-mail: welchm@mir.wustl.edu

    2002-11-01

    PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, {sup 18}F-FDG and {sup 11}C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 {mu}g dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received {sup 18}F-FDG, whereas the remaining eight animals were administered {sup 11}C-acetate. Rats were sacrificed at 120 min post-injection of {sup 18}F-FDG or 30 min post-injection of {sup 11}C-acetate. Pretreatment of the mouse model using DHT (200 {mu}g of DHT in 0.1 mL of sunflower seed oil) or DES (200 {mu}g of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in {sup 18}F-FDG study, while there was no significant difference in {sup 11}C-acetate uptake. These results indicate that changes in serum testosterone levels influence {sup 18}F-FDG uptake in the prostate gland, which is closely tied to glucose

  14. Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

    Science.gov (United States)

    Nakata, Daisuke; Nakayama, Kazuhide; Masaki, Tsuneo; Tanaka, Akira; Kusaka, Masami; Watanabe, Tatsuya

    2016-12-01

    Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the

  15. Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry.

    Science.gov (United States)

    Kami, Kenjiro; Fujimori, Tamaki; Sato, Hajime; Sato, Mutsuko; Yamamoto, Hiroyuki; Ohashi, Yoshiaki; Sugiyama, Naoyuki; Ishihama, Yasushi; Onozuka, Hiroko; Ochiai, Atsushi; Esumi, Hiroyasu; Soga, Tomoyoshi; Tomita, Masaru

    2013-04-01

    Metabolic microenvironment of tumor cells is influenced by oncogenic signaling and tissue-specific metabolic demands, blood supply, and enzyme expression. To elucidate tumor-specific metabolism, we compared the metabolomics of normal and tumor tissues surgically resected pairwise from nine lung and seven prostate cancer patients, using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Phosphorylation levels of enzymes involved in central carbon metabolism were also quantified. Metabolomic profiles of lung and prostate tissues comprised 114 and 86 metabolites, respectively, and the profiles not only well distinguished tumor from normal tissues, but also squamous cell carcinoma from the other tumor types in lung cancer and poorly differentiated tumors from moderately differentiated tumors in prostate cancer. Concentrations of most amino acids, especially branched-chain amino acids, were significantly higher in tumor tissues, independent of organ type, but of essential amino acids were particularly higher in poorly differentiated than moderately differentiated prostate cancers. Organ-dependent differences were prominent at the levels of glycolytic and tricarboxylic acid cycle intermediates and associated energy status. Significantly high lactate concentrations and elevated activating phosphorylation levels of phosphofructokinase and pyruvate kinase in lung tumors confirmed hyperactive glycolysis. We highlighted the potential of CE-TOFMS-based metabolomics combined with phosphorylated enzyme analysis for understanding tissue-specific tumor microenvironments, which may lead to the development of more effective and specific anticancer therapeutics.

  16. Probing Androgen Receptor Signaling in Circulating Tumor Cells in Prostate Cancer

    Science.gov (United States)

    2013-07-01

    2010). Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older. Diseases of the Esophagus , 23:316-23. Epub 2009...Circulating Tumor Cells in Prostate Cancer PRINCIPAL INVESTIGATOR: David T. Miyamoto, M.D., Ph.D... Cancer 5b. GRANT NUMBER W81XWH-12-1-0153 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER David T. Miyamoto, M.D., Ph.D. 5e

  17. Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts.

    Science.gov (United States)

    Mellinghoff, Ingo K; Tran, Chris; Sawyers, Charles L

    2002-09-15

    Experiments with human prostate cancer cell lines have shown that forced overexpression of the ErbB2-receptor tyrosine kinase (RTK) promotes androgen-independent growth and increases androgen receptor-transcriptional activity in a ligand-independent fashion. To investigate the relationship between ErbB-RTK signaling and androgen in genetically unmanipulated human prostate cancer, we performed biochemical and biological studies with the dual ErbB1/ErbB2 RTK inhibitor PKI-166 using human prostate cancer xenograft models with isogenic sublines reflecting the transition from androgen-dependent to androgen-independent growth. In the presence of low androgen concentrations, PKI-166 showed profound growth-inhibitory effects on tumor growth, which could be partially reversed by androgen add-back. At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI-166 to retard tumor growth. The level of extracellular signal-regulated kinase activation correlated with the response to PKI-166 treatment, whereas the expression levels of ErbB1 and ErbB2 did not. These results suggest that ErbB1/ErbB2 RTKs play an important role in the biology of androgen-independent prostate cancer and provide a rationale for clinical evaluation of inhibitors targeted to this pathway.

  18. LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality.

    Science.gov (United States)

    Fiano, Valentina; Zugna, Daniela; Grasso, Chiara; Trevisan, Morena; Delsedime, Luisa; Molinaro, Luca; Gillio-Tos, Anna; Merletti, Franco; Richiardi, Lorenzo

    2017-01-02

    Aberrant DNA methylation seems to be associated with prostate cancer behavior. We investigated LINE-1 methylation in prostate cancer and non-neoplastic tissue adjacent to tumor (NTAT) in association with mortality from prostate cancer. We selected 157 prostate cancer patients with available NTAT from 2 cohorts of patients diagnosed between 1982-1988 and 1993-1996, followed up until 2010. An association between LINE-1 hypomethylation and prostate cancer mortality in tumor was suggested [hazard ratio per 5% decrease in LINE-1 methylation levels: 1.40, 95% confidence interval (CI): 0.95-2.01]. After stratification of the patients for Gleason score, the association was present only for those with a Gleason score of at least 8. Among these, low (80%) LINE-1 methylation was associated with a hazard ratio of 4.68 (95% CI: 1.03-21.34). LINE-1 methylation in the NTAT was not associated with prostate cancer mortality. Our results are consistent with the hypothesis that tumor tissue global hypomethylation may be a late event in prostate cancerogenesis and is associated with tumor progression.

  19. 13C and 31P NMR [Nuclear Magnetic Resonance] studies of prostate tumor metabolism

    International Nuclear Information System (INIS)

    Sillerud, L.O.; Halliday, K.R.; Freyer, J.P; Griffey, R.H.; Fenoglio-Preiser, C.

    1989-01-01

    The current research on prostate cancer by NMR spectroscopy and microscopy will most significantly contribute to tumor diagnosis and characterization only if sound biochemical models of tumor metabolism are established and tested. Prior searches focused on universal markers of malignancy, have to date, revealed no universal markers by any method. It is unlikely that NMRS will succeed where other methods have failed, however, NMR spectroscopy does provide a non-invasive means to analyze multiple compounds simultaneously in vivo. In order to fully evaluate the ability of NMRS to differentiate non-malignant from malignant tissues it is necessary to determine sufficient multiple parameters from specific, well-diagnosed, histological tumor types that, in comparison to normal tissue and non-neoplastic, non-normal pathologies from which the given neoplasm must be differentiated, one has enough degrees of freedom to make a mathematically and statistically significant determination. Confounding factors may consist of tumor heterogeneity arising from regional variations in differentiation, ischemia, necrosis, hemorrhage, inflammation and the presence of intermingled normal tissue. One related aspect of our work is the development of { 13 C}- 1 H metabolic imaging of 13 C for metabolic characterization, with enhanced spatial localization (46). This should markedly extend the range of potential clinical NMR uses because the spatial variation in prostate metabolism may prove to be just as important in tumor diagnoses as bulk (volume-averaged) properties themselves. It is our hope that NMRS and spectroscopic imaging will reveal a sound correlation between prostate metabolism and tumor properties that will be clinically straightforward and useful for diagnosis

  20. Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development.

    Science.gov (United States)

    Ruan, W; Powell-Braxton, L; Kopchick, J J; Kleinberg, D L

    1999-05-01

    Insulin-like growth factor I (IGF-I) has been implicated as a factor that may predispose one to prostate cancer. However, no specific relationship between IGF-I and prostate development or cancer in vivo has been established. To determine whether IGF-I was important in prostate development, we examined prostate architecture in IGF-I(-/-) null mice and wild-type littermates. Glands from 44-day-old IGF-I-deficient animals were not only smaller than those from wild-type mice, but also had fewer terminal duct tips and branch points and deficits in tertiary and quaternary branching (P deficit by increasing those parameters of prostate development (P growth as an extension of a normal process.

  1. The Role of Tumor Associated Macrophage in Recurrent Growth of Tumor Stem Cell

    Science.gov (United States)

    2011-09-01

    recent cancer stem cell (CSC) theory, recurrent tumor must arise from a dormant tumor stem cell whose re-growth is triggered by shifting of...microenvironment. This project aims at clarifying the roles of TAM in recurrent growth of dormant stem cell in breast cancer. We hypothesize that the balance of...dormancy and recurrence is determined by the ability of the tumor stem cells to recruit TAM which in turn promotes self-renewal of the stem cell . We

  2. BRE enhances in vivo growth of tumor cells

    International Nuclear Information System (INIS)

    Chan, Ben Chung-Lap; Li Qing; Chow, Stephanie Ka-Yee; Ching, Arthur Kar-Keung; Liew, Choong Tsek; Lim, Pak-Leong; Lee, Kenneth Ka-Ho; Chan, John Yeuk-Hon; Chui, Y.-L.

    2005-01-01

    Human BRE, a death receptor-associating intracellular protein, attenuates apoptotic response of human and mouse tumor cell lines to death receptor stimuli in vitro. In this report, we addressed whether the in vitro antiapoptotic effect of BRE could impact on tumor growth in vivo. We have shown that the mouse Lewis lung carcinoma D122 stable transfectants of human BRE expression vector developed into local tumor significantly faster than the stable transfectants of empty vector and parental D122, in both the syngeneic C57BL/6 host and nude mice. In vitro growth of the BRE stable transfectants was, however, not accelerated. No significant difference in metastasis between the transfectants and the parental D122 was detected. Thus, overexpression of BRE promotes local tumor growth but not metastasis. We conclude that the enhanced tumor growth is more likely due to the antiapoptotic activity of BRE than any direct effect of the protein on cell proliferation

  3. Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

    Science.gov (United States)

    Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

    2012-01-01

    The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

  4. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    International Nuclear Information System (INIS)

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-01-01

    Highlights: • M-CSF and RANKL expressing HeLa cells induced osteoclastogenesis in vitro. • We established OGC-containing tumor model in vivo. • OGC-containing tumor became larger independent of M-CSF or RANKL effect. • VEGF-C secreted from OGCs was a one of candidates for OGC-containing tumor growth. - Abstract: Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-κB ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These

  5. Cryospectrophotometric determination of tumor intravascular oxyhemoglobin saturations: dependence on vascular geometry and tumor growth.

    Science.gov (United States)

    Fenton, B M; Rofstad, E K; Degner, F L; Sutherland, R M

    1988-12-21

    To delineate the complex relationships between overall tumor oxygenation and vascular configuration, intravascular oxyhemoglobin (HbO2) saturation distributions were measured with cryospectrophotometric techniques. Four factors related to vascular morphometry and tumor growth were evaluated: a) vessel diameter, b) distance of vessel from the tumor surface, c) tumor volume, and d) vascular density. To measure intertumor heterogeneity, two murine sarcomas (RIF-1 and KHT) and two human ovarian carcinoma xenografts (OWI and MLS) were utilized. In contrast to skeletal muscle, a preponderance of very low HbO2 saturations was observed for both large and small tumors of all lines. Saturations up to about 90% were also generally present, however, even in very large tumors. Variations in vascular configuration were predominantly tumor-line dependent rather than due to inherent characteristics of the host vasculature, and widely disparate HbO2 distributions were found for alternate lines implanted in identical host mice. Although peripheral saturations remained fairly constant with tumor growth, HbO2 values were markedly lower for vessels nearer the tumor center and further decreased with increasing tumor volume. HbO2 saturations did not change substantially with increasing vascular density (except for KHT tumors), although density did decrease with increasing distance from tumor surface. Combined effects of vessel diameter, tumor volume, and vessel location on HbO2 saturations were complex and varied markedly with both tumor line and vessel class. For specific classes, HbO2 distributions correlated closely with radiobiological hypoxic fractions, i.e., for tumor lines in which hypoxic fraction increased substantially with tumor volume, corresponding HbO2 values decreased, while for lines in which hypoxic fraction remained constant, HbO2 values also were unchanged. Although these trends may also be a function of differing oxygen consumption rates between tumor lines

  6. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    Energy Technology Data Exchange (ETDEWEB)

    Pagan, Jonathan, E-mail: jdpagan@uams.edu; Przybyla, Beata; Jamshidi-Parsian, Azemat [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States); Gupta, Kalpna [Vascular Biology Center and Division of Hematology-Oncology Transplantation, Department of Medicine, University of Minnesota Medical School, MN 72223 (United States); Griffin, Robert J. [Department of Radiation Oncology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205 (United States)

    2013-02-18

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm{sup 3}) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  7. Blood Outgrowth Endothelial Cells Increase Tumor Growth Rates and Modify Tumor Physiology: Relevance for Therapeutic Targeting

    International Nuclear Information System (INIS)

    Pagan, Jonathan; Przybyla, Beata; Jamshidi-Parsian, Azemat; Gupta, Kalpna; Griffin, Robert J.

    2013-01-01

    Endothelial cell precursors from human peripheral blood have been shown to home to areas of neovascularization and may assist tumor growth by increasing or fortifying blood vessel growth. In the present study, the influence of these cells on tumor growth and physiology was investigated and the role of these cells as a therapeutic target or in determining treatment sensitivity was tested. After isolation from human blood and expansion in vitro, actively growing cells with verified endothelial phenotype (Blood Outgrowth Endothelial Cell, BOEC) were injected i.v. into tumor bearing mice for three consecutive days. The growth rate was significantly enhanced in relatively small RERF human lung tumors (i.e., less than 150 mm 3 ) grown in immunocompromised mice by an average of 1.5-fold while it had no effect when injections were given to animals bearing larger tumors. There were no signs of toxicity or unwanted systemic effects. We also observed evidence of increased perfusion, vessel number, response to 15 Gy radiation and oxygenation in RERF tumors of animals injected with BOECs compared to control tumors. In addition, FSaII murine fibrosarcoma tumors were found to grow faster upon injection of BOECs. When FSaII tumors were subjected to a partial thermal ablation treatment using high intensity focused ultrasound (HIFU) there was consistently elevated detection of fluorescently labeled and i.v. injected endothelial precursors in the tumor when analyzed with optical imaging and/or histological preparations. Importantly, we also observed that BOECs treated with the novel anti-angiogenic peptide anginex in-vitro, show decreased proliferation and increased sensitivity to radiation. In vivo, the normal increase in FSaII tumor growth induced by injected BOECs was blunted by the addition of anginex treatment. It appears that endothelial precursors may significantly contribute to tumor vessel growth, tumor progression and/or repair of tumor damage and may improve the

  8. Mathematical models of tumor growth: translating absorbed dose to tumor control probability

    International Nuclear Information System (INIS)

    Sgouros, G.

    1996-01-01

    Full text: The dose-rate in internal emitter therapy is low and time-dependent as compared to external beam radiotherapy. Once the total absorbed dose delivered to a target tissue is calculated, however, most dosimetric analyses of radiopharmaceuticals are considered complete. To translate absorbed dose estimates obtained for internal emitter therapy to biologic effect, the growth characteristics, repair capacity, and radiosensitivity of the tumor must be considered. Tumor growth may be represented by the Gompertz equation in which tumor cells increase at an exponential growth rate that is itself decreasing at an exponential rate; as the tumor increases in size, the growth rate diminishes. The empirical Gompertz expression for tumor growth may be derived from a mechanistic model in which growth is represented by a balance between tumor-cell birth and loss. The birth rate is assumed to be fixed, while the cell loss rate is time-dependent and increases with tumor size. The birth rate of the tumors may be related to their potential doubling time. Multiple biopsies of individual tumors have demonstrated a heterogeneity in the potential doubling time of tumors. By extending the mechanistic model described above to allow for sub-populations of tumor cells with different birth rates, the effect of kinetic heterogeneity within a tumor may be examined. Model simulations demonstrate that the cell kinetic parameters of a tumor are predicted to change over time and measurements obtained using a biopsy are unlikely to reflect the kinetics of the tumor throughout its growth history. A decrease in overall tumor mass, in which each sub-population is reduced in proportion to its cell number, i.e., the log-kill assumption, leads to re-growth of a tumor that has a greater proliferation rate. Therapy that is linked to the potential doubling time or to the effective proliferation rate of the tumor may lead to re-growth of a tumor that is kinetically unchanged. The simplest model of

  9. Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils

    Directory of Open Access Journals (Sweden)

    Ming Yuan

    2016-01-01

    Full Text Available Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4+ and CD8+ T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth.

  10. Increased aPKC Expression Correlates with Prostatic Adenocarcinoma Gleason Score and Tumor Stage in the Japanese Population

    Directory of Open Access Journals (Sweden)

    Anthony S. Perry

    2014-01-01

    Full Text Available Background. Levels of the protein kinase aPKC have been previously correlated with prostate cancer prognosis in a British cohort. However, prostate cancer incidence and progression rates, as well as genetic changes in this disease, show strong ethnic variance, particularly in Asian populations. Objective. The aim of this study was to validate association of aPKC expression with prostatic adenocarcinoma stages in a Japanese cohort. Methods. Tissue microarrays consisting of 142 malignant prostate cancer cases and 21 benign prostate tissues were subject to immunohistological staining for aPKC. aPKC staining intensity was scored by three independent pathologists and categorized as absent (0, dim (1+, intermediate (2+, and bright (3+. aPKC staining intensities were correlated with Gleason score and tumor stage. Results. Increased aPKC staining was observed in malignant prostate cancer, in comparison to benign tissue. Additionally, aPKC staining levels correlated with Gleason score and tumor stage. Our results extend the association of aPKC with prostate cancer to a Japanese population and establish the suitability of aPKC as a universal prostate cancer biomarker that performs consistently across ethnicities.

  11. The p75NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

    International Nuclear Information System (INIS)

    Khwaja, Fatima; Tabassum, Arshia; Allen, Jeff; Djakiew, Daniel

    2006-01-01

    The p75 neurotrophin receptor (p75 NTR ) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75 NTR retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (ΔDD) dominant-negative antagonist of p75 NTR showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75 NTR -dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75 NTR expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75 NTR rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75 NTR was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75 NTR -dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75 NTR expressing prostate cancer cells

  12. The p75{sup NTR} tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Khwaja, Fatima [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057-1436 (United States); Tabassum, Arshia [Toronto Western Hospital, Toronto, ON, M5T258 (Canada); Allen, Jeff [National Center for Complementary and Alternative Medicine, N.I.H., Bethesda, MD 20892 (United States); Djakiew, Daniel [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057-1436 (United States) and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057-1436 (United States)

    2006-03-24

    The p75 neurotrophin receptor (p75{sup NTR}) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75{sup NTR} retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted ({delta}DD) dominant-negative antagonist of p75{sup NTR} showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75{sup NTR}-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75{sup NTR} expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75{sup NTR} rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75{sup NTR} was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75{sup NTR}-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75{sup NTR} expressing prostate cancer cells.

  13. Macrophages From Irradiated Tumors Express Higher Levels of iNOS, Arginase-I and COX-2, and Promote Tumor Growth

    International Nuclear Information System (INIS)

    Tsai, C.-S.; Chen, F.-H.; Wang, C.-C.; Huang, H.-L.; Jung, Shih-Ming; Wu, C.-J.; Lee, C.-C.; McBride, William H.; Chiang, C.-S.; Hong, J.-H.

    2007-01-01

    Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo

  14. A small molecule inhibitor of ETV1, YK-4-279, prevents prostate cancer growth and metastasis in a mouse xenograft model.

    Directory of Open Access Journals (Sweden)

    Said Rahim

    Full Text Available The erythroblastosis virus E26 transforming sequences (ETS family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.We recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S-YK-4-279 is the active enantiomer in prostate cancer cells.Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential

  15. Change of tumor vascular reactivity during tumor growth and postchemotherapy observed by near-infrared spectroscopy

    Science.gov (United States)

    Lee, Songhyun; Jeong, Hyeryun; Seong, Myeongsu; Kim, Jae Gwan

    2017-12-01

    Breast cancer is one of the most common cancers in females. To monitor chemotherapeutic efficacy for breast cancer, medical imaging systems such as x-ray mammography, computed tomography, magnetic resonance imaging, and ultrasound imaging have been used. Currently, it can take up to 3 to 6 weeks to see the tumor response from chemotherapy by monitoring tumor volume changes. We used near-infrared spectroscopy (NIRS) to predict breast cancer treatment efficacy earlier than tumor volume changes by monitoring tumor vascular reactivity during inhalational gas interventions. The results show that the amplitude of oxy-hemoglobin changes (vascular reactivity) during hyperoxic gas inhalation is well correlated with tumor growth and responded one day earlier than tumor volume changes after chemotherapy. These results may imply that NIRS with respiratory challenges can be useful in early detection of tumor and in the prediction of tumor response to chemotherapy.

  16. Hsp90 inhibitor 17-AAG inhibits progression of LuCaP35 xenograft prostate tumors to castration resistance.

    Science.gov (United States)

    O'Malley, Katherine J; Langmann, Gabrielle; Ai, Junkui; Ramos-Garcia, Raquel; Vessella, Robert L; Wang, Zhou

    2012-07-01

    Advanced prostate cancer is currently treated with androgen deprivation therapy (ADT). ADT initially results in tumor regression; however, all patients eventually relapse with castration-resistant prostate cancer. New approaches to delay the progression of prostate cancer to castration resistance are in desperate need. This study addresses whether targeting Heat shock protein 90 (HSP90) regulation of androgen receptor (AR) can inhibit prostate cancer progression to castration resistance. The HSP90 inhibitor 17-AAG was injected intraperitoneally into nude mice bearing LuCaP35 xenograft tumors to determine the effect of HSP90 inhibition on prostate cancer progression to castration resistance and host survival. Administration of 17-AAG maintained androgen-sensitivity, delayed the progression of LuCaP35 xenograft tumors to castration resistance, and prolonged the survival of host. In addition, 17-AAG prevented nuclear localization of endogenous AR in LuCaP35 xenograft tumors in castrated nude mice. Targeting Hsp90 or the mechanism by which HSP90 regulates androgen-independent AR nuclear localization and activation may lead to new approaches to prevent and/or treat castration-resistant prostate cancer. Copyright © 2011 Wiley Periodicals, Inc.

  17. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Archibald M

    2016-01-01

    Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

  18. Inhibitor of differentiation 4 (Id4) is a potential tumor suppressor in prostate cancer

    International Nuclear Information System (INIS)

    Carey, Jason PW; Asirvatham, Ananthi J; Galm, Oliver; Ghogomu, Tandeih A; Chaudhary, Jaideep

    2009-01-01

    Inhibitor of differentiation 4 (Id4), a member of the Id gene family is also a dominant negative regulator of basic helix loop helix (bHLH) transcription factors. Some of the functions of Id4 appear to be unique as compared to its other family members Id1, Id2 and Id3. Loss of Id4 gene expression in many cancers in association with promoter hypermethylation has led to the proposal that Id4 may act as a tumor suppressor. In this study we provide functional evidence that Id4 indeed acts as a tumor suppressor and is part of a cancer associated epigenetic re-programming. Data mining was used to demonstrate Id4 expression in prostate cancer. Methylation specific polymerase chain reaction (MSP) analysis was performed to understand molecular mechanisms associated with Id4 expression in prostate cancer cell lines. The effect of ectopic Id4 expression in DU145 cells was determined by cell cycle analysis (3H thymidine incorporation and FACS), expression of androgen receptor, p53 and cyclin dependent kinase inhibitors p27 and p21 by a combination of RT-PCR, real time-PCR, western blot and immuno-cytochemical analysis. Id4 expression was down-regulated in prostate cancer. Id4 expression was also down-regulated in prostate cancer line DU145 due to promoter hyper-methylation. Ectopic Id4 expression in DU145 prostate cancer cell line led to increased apoptosis and decreased cell proliferation due in part by an S-phase arrest. In addition to S-phase arrest, ectopic Id4 expression in PC3 cells also resulted in prolonged G2/M phase. At the molecular level these changes were associated with increased androgen receptor (AR), p21, p27 and p53 expression in DU145 cells. The results suggest that Id4 acts directly as a tumor suppressor by influencing a hierarchy of cellular processes at multiple levels that leads to a decreased cell proliferation and change in morphology that is possibly mediated through induction of previously silenced tumor suppressors

  19. Inhibitor of differentiation 4 (Id4 is a potential tumor suppressor in prostate cancer

    Directory of Open Access Journals (Sweden)

    Carey Jason PW

    2009-06-01

    Full Text Available Abstract Background Inhibitor of differentiation 4 (Id4, a member of the Id gene family is also a dominant negative regulator of basic helix loop helix (bHLH transcription factors. Some of the functions of Id4 appear to be unique as compared to its other family members Id1, Id2 and Id3. Loss of Id4 gene expression in many cancers in association with promoter hypermethylation has led to the proposal that Id4 may act as a tumor suppressor. In this study we provide functional evidence that Id4 indeed acts as a tumor suppressor and is part of a cancer associated epigenetic re-programming. Methods Data mining was used to demonstrate Id4 expression in prostate cancer. Methylation specific polymerase chain reaction (MSP analysis was performed to understand molecular mechanisms associated with Id4 expression in prostate cancer cell lines. The effect of ectopic Id4 expression in DU145 cells was determined by cell cycle analysis (3H thymidine incorporation and FACS, expression of androgen receptor, p53 and cyclin dependent kinase inhibitors p27 and p21 by a combination of RT-PCR, real time-PCR, western blot and immuno-cytochemical analysis. Results Id4 expression was down-regulated in prostate cancer. Id4 expression was also down-regulated in prostate cancer line DU145 due to promoter hyper-methylation. Ectopic Id4 expression in DU145 prostate cancer cell line led to increased apoptosis and decreased cell proliferation due in part by an S-phase arrest. In addition to S-phase arrest, ectopic Id4 expression in PC3 cells also resulted in prolonged G2/M phase. At the molecular level these changes were associated with increased androgen receptor (AR, p21, p27 and p53 expression in DU145 cells. Conclusion The results suggest that Id4 acts directly as a tumor suppressor by influencing a hierarchy of cellular processes at multiple levels that leads to a decreased cell proliferation and change in morphology that is possibly mediated through induction of previously

  20. Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors.

    Science.gov (United States)

    Bendinger, Alina L; Glowa, Christin; Peter, Jörg; Karger, Christian P

    2018-03-01

    A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

  1. Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors

    Science.gov (United States)

    Bendinger, Alina L.; Glowa, Christin; Peter, Jörg; Karger, Christian P.

    2018-03-01

    A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity.

  2. Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location.

    Science.gov (United States)

    Faisal, Farzana A; Sundi, Debasish; Tosoian, Jeffrey J; Choeurng, Voleak; Alshalalfa, Mohammed; Ross, Ashley E; Klein, Eric; Den, Robert; Dicker, Adam; Erho, Nicholas; Davicioni, Elai; Lotan, Tamara L; Schaeffer, Edward M

    2016-07-01

    Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, pprostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. Copyright © 2015. Published by Elsevier B.V.

  3. CCR 20th Anniversary Commentary: Circulating Tumor Cells in Prostate Cancer.

    Science.gov (United States)

    Mehra, Niven; Zafeiriou, Zafeiris; Lorente, David; Terstappen, Leon W M M; de Bono, Johann S

    2015-11-15

    Circulating tumor cells (CTC) have substantial promise for multipurpose biomarker studies in prostate cancer. The IMMC-38 trial conducted by de Bono and colleagues, which was published in the October 1, 2008, issue of Clinical Cancer Research, demonstrated for the first time that CTCs are the most accurate and independent predictor of overall survival in metastatic prostate cancer. Since the publication of prospective trials demonstrating prognostic utility, CTCs have been utilized for nucleic acid analyses, for protein analyses, and in intermediate endpoint studies. CTC studies are also now facilitating the analysis of intrapatient heterogeneity. See related article by de Bono et al., Clin Cancer Res 2008;14(19) October 1, 2008;6302-9. ©2015 American Association for Cancer Research.

  4. Mesenchymal stem cell 1 (MSC1-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ruth S Waterman

    Full Text Available Currently, there are many promising clinical trials using mesenchymal stem cells (MSCs in cell-based therapies of numerous diseases. Increasingly, however, there is a concern over the use of MSCs because they home to tumors and can support tumor growth and metastasis. For instance, we established that MSCs in the ovarian tumor microenvironment promoted tumor growth and favored angiogenesis. In parallel studies, we also developed a new approach to induce the conventional mixed pool of MSCs into two uniform but distinct phenotypes we termed MSC1 and MSC2.Here we tested the in vitro and in vivo stability of MSC1 and MSC2 phenotypes as well as their effects on tumor growth and spread. In vitro co-culture of MSC1 with various cancer cells diminished growth in colony forming units and tumor spheroid assays, while conventional MSCs or MSC2 co-culture had the opposite effect in these assays. Co-culture of MSC1 and cancer cells also distinctly affected their migration and invasion potential when compared to MSCs or MSC2 treated samples. The expression of bioactive molecules also differed dramatically among these samples. MSC1-based treatment of established tumors in an immune competent model attenuated tumor growth and metastasis in contrast to MSCs- and MSC2-treated animals in which tumor growth and spread was increased. Also, in contrast to these groups, MSC1-therapy led to less ascites accumulation, increased CD45+leukocytes, decreased collagen deposition, and mast cell degranulation.These observations indicate that the MSC1 and MSC2 phenotypes may be convenient tools for the discovery of critical components of the tumor stroma. The continued investigation of these cells may help ensure that cell based-therapy is used safely and effectively in human disease.

  5. Growth analysis of pulmonary metastases from salivary gland tumors.

    Science.gov (United States)

    Twardzik, F G; Sklaroff, D M

    1976-03-01

    Three cases of primary salivary gland tumors with lung metastasis are presented with extremely long survival (six, ten, and twelve years). The tumor doubling time was calculated and the growth rate of the pulmonary metastasis was found to be slow and erratic. A simplified table was devised, which permits rapid calculation of the tumor doubling time without the use of graphs. The presence of lung metastasis from some primary malignant salivary tumor is not necessarily an ominous sign: a long survival without symtoms is possible.

  6. Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth.

    Science.gov (United States)

    Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M; Yang, Jun; Starbuck, Michael W; Ravoori, Murali K; Kundra, Vikas; Vazquez, Elba; Navone, Nora M

    2012-03-01

    Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth

  7. A Big Bang model of human colorectal tumor growth.

    Science.gov (United States)

    Sottoriva, Andrea; Kang, Haeyoun; Ma, Zhicheng; Graham, Trevor A; Salomon, Matthew P; Zhao, Junsong; Marjoram, Paul; Siegmund, Kimberly; Press, Michael F; Shibata, Darryl; Curtis, Christina

    2015-03-01

    What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear 'born to be bad', with subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

  8. Hypoxia promotes tumor growth in linking angiogenesis to immune escape

    Directory of Open Access Journals (Sweden)

    Salem eCHOUAIB

    2012-02-01

    Full Text Available Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection and contains many overlapping mechanisms to evade antigen specific immunotherapy. Obviously, tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival and metastasis. Among the hypoxia-induced genes, hypoxia-inducible factor (HIF-1 and vascular endothelial growth factor (VEGF play a determinant role in promoting tumor cell growth and survival. In this regard, hypoxia is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.

  9. MRI to predict prostate growth and development in children, adolescents and young adults.

    Science.gov (United States)

    Ren, Jing; Liu, Huijia; Wang, He; Wen, Didi; Huang, Xufang; Ren, Fang; Huan, Yi

    2015-02-01

    The purpose of this study was to investigate the use of MRI in predicting prostate growth and development. A total of 1,500 healthy male volunteers who underwent MRI of the pelvis were included in this prospective study. Subjects were divided into five groups according to age (group A, 2-5 years; group B, 6-10 years; group C, 11-15 years; group D, 16-20 years; group E, 21-25 years). Total prostate volume (TPV) as well as prostate central zone (CZ) and peripheral zone (PZ) were measured and evaluated on MRI. Data of the different groups were compared using variance analysis, Scheffé's method, Kruskal-Wallis H-test, and Pearson's correlation. Statistical significance was inferred at P development scores were 0.08, 0.69, 1.56, 2.38, and 2.74, respectively. Both TPVs and zonal anatomy scores varied significantly among the five groups (P = 0.000). TPV and zonal anatomy score increased with increasing age. MRI provides a reliable quantitative reference for prostate growth and development. • When and how the prostate develops after birth remains unclear. • Prostate volume increases rapidly after the age of 10 years. • MRI provides a reliable objective and quantitative reference for prostate growth and development.

  10. Development of lutetium-labeled bombesin derivates: relationship between structure and diagnostic-therapeutic activity for prostate tumor

    International Nuclear Information System (INIS)

    Pujatti, Priscilla Brunelli

    2009-01-01

    Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor peptide - have been shown to be massively over expressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel series of bombesin derivatives with lutetium-177 and to evaluate the relationship between their structure and diagnostic-therapeutic activity for prostate tumor. The generic structure of studied peptides is DOTA-Phe-(Gly) n -BBN(6-14), where DOTA is the chelator, n is the number of glycine amino acids of Phe-(Gly) n spacer and BBN(6-14) is the bombesin sequence from the amino acid 6 to the amino acid 14. Preliminary studies were done to establish the ideal labeling conditions for obtaining the highest yield of labeled bombesin derivatives, determined by instant thin layer chromatography (ITLC-SG) and high performance liquid chromatography (HPLC). The stability of the preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C and the partition coefficient was determined in n:octanol:water. In vivo studies were performed in both healthy Balb-c and Nude mice bearing PC-3 xenografts, in order to characterize the biological properties of labeled peptides. In vitro studies involved the evaluation of cold bombesin derivatives effect in PC-3 cells proliferation. Bombesin derivatives were successfully labeled with high yield at optimized conditions and exhibited high stability at 4 degree C. The analysis of the

  11. A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells

    Science.gov (United States)

    Yu, Shu-Han; Zheng, Qizhi; Esopi, David; Macgregor-Das, Anne; Luo, Jun; Antonarakis, Emmanuel S.; Drake, Charles G.; Vessella, Robert; Morrissey, Colm; De Marzo, Angelo M.; Sfanos, Karen S.

    2015-01-01

    Correlative human studies suggest that the pleiotropic cytokine interleukin-6 (IL6) contributes to the development and/or progression of prostate cancer. However, the source of IL6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded (FFPE) tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR (q-RT-PCR) showed that benign prostate tissues often had higher expression of IL6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL6 mRNA. IL6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment – including endothelial cells and macrophages among other cell types. The number of IL6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined and IL6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL6 production is likely associated with any role for the cytokine in disease progression. PMID:26048576

  12. Detection of high GS risk group prostate tumors by diffusion tensor imaging and logistic regression modelling.

    Science.gov (United States)

    Ertas, Gokhan

    2018-07-01

    To assess the value of joint evaluation of diffusion tensor imaging (DTI) measures by using logistic regression modelling to detect high GS risk group prostate tumors. Fifty tumors imaged using DTI on a 3 T MRI device were analyzed. Regions of interests focusing on the center of tumor foci and noncancerous tissue on the maps of mean diffusivity (MD) and fractional anisotropy (FA) were used to extract the minimum, the maximum and the mean measures. Measure ratio was computed by dividing tumor measure by noncancerous tissue measure. Logistic regression models were fitted for all possible pair combinations of the measures using 5-fold cross validation. Systematic differences are present for all MD measures and also for all FA measures in distinguishing the high risk tumors [GS ≥ 7(4 + 3)] from the low risk tumors [GS ≤ 7(3 + 4)] (P Logistic regression modelling provides a favorable solution for the joint evaluations easily adoptable in clinical practice. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    International Nuclear Information System (INIS)

    Kato, Haruo; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-01-01

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling

  14. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Haruo, E-mail: hal.kato@gunma-u.ac.jp; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-05-22

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling.

  15. Multiple gingival pregnancy tumors with rapid growth

    OpenAIRE

    Wei-Lian Sun; Li-Hong Lei; Li-Li Chen; Zhong-Sheng Yu; Jian-Wei Zhou

    2014-01-01

    Pregnancy gingivitis is an acute form of gingivitis that affects pregnant women, with a prevalence of 30%, possibly ranging up to 100%. Sometimes, pregnancy gingivitis shows a tendency toward a localized hyperplasia called gingival pyogenic granuloma. Pregnancy tumor is a benign gingival hyperplasia with the gingiva as the most commonly involved site, but rarely it involves almost the entire gingiva. A 22-year-old woman was referred to our clinic with a chief complaint of gingival swelling th...

  16. In vivo MRI volumetric measurement of prostate regression and growth in mice

    Directory of Open Access Journals (Sweden)

    Nalcioglu Orhan

    2007-07-01

    Full Text Available Abstract Background Mouse models for treatment of late-stage prostate cancer are valuable tools, but assessing the extent of growth of the prostate and particularly its regression due to therapeutic intervention or castration is difficult due to the location, small size and interdigitated anatomy of the prostate gland in situ. Temporal monitoring of mouse prostate regression requires multiple animals and examination of histological sections. Methods Initially, T2-weighted magnetic resonance imaging (MRI was performed on normal year-old C57/BL6 mice. Individual mice were repeatedly imaged using inhalation anesthesia to establish the reproducibility of the method and to follow hormone manipulation of the prostate volume. Subsequently, MRI fat signal was suppressed using a chemical shift-selective (CHESS pulse to avoid signal contamination and enhance discrimination of the prostate. Results High field (7T MRI provides high resolution (117 × 117 μm in plane, highly reproducible images of the normal mouse prostate. Despite long imaging times, animals can be imaged repeatedly to establish reliability of volume measurements. Prostate volume declines following castration and subsequently returns to normal with androgen administration in the same animal. CHESS imaging allowed discrimination of both the margins of the prostate and the dorsal-lateral lobes of the prostate (DLP from the ventral lobes (VP. Castration results in a 40% reduction in the volume of the DLP and a 75% reduction in the volume of the VP. Conclusion MRI assessment of the volume of the mouse prostate is precise and reproducible. MRI improves volumetric determination of the extent of regression and monitoring of the same mouse over time during the course of treatment is possible. Since assessing groups of animals at each time point is avoided, this improves the accuracy of the measurement of any manipulation effect and reduces the number of animals required.

  17. Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo

    International Nuclear Information System (INIS)

    Perryman, L.A.; Blair, J.M.; Kingsley, E.A.; Szymanska, B.; Ow, K.T.; Wen, V.W.; MacKenzie, K.L.; Vermeulen, P.B.; Jackson, P.; Russell, P.J.

    2006-01-01

    This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous 'take rate' in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation

  18. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth

    Directory of Open Access Journals (Sweden)

    Roland El Ghazal

    2016-05-01

    Full Text Available In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1 in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4–deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  19. Immune mechanisms in Ehrlich ascites tumor growth in mice

    International Nuclear Information System (INIS)

    Marusic, M.

    1979-01-01

    Normal mice immunised with irradiated Ehrlich ascites tumor (EAT) cells rejected EAT challenge given 2 weeks later but T-cell-deficient thymectomised lethally irradiated, and bone-marrow-reconstituted (TIR) mice succumbed. However, when TIR mice were injected i.v. with thymus, lymph node, or spleen cells from normalsyngetic donors immediately following i.p. injection of irradiated EAT cells, they rejected the subsequent tumor challenge. This induction of immunity in TIR mice was shown to be T-cell dependent. Spleen cells from EAT- bearing mice given immediately after irradiated tumor cells were also able to promote rejection of EAT challenge in TIR mice. Spleen cells from EAT-immune mice inhibited EAT growth when admixed with tumor cells prior to i.p. injection into normal recipients, but had no effect on progressive tumor growth when given i.v. immediately after i.p. tumor injection. Immune serum inhibited i.p. EAT growth when given either i.p. or i.v. Whereas inhibition of EAT growth by admixed spleen cells was shown to be T-cell independent. The data indicate that T lymphocytes are required only in the induction phase of the immune reponse of mice against EAT, while the efferent phase of the response is accomplished by serum antibodies, perhaps through an interaction with host macrophages. (author)

  20. Understanding PSA and its derivatives in prediction of tumor volume: Addressing health disparities in prostate cancer risk stratification.

    Science.gov (United States)

    Chinea, Felix M; Lyapichev, Kirill; Epstein, Jonathan I; Kwon, Deukwoo; Smith, Paul Taylor; Pollack, Alan; Cote, Richard J; Kryvenko, Oleksandr N

    2017-03-28

    To address health disparities in risk stratification of U.S. Hispanic/Latino men by characterizing influences of prostate weight, body mass index, and race/ethnicity on the correlation of PSA derivatives with Gleason score 6 (Grade Group 1) tumor volume in a diverse cohort. Using published PSA density and PSA mass density cutoff values, men with higher body mass indices and prostate weights were less likely to have a tumor volume PSA derivatives when predicting for tumor volume. In receiver operator characteristic analysis, area under the curve values for all PSA derivatives varied across race/ethnicity with lower optimal cutoff values for Hispanic/Latino (PSA=2.79, PSA density=0.06, PSA mass=0.37, PSA mass density=0.011) and Non-Hispanic Black (PSA=3.75, PSA density=0.07, PSA mass=0.46, PSA mass density=0.008) compared to Non-Hispanic White men (PSA=4.20, PSA density=0.11 PSA mass=0.53, PSA mass density=0.014). We retrospectively analyzed 589 patients with low-risk prostate cancer at radical prostatectomy. Pre-operative PSA, patient height, body weight, and prostate weight were used to calculate all PSA derivatives. Receiver operating characteristic curves were constructed for each PSA derivative per racial/ethnic group to establish optimal cutoff values predicting for tumor volume ≥0.5 cm3. Increasing prostate weight and body mass index negatively influence PSA derivatives for predicting tumor volume. PSA derivatives' ability to predict tumor volume varies significantly across race/ethnicity. Hispanic/Latino and Non-Hispanic Black men have lower optimal cutoff values for all PSA derivatives, which may impact risk assessment for prostate cancer.

  1. Dietary rice bran component γ-oryzanol inhibits tumor growth in tumor-bearing mice.

    Science.gov (United States)

    Kim, Sung Phil; Kang, Mi Young; Nam, Seok Hyun; Friedman, Mendel

    2012-06-01

    We investigated the effects of rice bran and components on tumor growth in mice. Mice fed standard diets supplemented with rice bran, γ-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet for two additional weeks. Tumor mass was significantly lower in the γ-oryzanol and less so in the phytic acid group. Tumor inhibition was associated with the following biomarkers: increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages increases in released the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 from macrophages; and reductions in the number of blood vessels inside the tumor. Pro-angiogenic biomarkers vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase-5 (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX up to 30%. Reduced COX-2 and 5-LOX expression downregulated VEGF and inhibited neoangiogenesis inside the tumors. Induction of NK activity, activation of macrophages, and inhibition of angiogenesis seem to contribute to the inhibitory mechanism of tumor regression by γ-oryzanol. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Molecular Cochaperones: Tumor Growth and Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Stuart K. Calderwood

    2013-01-01

    Full Text Available Molecular chaperones play important roles in all cellular organisms by maintaining the proteome in an optimally folded state. They appear to be at a premium in cancer cells whose evolution along the malignant pathways requires the fostering of cohorts of mutant proteins that are employed to overcome tumor suppressive regulation. To function at significant rates in cells, HSPs interact with cochaperones, proteins that assist in catalyzing individual steps in molecular chaperoning as well as in posttranslational modification and intracellular localization. We review current knowledge regarding the roles of chaperones such as heat shock protein 90 (Hsp90 and Hsp70 and their cochaperones in cancer. Cochaperones are potential targets for cancer therapy in themselves and can be used to assess the likely prognosis of individual malignancies. Hsp70 cochaperones Bag1, Bag3, and Hop play significant roles in the etiology of some cancers as do Hsp90 cochaperones Aha1, p23, Cdc37, and FKBP1. Others such as the J domain protein family, HspBP1, TTC4, and FKBPL appear to be associated with more benign tumor phenotypes. The key importance of cochaperones for many pathways of protein folding in cancer suggests high promise for the future development of novel pharmaceutical agents.

  3. Bifurcation analysis of a delayed mathematical model for tumor growth

    International Nuclear Information System (INIS)

    Khajanchi, Subhas

    2015-01-01

    In this study, we present a modified mathematical model of tumor growth by introducing discrete time delay in interaction terms. The model describes the interaction between tumor cells, healthy tissue cells (host cells) and immune effector cells. The goal of this study is to obtain a better compatibility with reality for which we introduced the discrete time delay in the interaction between tumor cells and host cells. We investigate the local stability of the non-negative equilibria and the existence of Hopf-bifurcation by considering the discrete time delay as a bifurcation parameter. We estimate the length of delay to preserve the stability of bifurcating periodic solutions, which gives an idea about the mode of action for controlling oscillations in the tumor growth. Numerical simulations of the model confirm the analytical findings

  4. NADPH promotes the rapid growth of the tumor

    Directory of Open Access Journals (Sweden)

    Hao Sheng

    2018-04-01

    Full Text Available NADPH oxidase is the main source of intracellular reactive oxygen species (ROS. ROS plays an important role in a variety of tumor types. The ROS mediated by NADPH oxidase increases the expression of hypoxia-inducible factor alpha (HIF-α through multiple signaling pathways in tumor, and HIF-α could be regulated and controlled by downstream multiple targeted genes such as vascular endothelial growth factor, glucose transporter to promote tumor angiogenesis, cell energy metabolism reprogram and tumor metastasis. Meanwhile, HIF-α can also regulate the expression of NADPH oxidase by ROS, thus further promoting development of tumor. In this review, we summarized the functions of NADPH in tumorigenesis and discussed their potential implications in cancer therapy.

  5. Fibroblast Growth Factor Receptor-4 and Prostate Cancer Progression

    Science.gov (United States)

    2007-10-01

    difference between the two FGFR-4 variants? Achondroplasia ( dwarfism ) is caused by a similar mutation in FGFR-3 (Gly380 to Arg380). Increased FGFR-3...US men, with approximately 230,000 new cases and 29,000 deaths in 2004 [1]. Prostate cancer deaths are a result of metastatic disease and treatment of...such metastatic disease is one of the major therapeutic challenges in prostate cancer treatment . Many studies have been focused on identification of

  6. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

    Science.gov (United States)

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.

    2016-01-01

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  7. [Fluorine-18 labeled androgens and progestins; imaging agents for tumors of prostate and breast]: Technical progress report, February 1, 1987-January 31, 1988

    International Nuclear Information System (INIS)

    Katzenellenbogen, J.A.

    1987-01-01

    This project develops fluorine-18 labeled steroids that possess high binding affinity and selectivity for androgen and progesterone receptors and can be used as positron-emission tomographic imaging agents for prostate tumors and breast tumors, respectively. These novel diagnostic agents may enable an accurate estimation of tumor dissemination, such as metastasis of prostate cancer and lymph node involvement of breast cancer, and an in vivo determination of the endocrine responsiveness of these tumors. They will provide essential information for the selection of alternative therapies thereby improving the management of prostate and breast cancer patients. 14 refs., 1 tab

  8. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    International Nuclear Information System (INIS)

    De Veirman, Kim; Rao, Luigia; De Bruyne, Elke; Menu, Eline; Van Valckenborgh, Els; Van Riet, Ivan; Frassanito, Maria Antonia; Di Marzo, Lucia; Vacca, Angelo; Vanderkerken, Karin

    2014-01-01

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease

  9. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    Energy Technology Data Exchange (ETDEWEB)

    De Veirman, Kim, E-mail: kdeveirm@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Rao, Luigia [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari Medical School, Bari I-70124 (Italy); De Bruyne, Elke; Menu, Eline; Van Valckenborgh, Els [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Van Riet, Ivan [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Stem Cell Laboratory, Division of Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels 1090 (Belgium); Frassanito, Maria Antonia [Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari Medical School, Bari I-70124 (Italy); Di Marzo, Lucia; Vacca, Angelo [Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari Medical School, Bari I-70124 (Italy); Vanderkerken, Karin, E-mail: kdeveirm@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium)

    2014-06-27

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease.

  10. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  11. PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice.

    Science.gov (United States)

    Langut, Yael; Talhami, Alaa; Mamidi, Samarasimhareddy; Shir, Alexei; Zigler, Maya; Joubran, Salim; Sagalov, Anna; Flashner-Abramson, Efrat; Edinger, Nufar; Klein, Shoshana; Levitzki, Alexander

    2017-12-26

    There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine-polyethyleneglycol (PEI-PEG) tethered to the PSMA ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use.

  12. Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth-suppressor gene

    Science.gov (United States)

    Ifere, Godwin O.; Equan, Anita; Gordon, Kereen; Nagappan, Peri; Igietseme, Joseph U.; Ananaba, Godwin A.

    2010-01-01

    Background The purpose of our study was to show the distinction between the apoptotic and anti-proliferative signaling of phytosterols and cholesterol enrichment in prostate cancer cell lines, mediated by the differential transcription of caveolin-1, and N-myc downstream regulated gene1 (NDRG1), a pro-apoptotic androgen-regulated tumor suppressor. Methods PC-3 and DU145 cells were treated with sterols (cholesterol and phytosterols) for 72 h, followed by trypan blue dye exclusion measurement of necrosis and cell growth measured with a Coulter counter. Sterol induction of cell growth-suppressor gene expression was evaluated by mRNA transcription using RT-PCR, while cell cycle analysis was performed by FACS analysis. Altered expression of Ndrg1 protein was confirmed by Western blot analysis. Apoptosis was evaluated by real time RT-PCR amplification of P53, Bcl-2 gene and its related pro- and anti-apoptotic family members. Results Physiological doses (16 µM) of cholesterol and phytosterols were not cytotoxic in these cells. Cholesterol enrichment promoted cell growth (Pphytosterols significantly induced growth-suppression (Pphytosterols decreased mitotic subpopulations. We demonstrated for the first time that cholesterols concertedly attenuated the expression of caveolin-1(cav-1) and NDRG1 genes in both prostate cancer cell lines. Phytosterols had the opposite effect by inducing overexpression of cav-1, a known mediator of androgen-dependent signals that presumably control cell growth or apoptosis. Conclusions Cholesterol and phytosterol treatment differentially regulated the growth of prostate cancer cells and the expression of p53 and cav-1, a gene that regulates androgen-regulated signals. These sterols also differentially regulated cell cycle arrest, downstream pro-apoptotic androgen-regulated tumor-suppressor, NDRG1 suggesting that cav-1 may mediate pro-apoptotic NDRG1 signals. Elucidation of the mechanism for sterol modulation of growth and apoptosis signaling

  13. PCOTH, a novel gene overexpressed in prostate cancers, promotes prostate cancer cell growth through phosphorylation of oncoprotein TAF-Ibeta/SET.

    Science.gov (United States)

    Anazawa, Yoshio; Nakagawa, Hidewaki; Furihara, Mutsuo; Ashida, Shingo; Tamura, Kenji; Yoshioka, Hiroki; Shuin, Taro; Fujioka, Tomoaki; Katagiri, Toyomasa; Nakamura, Yusuke

    2005-06-01

    Through genome-wide cDNA microarray analysis coupled with microdissection of prostate cancer cells, we identified a novel gene, prostate collagen triple helix (PCOTH), showing overexpression in prostate cancer cells and its precursor cells, prostatic intraepithelial neoplasia (PIN). Immunohistochemical analysis using polyclonal anti-PCOTH antibody confirmed elevated expression of PCOTH, a 100-amino-acid protein containing collagen triple-helix repeats, in prostate cancer cells and PINs. Knocking down PCOTH expression by small interfering RNA (siRNA) resulted in drastic attenuation of prostate cancer cell growth, and concordantly, LNCaP derivative cells that were designed to constitutively express exogenous PCOTH showed higher growth rate than LNCaP cells transfected with mock vector, suggesting the growth-promoting effect of PCOTH on prostate cancer cell. To investigate the biological mechanisms of this growth-promoting effect, we applied two-dimensional differential gel electrophoresis (2D-DIGE) to analyze the phospho-protein fractions in LNCaP cells transfected with PCOTH. We found that the phosphorylation level of oncoprotein TAF-Ibeta/SET was significantly elevated in LNCaP cells transfected with PCOTH than control LNCaP cells, and these findings were confirmed by Western blotting and in-gel kinase assay. Furthermore, knockdown of endogenous TAF-Ibeta expression by siRNA also attenuated viability of prostate cancer cells as well. These findings suggest that PCOTH is involved in growth and survival of prostate cancer cells thorough, in parts, the TAF-Ibeta pathway, and that this molecule should be a promising target for development of new therapeutic strategies for prostate cancers.

  14. Intracrine prostaglandin E2 pro-tumoral actions in prostate epithelial cells originate from non-canonical pathways.

    Science.gov (United States)

    Madrigal-Martínez, Antonio; Fernández-Martínez, Ana B; Lucio Cazaña, Francisco J

    2018-04-01

    Prostaglandin E 2 (PGE 2 ) increases cell proliferation and stimulates migratory and angiogenic abilities in prostate cancer cells. However, the effects of PGE 2 on non-transformed prostate epithelial cells are unknown, despite the fact that PGE 2 overproduction has been found in benign hyperplastic prostates. In the present work we studied the effects of PGE 2 in immortalized, non-malignant prostate epithelial RWPE-1 cells and found that PGE 2 increased cell proliferation, cell migration, and production of vascular endothelial growth factor-A, and activated in vitro angiogenesis. These actions involved a non-canonic intracrine mechanism in which the actual effector was intracellular PGE 2 (iPGE 2 ) instead of extracellular PGE 2 : inhibition of the prostaglandin uptake transporter (PGT) or antagonism of EP receptors prevented the effects of PGE 2 , which indicated that PGE 2 activity depended on its carrier-mediated translocation from the outside to the inside of cells and that EP receptors located intracellularly (iEP) mediated the effects of PGE 2 . iPGE 2 acted through transactivation of epidermal growth factor-receptor (EGFR) by iEP, leading to increased expression and activity of hypoxia-inducible factor-1α (HIF-1α). Interestingly, iPGE 2 also mediates the effects of PGE 2 on prostate cancer PC3 cells through the axis iPGE 2 -iEP receptors-EGFR-HIF-1α. Thus, this axis might be responsible for the growth-stimulating effects of PGE 2 on prostate epithelial cells, thereby contributing to prostate proliferative diseases associated with chronic inflammation. Since this PGT-dependent non-canonic intracrine mechanism of PGE 2 action operates in both benign and malignant prostate epithelial cells, PGT inhibitors should be tested as a novel therapeutic modality to treat prostate proliferative disease. © 2017 Wiley Periodicals, Inc.

  15. Inhibition of IL-17A suppresses enhanced-tumor growth in low dose pre-irradiated tumor beds.

    Directory of Open Access Journals (Sweden)

    Eun-Jung Lee

    Full Text Available Ionizing radiation induces modification of the tumor microenvironment such as tumor surrounding region, which is relevant to treatment outcome after radiotherapy. In this study, the effects of pre-irradiated tumor beds on the growth of subsequently implanted tumors were investigated as well as underlying mechanism. The experimental model was set up by irradiating the right thighs of C3H/HeN mice with 5 Gy, followed by the implantation of HCa-I and MIH-2. Both implanted tumors in the pre-irradiated bed showed accelerated-growth compared to the control. Tumor-infiltrated lymphocyte (TIL levels were increased, as well as pro-tumor factors such as IL-6 and transforming growth factor-beta1 (TGF-β1 in the pre-irradiated group. In particular, the role of pro-tumor cytokine interleukin-17A (IL-17A was investigated as a possible target mechanism because IL-6 and TGF-β are key factors in Th17 cells differentiation from naïve T cells. IL-17A expression was increased not only in tumors, but also in CD4+ T cells isolated from the tumor draining lymph nodes. The effect of IL-17A on tumor growth was confirmed by treating tumors with IL-17A antibody, which abolished the acceleration of tumor growth. These results indicate that the upregulation of IL-17A seems to be a key factor for enhancing tumor growth in pre-irradiated tumor beds.

  16. Epigenetics in prostate cancer.

    Science.gov (United States)

    Albany, Costantine; Alva, Ajjai S; Aparicio, Ana M; Singal, Rakesh; Yellapragada, Sarvari; Sonpavde, Guru; Hahn, Noah M

    2011-01-01

    Prostate cancer (PC) is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG) rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a "normal" epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  17. Epigenetics in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  18. Growth of melanoma brain tumors monitored by photoacoustic microscopy

    Science.gov (United States)

    Staley, Jacob; Grogan, Patrick; Samadi, Abbas K.; Cui, Huizhong; Cohen, Mark S.; Yang, Xinmai

    2010-07-01

    Melanoma is a primary malignancy that is known to metastasize to the brain and often causes death. The ability to image the growth of brain melanoma in vivo can provide new insights into its evolution and response to therapies. In our study, we use a reflection mode photoacoustic microscopy (PAM) system to detect the growth of melanoma brain tumor in a small animal model. The melanoma tumor cells are implanted in the brain of a mouse at the beginning of the test. Then, PAM is used to scan the region of implantation in the mouse brain, and the growth of the melanoma is monitored until the death of the animal. It is demonstrated that PAM is capable of detecting and monitoring the brain melanoma growth noninvasively in vivo.

  19. Inorganic Arsenic?Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell?Conditioned Media Model

    OpenAIRE

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal?epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate...

  20. Radiologic-pathologic findings of solitary fibrous tumor of the prostate presenting as a large mass with delayed filling-in on MRI.

    Science.gov (United States)

    Bhargava, Puneet; Lee, Jean Hwa; Gupta, Saurabh; Seyal, Adeel Rahim; Vakar-Lopez, Funda; Moshiri, Mariam; Dighe, Manjiri Kiran

    2012-01-01

    We report a case of a solitary fibrous tumor of prostate presenting with urinary retention and a large prostate mass. We describe the clinical presentation, magnetic resonance imaging findings, and histopathology of this rare, benign tumor. Although clinical and radiologic appearances embrace various differential diagnoses including sarcoma, this mass was confirmed by histologic analysis following surgical resection. We report this rare, benign tumor to help the radiologist suggest the diagnosis when presented with a similar case.

  1. Epidermal growth factor increases LRF/Pokemon expression in human prostate cancer cells.

    Science.gov (United States)

    Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K

    2011-10-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

    Science.gov (United States)

    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  3. Cloning of Tumor Suppressor Genes in Prostate Cancer by a Novel Tumor Reversion Method

    National Research Council Canada - National Science Library

    Bolger, Graeme

    2002-01-01

    .... We then tested the ability of the transferred human DNA to revert (render less tumorigenic) the neoplastic phenotype of the cancer cell lines, using several criteria, including morphological changes in the cells, doubling time and growth in soft agar...

  4. Building Context with Tumor Growth Modeling Projects in Differential Equations

    Science.gov (United States)

    Beier, Julie C.; Gevertz, Jana L.; Howard, Keith E.

    2015-01-01

    The use of modeling projects serves to integrate, reinforce, and extend student knowledge. Here we present two projects related to tumor growth appropriate for a first course in differential equations. They illustrate the use of problem-based learning to reinforce and extend course content via a writing or research experience. Here we discuss…

  5. Dietary branched-chain amino acid (BCAA) and tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Chan, W.; Baron, L.; Baron, P.; White, F.; Banks, W.L. Jr.

    1986-03-05

    The effects of high dietary BCAA on tumor growth was examined in adult male Fischer 344 rats inoculated with 10/sup 6/ viable MCA fibrosarcoma cells. Ten days after tumor inoculation, when tumors were of palpable size, rats were divided into two groups at random. The experimental(E) group was fed the AIN-76 diet supplemented with 4X the BCAA content of diet casein and the control(C) group was fed the AIN-76 made isonitrogenous with the E diet by glutamic acid supplementation. Five rats from each group were killed at days 0,3,6, and 9. Rats were injected with /sup 14/C-Tyrosine and /sup 3/H-Thymidine i.p. (2 and 4 uCi/100g BW, respectively) an hour before they were killed. The incorporation of /sup 14/C and /sup 3/H into the acid insoluble fraction of the tumor tissues samples were measured. Single cell suspension of tumor were prepared for cell cycle kinetics analysis using a Coulter EPICS IV flow microflorometer. The percentage of normal and hyperdiploid cells were analyzed. Results showed that both tumor size and weight were doubled at each time point the rats were killed. At day 0, the /sup 3/H and /sup 14/C incorporation were 32 +/- 10dpm and 27 +/- 4dpm/mg tumor, respectively. The /sup 3/H incorporation dropped in both diet groups at days 6 and 9 but the /sup 14/C incorporation showed a decrease only at day 9. These changes were statistically significant, P>0.05. No difference in the tumor growth parameters used in this study can be attributed to the high dietary BCAA.

  6. Dietary branched-chain amino acid (BCAA) and tumor growth

    International Nuclear Information System (INIS)

    Chan, W.; Baron, L.; Baron, P.; White, F.; Banks, W.L. Jr.

    1986-01-01

    The effects of high dietary BCAA on tumor growth was examined in adult male Fischer 344 rats inoculated with 10 6 viable MCA fibrosarcoma cells. Ten days after tumor inoculation, when tumors were of palpable size, rats were divided into two groups at random. The experimental(E) group was fed the AIN-76 diet supplemented with 4X the BCAA content of diet casein and the control(C) group was fed the AIN-76 made isonitrogenous with the E diet by glutamic acid supplementation. Five rats from each group were killed at days 0,3,6, and 9. Rats were injected with 14 C-Tyrosine and 3 H-Thymidine i.p. (2 and 4 uCi/100g BW, respectively) an hour before they were killed. The incorporation of 14 C and 3 H into the acid insoluble fraction of the tumor tissues samples were measured. Single cell suspension of tumor were prepared for cell cycle kinetics analysis using a Coulter EPICS IV flow microflorometer. The percentage of normal and hyperdiploid cells were analyzed. Results showed that both tumor size and weight were doubled at each time point the rats were killed. At day 0, the 3 H and 14 C incorporation were 32 +/- 10dpm and 27 +/- 4dpm/mg tumor, respectively. The 3 H incorporation dropped in both diet groups at days 6 and 9 but the 14 C incorporation showed a decrease only at day 9. These changes were statistically significant, P>0.05. No difference in the tumor growth parameters used in this study can be attributed to the high dietary BCAA

  7. The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress

    Directory of Open Access Journals (Sweden)

    Stathopoulos Efstathios N

    2010-09-01

    Full Text Available Abstract Introduction Stress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo. Methods For this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis. Results Array analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this

  8. In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Che-Ming Liu

    Full Text Available Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4 expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1, which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.

  9. Selection, calibration, and validation of models of tumor growth.

    Science.gov (United States)

    Lima, E A B F; Oden, J T; Hormuth, D A; Yankeelov, T E; Almeida, R C

    2016-11-01

    This paper presents general approaches for addressing some of the most important issues in predictive computational oncology concerned with developing classes of predictive models of tumor growth. First, the process of developing mathematical models of vascular tumors evolving in the complex, heterogeneous, macroenvironment of living tissue; second, the selection of the most plausible models among these classes, given relevant observational data; third, the statistical calibration and validation of models in these classes, and finally, the prediction of key Quantities of Interest (QOIs) relevant to patient survival and the effect of various therapies. The most challenging aspects of this endeavor is that all of these issues often involve confounding uncertainties: in observational data, in model parameters, in model selection, and in the features targeted in the prediction. Our approach can be referred to as "model agnostic" in that no single model is advocated; rather, a general approach that explores powerful mixture-theory representations of tissue behavior while accounting for a range of relevant biological factors is presented, which leads to many potentially predictive models. Then representative classes are identified which provide a starting point for the implementation of OPAL, the Occam Plausibility Algorithm (OPAL) which enables the modeler to select the most plausible models (for given data) and to determine if the model is a valid tool for predicting tumor growth and morphology ( in vivo ). All of these approaches account for uncertainties in the model, the observational data, the model parameters, and the target QOI. We demonstrate these processes by comparing a list of models for tumor growth, including reaction-diffusion models, phase-fields models, and models with and without mechanical deformation effects, for glioma growth measured in murine experiments. Examples are provided that exhibit quite acceptable predictions of tumor growth in laboratory

  10. Inhibition of tumor cell growth by Sigma1 ligand mediated translational repression

    International Nuclear Information System (INIS)

    Kim, Felix J.; Schrock, Joel M.; Spino, Christina M.; Marino, Jacqueline C.; Pasternak, Gavril W.

    2012-01-01

    Highlights: ► Sigma1 ligand treatment mediates decrease in tumor cell mass. ► Identification of a Sigma1 ligand with reversible translational repressor actions. ► Demonstration of a role for Sigma1 in cellular protein synthesis. -- Abstract: Treatment with sigma1 receptor (Sigma1) ligands can inhibit cell proliferation in vitro and tumor growth in vivo. However, the cellular pathways engaged in response to Sigma1 ligand treatment that contribute to these outcomes remain largely undefined. Here, we show that treatment with putative antagonists of Sigma1 decreases cell mass. This effect corresponds with repressed cap-dependent translation initiation in multiple breast and prostate cancer cell lines. Sigma1 antagonist treatment suppresses phosphorylation of translational regulator proteins p70S6K, S6, and 4E-BP1. RNAi-mediated knockdown of Sigma1 also results in translational repression, consistent with the effects of antagonist treatment. Sigma1 antagonist mediated translational repression and decreased cell size are both reversible. Together, these data reveal a role for Sigma1 in tumor cell protein synthesis, and demonstrate that small molecule Sigma1 ligands can be used as modulators of protein translation.

  11. A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice

    Science.gov (United States)

    Khan, Naghma; Asim, Mohammad; Afaq, Farrukh; Zaid, Mohammad Abu; Mukhtar, Hasan

    2010-01-01

    Androgen receptor (AR)–mediated signaling plays an important role in the development and progression of prostate cancer (PCa). Hormonal therapies, mainly with combinations of antiandrogens and androgen deprivation, are the mainstay treatment for advanced disease. However, emergence of androgen resistance largely due to inefficient antihormone action limits their therapeutic usefulness. Here, we report that fisetin, a novel dietary flavonoid, acts as a novel AR ligand by competing with the high-affinity androgen to interact with the ligand binding domain of AR. We show that this physical interaction results in substantial decrease in AR stability and decrease in amino-terminal/carboxyl-terminal (N-C) interaction of AR. This results in blunting of AR-mediated transactivation of target genes including prostate-specific antigen (PSA). In addition, treatment of LNCaP cells with fisetin decreased AR protein levels, in part, by decreasing its promoter activity and by accelerating its degradation. Fisetin also synergized with Casodex in inducing apoptosis in LNCaP cells. Treatment with fisetin in athymic nude mice implanted with AR-positive CWR22Rυ1 human PCa cells resulted in inhibition of tumor growth and reduction in serum PSA levels. These data identify fisetin as an inhibitor of AR signaling axis and suggest that it could be a useful chemopreventive and chemotherapeutic agent to delay progression of PCa. PMID:18922931

  12. YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth

    DEFF Research Database (Denmark)

    Jiang, Ning; Ke, Binghu; Hjort-Jensen, Kim

    2017-01-01

    Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which...... is negatively regulated by AR, influences prostate cancer (PCa) cell self-renewal and CRPC development. Specifically, we found that AR directly regulates the methylation of YAP1 gene promoter via the formation of a complex with Polycomb group protein EZH2 and DNMT3a. In normal conditions, AR recruits EZH2......-differentiation of PCa cells to stem/progenitor-like cells (PCSC), which potentially contribute to disease recurrence. Finally, the knock down of YAP1 expression or the inhibition of YAP1 function by Verteporfin in TRAMP prostate cancer mice significantly suppresses tumor recurrence following castration. In conclusion...

  13. Growth of Malignant Non-CNS Tumors Alters Brain Metabolome

    Science.gov (United States)

    Kovalchuk, Anna; Nersisyan, Lilit; Mandal, Rupasri; Wishart, David; Mancini, Maria; Sidransky, David; Kolb, Bryan; Kovalchuk, Olga

    2018-01-01

    Cancer survivors experience numerous treatment side effects that negatively affect their quality of life. Cognitive side effects are especially insidious, as they affect memory, cognition, and learning. Neurocognitive deficits occur prior to cancer treatment, arising even before cancer diagnosis, and we refer to them as “tumor brain.” Metabolomics is a new area of research that focuses on metabolome profiles and provides important mechanistic insights into various human diseases, including cancer, neurodegenerative diseases, and aging. Many neurological diseases and conditions affect metabolic processes in the brain. However, the tumor brain metabolome has never been analyzed. In our study we used direct flow injection/mass spectrometry (DI-MS) analysis to establish the effects of the growth of lung cancer, pancreatic cancer, and sarcoma on the brain metabolome of TumorGraft™ mice. We found that the growth of malignant non-CNS tumors impacted metabolic processes in the brain, affecting protein biosynthesis, and amino acid and sphingolipid metabolism. The observed metabolic changes were similar to those reported for neurodegenerative diseases and brain aging, and may have potential mechanistic value for future analysis of the tumor brain phenomenon. PMID:29515623

  14. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels.

    Directory of Open Access Journals (Sweden)

    Aejaz Sayeed

    Full Text Available Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

  15. MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

    Science.gov (United States)

    Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James; Jiang, Steve B; Mason, Ralph P; Stojadinovic, Strahinja

    2018-01-01

    Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT) imaging alone. In this study, we characterized a research magnetic resonance (MR) scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV) was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This novel protocol

  16. Detection of tumor markers in prostate cancer and comparison of sensitivity between real time and nested PCR.

    Science.gov (United States)

    Matsuoka, Takayuki; Shigemura, Katsumi; Yamamichi, Fukashi; Fujisawa, Masato; Kawabata, Masato; Shirakawa, Toshiro

    2012-06-27

    The objective of this study is to investigate and compare the sensitivity in conventional PCR, quantitative real time PCR, nested PCR and western blots for detection of prostate cancer tumor markers using prostate cancer (PCa) cells. We performed conventional PCR, quantitative real time PCR, nested PCR, and western blots using 5 kinds of PCa cells. Prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), and androgen receptor (AR) were compared for their detection sensitivity by real time PCR and nested PCR. In real time PCR, there was a significant correlation between cell number and the RNA concentration obtained (R(2)=0.9944) for PSA, PSMA, and AR. We found it possible to detect these markers from a single LNCaP cell in both real time and nested PCR. By comparison, nested PCR reached a linear curve in fewer PCR cycles than real time PCR, suggesting that nested PCR may offer PCR results more quickly than real time PCR. In conclusion, nested PCR may offer tumor maker detection in PCa cells more quickly (with fewer PCR cycles) with the same high sensitivity as real time PCR. Further study is necessary to establish and evaluate the best tool for PCa tumor marker detection.

  17. Overexpression of prostate tumor overexpressed 1 correlates with tumor progression and predicts poor prognosis in breast cancer

    International Nuclear Information System (INIS)

    Lei, Fangyong; Zhang, Longjuan; Li, Xinghua; Lin, Xi; Wu, Shu; Li, Fengyan; Liu, Junling

    2014-01-01

    Prostate tumor overexpressed 1 (PTOV1) was demonstrated to play an important role in cancer progression and was correlated with unfavorable clinical outcome. However, the clinical role of PTOV1 in cancer remains largely unknown. This study aimed to investigate the expression and clinicopathological significance of PTOV1 in breast cancer. The mRNA and protein expression levels of PTOV1 were analyzed in 12 breast cancer cell lines and eight paired breast cancer tumors by semi-quantitative real time-PCR and western blotting, respectively. Immunohistochemistry was performed to assess PTOV1 protein expression in 169 paraffin-embedded, archived breast cancer samples. Survival analysis and Cox regression analysis were performed to investigate the clinicopathological significance of PTOV1 expression. Our data revealed that PTOV1 was frequently overexpressed in breast cancer cell lines compared to normal human breast epithelial cells and in primary breast cancer samples compared to adjacent noncancerous breast tissues, at both the mRNA and protein levels. Moreover, high expression of PTOV1 in breast cancer is strongly associated with clinicopathological characteristics and estrogen receptor expression status (P = 0.003). Breast cancer patients with higher PTOV1 expression had substantially shorter survival times than patients with lower PTOV1 expression (P < 0.001). Univariate and multivariate analysis revealed that PTOV1 might be an independent prognostic factor for breast cancer patients (P = 0.005). Our study showed that PTOV1 is upregulated in breast cancer cell lines and clinical samples, and its expression was positively associated with progression and aggressiveness of breast cancer, suggesting that PTOV1 could serve as an independent prognostic marker

  18. Plant-derived SAC domain of PAR-4 (Prostate Apoptosis Response 4 exhibits growth inhibitory effects in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Shayan eSarkar

    2015-10-01

    Full Text Available The gene Par-4 (Prostate Apoptosis Response 4 was originally identified in prostate cancer cells undergoing apoptosis and its product Par-4 showed cancer specific pro-apoptotic activity. Particularly, the SAC domain of Par-4 (SAC-Par-4 selectively kills cancer cells leaving normal cells unaffected. The therapeutic significance of bioactive SAC-Par-4 is enormous in cancer biology; however, its large scale production is still a matter of concern. Here we report the production of SAC-Par-4-GFP fusion protein coupled to translational enhancer sequence (5′ AMV and apoplast signal peptide (aTP in transgenic Nicotiana tabacum cv. Samsun NN plants under the control of a unique recombinant promoter M24. Transgene integration was confirmed by genomic DNA PCR, Southern and Northern blotting, Real-time PCR and Nuclear run-on assays. Results of Western blot analysis and ELISA confirmed expression of recombinant SAC-Par-4-GFP protein and it was as high as 0.15% of total soluble protein. In addition, we found that targeting of plant recombinant SAC-Par-4-GFP to the apoplast and endoplasmic reticulum (ER was essential for the stability of plant recombinant protein in comparison to the bacterial derived SAC-Par-4. Deglycosylation analysis demonstrated that ER-targeted SAC-Par-4-GFP-SEKDEL undergoes O-linked glycosylation unlike apoplast-targeted SAC-Par-4-GFP. Furthermore, various in vitro studies like mammalian cells proliferation assay (MTT, apoptosis induction assays, and NF-κB suppression suggested the cytotoxic and apoptotic properties of plant-derived SAC-Par-4-GFP against multiple prostate cancer cell lines. Additionally, pre-treatment of MAT-LyLu prostate cancer cells with purified SAC-Par-4-GFP significantly delayed the onset of tumor in a syngeneic rat prostate cancer model. Taken altogether, we proclaim that plant made SAC-Par-4 may become a useful alternate therapy for effectively alleviating cancer in the new era.

  19. mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Gordon M Cann

    Full Text Available Circulating tumor cells (CTC mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

  20. mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer.

    Science.gov (United States)

    Cann, Gordon M; Gulzar, Zulfiqar G; Cooper, Samantha; Li, Robin; Luo, Shujun; Tat, Mai; Stuart, Sarah; Schroth, Gary; Srinivas, Sandhya; Ronaghi, Mostafa; Brooks, James D; Talasaz, Amirali H

    2012-01-01

    Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

  1. An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer.

    Science.gov (United States)

    Miyamoto, David T; Lee, Richard J; Kalinich, Mark; LiCausi, Joseph A; Zheng, Yu; Chen, Tianqi; Milner, John D; Emmons, Erin; Ho, Uyen; Broderick, Katherine; Silva, Erin; Javaid, Sarah; Kwan, Tanya Todorova; Hong, Xin; Dahl, Douglas M; McGovern, Francis J; Efstathiou, Jason A; Smith, Matthew R; Sequist, Lecia V; Kapur, Ravi; Wu, Chin-Lee; Stott, Shannon L; Ting, David T; Giobbie-Hurder, Anita; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A

    2018-03-01

    Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC M score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC L score predicts microscopic dissemination to seminal vesicles and/or lymph nodes ( P digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288-303. ©2018 AACR. See related commentary by Heitzer and Speicher, p. 269 This article is highlighted in the In This Issue feature, p. 253 . ©2018 American Association for Cancer Research.

  2. A comparison of prostate tumor targeting strategies using magnetic resonance imaging-targeted, transrectal ultrasound-guided fusion biopsy.

    Science.gov (United States)

    Martin, Peter R; Cool, Derek W; Fenster, Aaron; Ward, Aaron D

    2018-03-01

    Magnetic resonance imaging (MRI)-targeted, three-dimensional (3D) transrectal ultrasound (TRUS)-guided prostate biopsy aims to reduce the 21-47% false-negative rate of clinical two-dimensional (2D) TRUS-guided systematic biopsy, but continues to yield false-negative results. This may be improved via needle target optimization, accounting for guidance system errors and image registration errors. As an initial step toward the goal of optimized prostate biopsy targeting, we investigated how needle delivery error impacts tumor sampling probability for two targeting strategies. We obtained MRI and 3D TRUS images from 49 patients. A radiologist and radiology resident assessed these MR images and contoured 81 suspicious regions, yielding tumor surfaces that were registered to 3D TRUS. The biopsy system's root-mean-squared needle delivery error (RMSE) and systematic error were modeled using an isotropic 3D Gaussian distribution. We investigated two different prostate tumor-targeting strategies using (a) the tumor's centroid and (b) a ring in the lateral-elevational plane. For each simulation, targets were spaced at equal arc lengths on a ring with radius equal to the systematic error magnitude. A total of 1000 biopsy simulations were conducted for each tumor, with RMSE and systematic error magnitudes ranging from 1 to 6 mm. The difference in median tumor sampling probability and probability of obtaining a 50% core involvement was determined for ring vs centroid targeting. Our simulation results indicate that ring targeting outperformed centroid targeting in situations where systematic error exceeds RMSE. In these instances, we observed statistically significant differences showing 1-32% improvement in sampling probability due to ring targeting. Likewise, we observed statistically significant differences showing 1-39% improvement in 50% core involvement probability due to ring targeting. Our results suggest that the optimal targeting scheme for prostate biopsy depends on

  3. Saw Palmetto induces growth arrest and apoptosis of androgen-dependent prostate cancer LNCaP cells via inactivation of STAT 3 and androgen receptor signaling.

    Science.gov (United States)

    Yang, Yang; Ikezoe, Takayuki; Zheng, Zhixing; Taguchi, Hirokuni; Koeffler, H Phillip; Zhu, Wei-Guo

    2007-09-01

    PC-SPES is an eight-herb mixture that has an activity against prostate cancer. Recently, we purified Saw Palmetto (Serenoa repens) from PC-SPES and found that Saw Palmetto induced growth arrest of prostate cancer LNCaP, DU145, and PC3 cells with ED50s of approximately 2.0, 2.6, and 3.3 microl/ml, respectively, as measured by mitochondrial-dependent conversion of the the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Saw Palmetto induced apoptosis of LNCaP cells in a time- and dose-dependent manner as measured by TUNEL assays. Also, Saw Palmetto increased the expression of p21waf1 and p53 protein in LNCaP cells. In addition, we found that Saw Palmetto down-regulated DHT- or IL-6-induced expression of prostate specific antigen in conjunction with down-regulation of the level of androgen receptor in the nucleus as measured by Western blot analysis. Moreover, Saw Palmetto down-regulated the IL-6-induced level of the phosphorylated form of STAT 3 in LNCaP cells. Furthermore, Saw Palmetto inhibited the growth of LNCaP cells present as tumor xenografts in BALB/c nude mice without adverse effect. These results indicate that Saw Palmetto might be useful for the treatment of individuals with prostate cancer.

  4. Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate

    International Nuclear Information System (INIS)

    Carlsson, Jessica; Helenius, Gisela; Karlsson, Mats G; Andrén, Ove; Klinga-Levan, Karin; Olsson, Björn

    2013-01-01

    The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate. Patients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers. The t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified. The results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate mi

  5. In vitro and in vivo imaging of prostate cancer angiogenesis using anti-vascular endothelial growth factor receptor 2 antibody-conjugated quantum dot

    International Nuclear Information System (INIS)

    Kwon, Haejin; Lee, Jiyeon; Song, Rita; Lee, Jung Han; Hwang, Sung Il; Lee, Hak Jong; Kim, Young Hwa

    2013-01-01

    Authors aimed to determine the targeting ability of vascular endothelial growth factor receptor 2 (VEGFR2)-conjugated quantum dots (QDs) in vitro, and apply it for a xenograft prostate cancer mouse model. Conjugation reaction of QDs was performed by using the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and sulfo-(N-hydroxysulfosuccinimide) (Sulfo-NHS). The human umbilical vein cord endothelial cells (HUVECs) were incubated with QDs, conjugated with antiVGFR2, to see a specific binding in vitro. Fluorescent cell images were taken by a confocal microscope. The human prostate cancer cells (PC3) were injected to five nude mice on hind limbs to make the xenograft tumor model. QD-antiVEGFR2 antibody complex was injected into the tumor model and fluorescence measurements were performed at 1, 4, 9, 12, 15, and 24 hours after the injection. The specific interaction between HUVECs and QD-antiVEGFR2 antibody was clearly shown in vitro. The in vivo fluorescence image disclosed that there was an increased signal of tumor, 12 hours after the injection of QDs. By showing endothelial cells binding with QDs-antiVEGFR2 antibodyand an experimental application of the antibody for VEGFR2 imaging in the prostate cancer xenograft mouse model, we suggests that the antibody-conjugated QDs can be a potential imaging tool for angiogenesis of the cancer.

  6. MRI to predict prostate growth and development in children, adolescents and young adults

    International Nuclear Information System (INIS)

    Ren, Jing; Liu, Huijia; Wen, Didi; Huang, Xufang; Ren, Fang; Huan, Yi; Wang, He

    2015-01-01

    The purpose of this study was to investigate the use of MRI in predicting prostate growth and development. A total of 1,500 healthy male volunteers who underwent MRI of the pelvis were included in this prospective study. Subjects were divided into five groups according to age (group A, 2-5 years; group B, 6-10 years; group C, 11-15 years; group D, 16-20 years; group E, 21-25 years). Total prostate volume (TPV) as well as prostate central zone (CZ) and peripheral zone (PZ) were measured and evaluated on MRI. Data of the different groups were compared using variance analysis, Scheffe's method, Kruskal-Wallis H-test, and Pearson's correlation. Statistical significance was inferred at P 3 , 0.05 cm 3 , 2.83 cm 3 , 8.32 cm 3, and 11.56 cm 3 , respectively, and the median prostate development scores were 0.08, 0.69, 1.56, 2.38, and 2.74, respectively. Both TPVs and zonal anatomy scores varied significantly among the five groups (P = 0.000). TPV and zonal anatomy score increased with increasing age. MRI provides a reliable quantitative reference for prostate growth and development. (orig.)

  7. Role for DNA topoisomerase II in prostatic growth

    International Nuclear Information System (INIS)

    Nelson, W.G. V.

    1987-01-01

    In the studies presented the role of the mammalian type II topoisomerase in the proliferation of normal and neoplastic rat prostate cells in vitro and in vivo was evaluated. First, the utility of mammalian type II topoisomerase inhibitors for the study of the biologic functions of the enzyme was assessed. Novobiocin inhibited rat topoisomerase II, but also interacted directly with chromatin in rat ventral prostate nuclei as well. Teniposide and amsacrine both trapped topoisomerase II in a covalent enzyme-DNA reaction intermediate that could be recovered using a K-SDS precipitation assay. The specific trapping of covalent topoisomerase II-DNA complexes by teniposide was exploited to implicate topoisomerase II in DNA replication in cultured Dunning R3327-G rat prostatic adenocarcinoma cells. In 3 H-thymidine pulse and pulse-chase labelling experiments, newly replicated DNA was found to be enriched among DNA linked topoisomerase II following teniposide treatment. Additional experiments demonstrated that topoisomerase II formed covalent complexes in the presence of teniposide directly with nascent DNA chains. On the basis of this data, a model for topoisomerase II function in untangling intertwined daughter DNA strands during replication by acting in the wake of the DNA replication fork near the site of DNA synthesis was proposed

  8. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Thobe, Megan N. [Section of Urology, Department of Surgery, The University of Chicago, Chicago, IL 60637 (United States); Clark, Robert J. [Department of Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, IL 60637 (United States); Bainer, Russell O. [Department of Human Genetics, The University of Chicago, Chicago, IL 60637 (United States); Prasad, Sandip M.; Rinker-Schaeffer, Carrie W., E-mail: crinkers@uchicago.edu [Section of Urology, Department of Surgery, The University of Chicago, Chicago, IL 60637 (United States)

    2011-01-27

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies.

  9. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    International Nuclear Information System (INIS)

    Thobe, Megan N.; Clark, Robert J.; Bainer, Russell O.; Prasad, Sandip M.; Rinker-Schaeffer, Carrie W.

    2011-01-01

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies

  10. The Impact of Environmental Light Intensity on Experimental Tumor Growth.

    Science.gov (United States)

    Suckow, Mark A; Wolter, William R; Duffield, Giles E

    2017-09-01

    Cancer research requires for consistent models that minimize environmental variables. Within the typical laboratory animal housing facility, animals may be exposed to varying intensities of light as a result of cage type, cage position, light source, and other factors; however, studies evaluating the differential effect of light intensity during the light phase on tumor growth are lacking. The effect of cage face light intensity, as determined by cage rack position was evaluated with two tumor models using the C57Bl/6NHsd mouse and transplantable B16F10 melanoma cells or Lewis lung carcinoma (LLC) cells. Animals were housed in individually-ventilated cages placed at the top, middle, or bottom of the rack in a diagonal pattern so that the top cage was closest to the ceiling light source, and cage face light intensity was measured. Following a two-week acclimation period at the assigned cage position, animals were subcutaneously administered either 1.3×10 6 B16F10 melanoma cells or 2.5×10 5 Lewis lung carcinoma cells. Weights of excised tumors were measured following euthanasia 18 days (melanoma) or 21 days (LCC) after tumor cell administration. Cage face light intensity was significantly different depending on the location of the cage, with cages closest to the light source have the greatest intensity. Mean tumor weights were significantly less (plight intensity mice compared to high and low light intensity mice. The environmental light intensity to which experimental animals are exposed may vary markedly with cage location and can significantly influence experimental tumor growth, thus supporting the idea that light intensity should be controlled as an experimental variable for animals used in cancer research. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  11. Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels1

    Science.gov (United States)

    Tang, Yaxiong; Parmakhtiar, Basmina; Simoneau, Anne R; Xie, Jun; Fruehauf, John; Lilly, Michael; Zi, Xiaolin

    2011-01-01

    Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination. PMID:21403837

  12. Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species

    Science.gov (United States)

    Alcayaga-Miranda, Francisca; González, Paz L.; Lopez-Verrilli, Alejandra; Varas-Godoy, Manuel; Aguila-Díaz, Carolina; Contreras, Luis; Khoury, Maroun

    2016-01-01

    Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancer-cell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-κB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-κB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1α expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies. PMID:27286448

  13. Senescence from glioma stem cell differentiation promotes tumor growth

    International Nuclear Information System (INIS)

    Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro; Nakano, Ichiro; Seimiya, Hiroyuki

    2016-01-01

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  14. Senescence from glioma stem cell differentiation promotes tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Ouchi, Rie [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Okabe, Sachiko; Migita, Toshiro [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Nakano, Ichiro [Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233 (United States); Seimiya, Hiroyuki, E-mail: hseimiya@jfcr.or.jp [Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Laboratory of Molecular Target Therapy of Cancer, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)

    2016-02-05

    Glioblastoma (GBM) is a lethal brain tumor composed of heterogeneous cellular populations including glioma stem cells (GSCs) and differentiated non-stem glioma cells (NSGCs). While GSCs are involved in tumor initiation and propagation, NSGCs' role remains elusive. Here, we demonstrate that NSGCs undergo senescence and secrete pro-angiogenic proteins, boosting the GSC-derived tumor formation in vivo. We used a GSC model that maintains stemness in neurospheres, but loses the stemness and differentiates into NSGCs upon serum stimulation. These NSGCs downregulated telomerase, shortened telomeres, and eventually became senescent. The senescent NSGCs released pro-angiogenic proteins, including vascular endothelial growth factors and senescence-associated interleukins, such as IL-6 and IL-8. Conditioned medium from senescent NSGCs promoted proliferation of brain microvascular endothelial cells, and mixed implantation of GSCs and senescent NSGCs into mice enhanced the tumorigenic potential of GSCs. The senescent NSGCs seem to be clinically relevant, because both clinical samples and xenografts of GBM contained tumor cells that expressed the senescence markers. Our data suggest that senescent NSGCs promote malignant progression of GBM in part via paracrine effects of the secreted proteins. - Highlights: • Non-stem glioma cells (NSGCs) lose telomerase and eventually become senescent. • Senescent NSGCs secrete pro-angiogenic proteins, such as VEGFs, IL-6, and IL-8. • Senescent NSGCs enhance the growth of brain microvascular endothelial cells. • Senescent NSGCs enhance the tumorigenic potential of glioma stem cells in vivo.

  15. Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.

    Science.gov (United States)

    McIntyre, Alan; Hulikova, Alzbeta; Ledaki, Ioanna; Snell, Cameron; Singleton, Dean; Steers, Graham; Seden, Peter; Jones, Dylan; Bridges, Esther; Wigfield, Simon; Li, Ji-Liang; Russell, Angela; Swietach, Pawel; Harris, Adrian L

    2016-07-01

    Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Growth hormone deficiency in children with brain tumors

    International Nuclear Information System (INIS)

    Shalet, S.M.; Beardwell, C.G.; Morris-Jones, P.; Bamford, F.N.; Ribeiro, G.G.; Pearson, D.

    1976-01-01

    Nine children with brain tumors are described who have received various combinations of treatment, including surgery, radiotherapy, and chemotherapy. Many of the children were noted to be of short stature. Endocrine assessment was carried out from 2 to 10 years after treatment. The combined results of insulin tolerance and Bovril stimulation tests show an impaired growth hormone response in six of the nine children. Bone age is retarded in all cases, and the present height is below the 10th percentile in five of the six. The cause of this growth hormone deficiency is obscure, but further studies are in progress

  17. Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner

    DEFF Research Database (Denmark)

    Hald, Andreas; Eickhardt, Hanne; Maerkedahl, Rasmus Baadsgaard

    2012-01-01

    deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted...

  18. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Matthew A Ingersoll

    Full Text Available Prostate cancer (PCa is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  19. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

    Science.gov (United States)

    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  20. Taxane-Grafted Metal-Oxide Nanoparticles as a New Theranostic Tool against Cancer: The Promising Example of Docetaxel-Functionalized Titanate Nanotubes on Prostate Tumors.

    Science.gov (United States)

    Loiseau, Alexis; Boudon, Julien; Mirjolet, Céline; Créhange, Gilles; Millot, Nadine

    2017-08-01

    The combination of anticancer drugs and metal oxide nanoparticles is of great interest in cancer nanomedicine. Here, the development of a new nanohybrid, titanate nanotube-docetaxel (TiONts-DTX) is reported, the two parts of which are conjugated by covalent linkages. Unlike most nanoparticles currently being developed for biomedical purposes, TiONts present a needle-shaped morphology. The surface of TiONts is linked with 3-aminopropyl triethoxysilane and with a hetero-bifunctional polymer (polyethylene glycol) to create well-dispersed and biocompatible nanovectors. The prefunctionalized surface of this scaffold has valuable attachments to graft therapeutic agents (DTX in our case) as well as chelating agents (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to monitor the nanohybrids. To evaluate drug efficacy, in vitro tests have demonstrated that the association between TiONts and DTX shows cytotoxic activity against a hormone-refractory prostate cancer cell line (22Rv1) whereas TiONts without DTX do not. Finally, the first in vivo tests with intratumoral injections show that more than 70% of TiONts nanovectors are retained within the tumor for at least 7 d. Moreover, tumor growth in mice receiving TiONts-DTX is significantly slower than that in mice receiving free DTX. This nanohybrid can thus become a promising new tool in biomedicine to fight against prostate cancer. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Interfacial properties in a discrete model for tumor growth

    Science.gov (United States)

    Moglia, Belén; Guisoni, Nara; Albano, Ezequiel V.

    2013-03-01

    We propose and study, by means of Monte Carlo numerical simulations, a minimal discrete model for avascular tumor growth, which can also be applied for the description of cell cultures in vitro. The interface of the tumor is self-affine and its width can be characterized by the following exponents: (i) the growth exponent β=0.32(2) that governs the early time regime, (ii) the roughness exponent α=0.49(2) related to the fluctuations in the stationary regime, and (iii) the dynamic exponent z=α/β≃1.49(2), which measures the propagation of correlations in the direction parallel to the interface, e.g., ξ∝t1/z, where ξ is the parallel correlation length. Therefore, the interface belongs to the Kardar-Parisi-Zhang universality class, in agreement with recent experiments of cell cultures in vitro. Furthermore, density profiles of the growing cells are rationalized in terms of traveling waves that are solutions of the Fisher-Kolmogorov equation. In this way, we achieved excellent agreement between the simulation results of the discrete model and the continuous description of the growth front of the culture or tumor.

  2. Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Takeshi Chiyomaru

    Full Text Available Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs. In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1 and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3' UTR of several target genes (such as RAC1, EGFR and EP300 that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa.

  3. Tumor Cells Express FcγRl Which Contributes to Tumor Cell Growth and a Metastatic Phenotype

    Directory of Open Access Journals (Sweden)

    M. Bud Nelson

    2001-01-01

    Full Text Available High levels of circulating immune complexes containing tumor-associated antigens are associated with a poor prognosis for individuals with cancer. The ability of B cells, previously exposed to tumor-associated antigens, to promote both in vitro and in vivo tumor growth formed the rationale to evaluate the mechanism by which immune complexes may promote tumor growth. In elucidating this mechanism, FcγRl expression by tumor cells was characterized by flow cytometry, polymerase chain reaction, and sequence analysis. Immune complexes containing shed tumor antigen and anti-shed tumor antigen Ab cross-linked FcγRl-expressing tumor cells, which resulted in an induction of tumor cell proliferation and of shed tumor antigen production. Use of selective tyrosine kinase inhibitors demonstrated that tumor cell proliferation induced by immune complex cross-linking of FcγRl is dependent on the tyrosine kinase signal transduction pathway. A selective inhibitor of phosphatidylinositol-3 kinase also inhibited this induction of tumor cell proliferation. These findings support a role for immune complexes and FcγRl expression by tumor cells in augmentation of tumor growth and a metastatic phenotype.

  4. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Paolo Kunderfranco

    2010-05-01

    Full Text Available ETS transcription factors regulate important signaling pathways involved in cell differentiation and development in many tissues and have emerged as important players in prostate cancer. However, the biological impact of ETS factors in prostate tumorigenesis is still debated.We performed an analysis of the ETS gene family using microarray data and real-time PCR in normal and tumor tissues along with functional studies in normal and cancer cell lines to understand the impact in prostate tumorigenesis and identify key targets of these transcription factors. We found frequent dysregulation of ETS genes with oncogenic (i.e., ERG and ESE1 and tumor suppressor (i.e., ESE3 properties in prostate tumors compared to normal prostate. Tumor subgroups (i.e., ERG(high, ESE1(high, ESE3(low and NoETS tumors were identified on the basis of their ETS expression status and showed distinct transcriptional and biological features. ERG(high and ESE3(low tumors had the most robust gene signatures with both distinct and overlapping features. Integrating genomic data with functional studies in multiple cell lines, we demonstrated that ERG and ESE3 controlled in opposite direction transcription of the Polycomb Group protein EZH2, a key gene in development, differentiation, stem cell biology and tumorigenesis. We further demonstrated that the prostate-specific tumor suppressor gene Nkx3.1 was controlled by ERG and ESE3 both directly and through induction of EZH2.These findings provide new insights into the role of the ETS transcriptional network in prostate tumorigenesis and uncover previously unrecognized links between aberrant expression of ETS factors, deregulation of epigenetic effectors and silencing of tumor suppressor genes. The link between aberrant ETS activity and epigenetic gene silencing may be relevant for the clinical management of prostate cancer and design of new therapeutic strategies.

  5. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

    International Nuclear Information System (INIS)

    Demir, Ummuhan; Koehler, Andrea; Schneider, Rainer; Schweiger, Susann; Klocker, Helmut

    2014-01-01

    Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin

  6. Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN-depleted head and neck cancer tumor cells.

    Science.gov (United States)

    Liu, Zhiyong; Hartman, Yolanda E; Warram, Jason M; Knowles, Joseph A; Sweeny, Larissa; Zhou, Tong; Rosenthal, Eben L

    2011-08-01

    Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma-mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer, there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here, we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were cocultured with fibroblasts or inoculated with fibroblasts into severe combined immunodeficient mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Coculture experiments showed fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN-silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN-silenced cells compared with control vector-transfected cells, whereas inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast coculture, suggesting the importance of FGFR2 signaling in fibroblast-mediated tumor growth. Analysis of xenografted tumors revealed that EMMPRIN-silenced tumors had a larger stromal compartment compared with control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast-independent tumor growth.

  7. Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN depleted head and neck cancer tumor cells

    Science.gov (United States)

    Liu, Zhiyong; Hartman, Yolanda E.; Warram, Jason M.; Knowles, Joseph A.; Sweeny, Larrisa; Zhou, Tong; Rosenthal, Eben L.

    2011-01-01

    Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were co-cultured with fibroblasts or inoculated with fibroblasts into SCID mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Co-culture experiments demonstrated fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN silenced cells compared to control vector transfected cells, while inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast co-culture, suggesting the importance of FGFR2 signaling in fibroblast mediated tumor growth. Analysis of xenografted tumors revealed EMMPRIN silenced tumors had a larger stromal compartment compared to control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast independent tumor growth. PMID:21665938

  8. Serum platelet-derived growth factor and fibroblast growth factor in patients with benign and malignant ovarian tumors

    DEFF Research Database (Denmark)

    Madsen, Christine Vestergaard; Steffensen, Karina Dahl; Olsen, Dorte Aalund

    2012-01-01

    New biological markers with predictive or prognostic value are highly warranted in the treatment of ovarian cancer. The platelet-derived growth factor (PDGF) system and fibroblast growth factor (FGF) system are important components in tumor growth and angiogenesis....

  9. MRI to predict prostate growth and development in children, adolescents and young adults

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Jing; Liu, Huijia; Wen, Didi; Huang, Xufang; Ren, Fang; Huan, Yi [Fourth Military Medical University, Department of Radiology, Xijing Hospital, Xi' an City (China); Wang, He [Fourth Military Medical University, Department of Urology, Tangdu Hospital, Xi' an City (China)

    2014-08-06

    The purpose of this study was to investigate the use of MRI in predicting prostate growth and development. A total of 1,500 healthy male volunteers who underwent MRI of the pelvis were included in this prospective study. Subjects were divided into five groups according to age (group A, 2-5 years; group B, 6-10 years; group C, 11-15 years; group D, 16-20 years; group E, 21-25 years). Total prostate volume (TPV) as well as prostate central zone (CZ) and peripheral zone (PZ) were measured and evaluated on MRI. Data of the different groups were compared using variance analysis, Scheffe's method, Kruskal-Wallis H-test, and Pearson's correlation. Statistical significance was inferred at P < 0.05. In groups A and B, the prostates were barely visible. In group C, although TPV was measured, it was hard to distinguish CZ and PZ. In group D, 136 CZ and PZ were clearly visible. In group E, 377 CZ and PZ were clearly visible on T2-weighted imaging (T2WI). The median TPVs of groups A, B, C, D, and E were 0.00 cm{sup 3}, 0.05 cm{sup 3}, 2.83 cm{sup 3}, 8.32 cm{sup 3,} and 11.56 cm{sup 3}, respectively, and the median prostate development scores were 0.08, 0.69, 1.56, 2.38, and 2.74, respectively. Both TPVs and zonal anatomy scores varied significantly among the five groups (P = 0.000). TPV and zonal anatomy score increased with increasing age. MRI provides a reliable quantitative reference for prostate growth and development. (orig.)

  10. The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice.

    Directory of Open Access Journals (Sweden)

    Neri Mercatelli

    Full Text Available BACKGROUND: MiR-221 and miR-222 are two highly homologous microRNAs whose upregulation has been recently described in several types of human tumors, for some of which their oncogenic role was explained by the discovery of their target p27, a key cell cycle regulator. We previously showed this regulatory relationship in prostate carcinoma cell lines in vitro, underlying the role of miR-221/222 as inducers of proliferation and tumorigenicity. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a number of in vivo approaches confirming our previous data. The ectopic overexpression of miR-221 is able, per se, to confer a high growth advantage to LNCaP-derived tumors in SCID mice. Consistently, the anti-miR-221/222 antagomir treatment of established subcutaneous tumors derived from the highly aggressive PC3 cell line, naturally expressing high levels of miR-221/222, reduces tumor growth by increasing intratumoral p27 amount; this effect is long lasting, as it is detectable as long as 25 days after the treatment. Furthermore, we provide evidence in favour of a clinical relevance of the role of miR-221/222 in prostate carcinoma, by showing their general upregulation in patient-derived primary cell lines, where we find a significant inverse correlation with p27 expression. CONCLUSIONS/SIGNIFICANCE: These findings suggest that modulating miR-221/222 levels may have a therapeutic potential in prostate carcinoma.

  11. Terrestrosin D, a steroidal saponin from Tribulus terrestris L., inhibits growth and angiogenesis of human prostate cancer in vitro and in vivo.

    Science.gov (United States)

    Wei, Shihu; Fukuhara, Hideo; Chen, Guang; Kawada, Chiaki; Kurabayashi, Atsushi; Furihata, Mutsuo; Inoue, Keiji; Shuin, Taro

    2014-01-01

    The aim of this study was to investigate whether terrestrosin D (TED) inhibits the progression of castration-resistant prostate cancer and consider its mechanism. Cell cycle, mitochondrial membrane potential (ΔΨm) and apoptosis were determined by flow cytometry. Caspase-3 activity and vascular endothelial growth factor secretion were detected by a caspase-3 assay and human vascular endothelial growth factor kit, respectively. A PC-3 xenograft mouse model was used to evaluate the anticancer effect of TED in vivo. In vitro, TED strongly suppressed the growth of prostate cancer cells and endothelial cells in a dose-dependent manner. TED induced cell cycle arrest and apoptosis in PC-3 cells and human umbilical vascular endothelial cells (HUVECs). TED-induced apoptosis did not involve the caspase pathway. TED also decreased ΔΨm in PC-3 cells and HUVECs. In vivo, TED significantly suppressed tumor growth in nude mice bearing PC-3 cells, without any overt toxicity. Immunohistochemical analysis showed TED induced apoptotic cell death and inhibited angiogenesis in xenograft tumor cells. Cell cycle arrest and induction of apoptosis in cancer cells and endothelial cells might be plausible mechanisms of actions for the observed antitumor and antiangiogenic activities of TED. © 2014 S. Karger AG, Basel.

  12. Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice.

    Science.gov (United States)

    Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Meng; Costyn, Leah; Beharry, Zanna; Bartlett, Michael G; Cai, Houjian

    2017-11-10

    Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells During Prostate Cancer Metastasis

    Science.gov (United States)

    Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L.; Mulholland, David J.; Wu, Hong

    2015-01-01

    The epithelial-mesenchymal transition (EMT) has been postulated as a mechanism by which cancer cells acquire the invasive and stem-like traits necessary for distant metastasis. However, direct in vivo evidence for the role of EMT in the formation of cancer stem-like cells (CSC) and the metastatic cascade remains lacking. Here we report the first isolation and characterization of mesenchymal and EMT tumor cells, which harbor both epithelial and mesenchymal characteristics, in an autochthonous murine model of prostate cancer. By crossing the established Pb-Cre+/−;PtenL/L;KrasG12D/+ prostate cancer model with a vimentin-GFP reporter strain, generating CPKV mice, we were able to isolate epithelial, EMT and mesenchymal cancer cells based on expression of vimentin and EpCAM. CPKV mice (but not mice with Pten deletion alone) exhibited expansion of cells with EMT (EpCAM+/Vim-GFP+) and mesenchymal (EpCAM−/Vim-GFP+) characteristics at the primary tumor site and in circulation. These EMT and mesenchymal tumor cells displayed enhanced stemness and invasive character compared to epithelial tumor cells. Moreover, they displayed an enriched tumor-initiating capacity and could regenerate epithelial glandular structures in vivo, indicative of epithelia-mesenchyme plasticity. Interestingly, while mesenchymal tumor cells could persist in circulation and survive in the lung following intravenous injection, only epithelial and EMT tumor cells could form macrometastases. Our work extends the evidence that mesenchymal and epithelial states in cancer cells contribute differentially to their capacities for tumor initiation and metastatic seeding, respectively, and that EMT tumor cells exist with plasticity that can contribute to multiple stages of the metastatic cascade. PMID:25948589

  14. Markers of epithelial-to-mesenchymal transition reflect tumor biology according to patient age and Gleason score in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Dorota Jędroszka

    Full Text Available Prostate carcinoma (PRAD is one of the most frequently diagnosed malignancies amongst men worldwide. It is well-known that androgen receptor (AR plays a pivotal role in a vast majority of prostate tumors. However, recent evidence emerged stating that estrogen receptors (ERs may also contribute to prostate tumor development. Moreover, progression and aggressiveness of prostate cancer may be associated with differential expression genes of epithelial-to-mesenchymal transition (EMT. Therefore we aimed to assess the significance of receptors status as well as EMT marker genes expression among PRAD patients in accordance to their age and Gleason score.We analyzed TCGA gene expression profiles of 497 prostate tumor samples according to 43 genes involved in EMT and 3 hormone receptor genes (AR, ESR1, ESR2 as well as clinical characteristic of cancer patients. Then patients were divided into four groups according to their age and 5 groups according to Gleason score. Next, we evaluated PRAD samples according to relationship between the set of variables in different combinations and compared differential expression in subsequent groups of patients. The analysis was applied using R packages: FactoMineR, gplots, RColorBrewer and NMF.MFA analysis resulted in distinct grouping of PRAD patients into four age categories according to expression level of AR, ESR1 and ESR2 with the most distinct group of age less than 50 years old. Further investigations indicated opposite expression profiles of EMT markers between different age groups as well as strong association of EMT gene expression with Gleason score. We found that depending on age of prostate cancer patients and Gleason score EMT genes with distinctly altered expression are: KRT18, KRT19, MUC1 and COL4A1, CTNNB1, SNAI2, ZEB1 and MMP3.Our major observation is that prostate cancer from patients under 50 years old compared to older ones has entirely different EMT gene expression profiles showing potentially

  15. Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

    Science.gov (United States)

    Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

    2016-07-01

    Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. Copyright © 2016 the American Physiological Society.

  16. MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

    Directory of Open Access Journals (Sweden)

    Tsuicheng D Chiu

    Full Text Available Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT imaging alone. In this study, we characterized a research magnetic resonance (MR scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This

  17. Involvement of Fibroblast Growth Factor Receptor Genes in Benign Prostate Hyperplasia in a Korean Population

    Directory of Open Access Journals (Sweden)

    Hae Jeong Park

    2013-01-01

    Full Text Available Fibroblast growth factors (FGFs and their receptors (FGFRs have been implicated in prostate growth and are overexpressed in benign prostatic hyperplasia (BPH. In this study, we investigated whether single nucleotide polymorphisms (SNPs of the FGFR genes (FGFR1 and FGFR2 were associated with BPH and its clinical phenotypes in a population of Korean men. We genotyped four SNPs in the exons of FGFR1 and FGFR2 (rs13317 in FGFR1; rs755793, rs1047100, and rs3135831 in FGFR2 using direct sequencing in 218 BPH patients and 213 control subjects. No SNPs of FGFR1 or FGFR2 genes were associated with BPH. However, analysis according to clinical phenotypes showed that rs1047100 of FGFR2 was associated with prostate volume in BPH in the dominant model (GA/AA versus GG, P = 0.010. In addition, a significant association was observed between rs13317 of FGFR1 and international prostate symptom score (IPSS in the additive (TC versus CC versus TT, P = 0.0022 and dominant models (TC/CC versus TT, P = 0.005. Allele frequency analysis also showed significant association between rs13317 and IPSS (P = 0.005. These results suggested that FGFR genes could be related to progression of BPH.

  18. Inhibition of Androgen-Independent Growth of Prostate Cancer by siRNA- Mediated Androgen Receptor Gene Silencing

    Science.gov (United States)

    2008-02-01

    and then photographed using a digital camera . AAV production and infection. To silence AR gene expression, a hairpin- structured expression vector...Sandusky GE, Vessella RL, Neubauer BL. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor...HeNe laser. The spectrograph has an f/2.0 Czerny–Turner imaging spec- trometer plus a thermo-electrically cooled Kodak 0401 CCD camera . The fiberoptic

  19. Methylated DNA for monitoring tumor growth and regression

    DEFF Research Database (Denmark)

    Kristiansen, Søren; Nielsen, Dorte; Söletormos, Georg

    2014-01-01

    Abstract A wide range of protein cancer biomarkers is currently recommended in international guidelines for monitoring the growth and regression of solid tumors. However, a number of these markers are also present in low concentrations in blood obtained from healthy individuals and from patients...... of gene promoters. Because tumor cells naturally secrete DNA and upon cell death leak DNA, modified methylated DNA can be detected in blood, urine, sputum and other body fluids. At present international guidelines do not include recommendations for monitoring modified methylated DNA. The low level...... of evidence can partly be explained by incomplete collection of serial blood samples, by analytical challenges, and by lack of knowledge of how monitoring studies should be designed and how serial marker data obtained from individual patients should be interpreted. Here, we review the clinical validity...

  20. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers

    DEFF Research Database (Denmark)

    Sturgeon, Catharine M.; Duffy, Michael J.; Stenman, Ulf-Håkan

    2008-01-01

    BACKGROUND: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS: Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast...... for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign...... prostatic disease when total PSA is cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50...

  1. Multicriteria plan optimization in the hands of physicians: a pilot study in prostate cancer and brain tumors.

    Science.gov (United States)

    Müller, Birgit S; Shih, Helen A; Efstathiou, Jason A; Bortfeld, Thomas; Craft, David

    2017-11-06

    The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and template based plan optimization. Exploiting the full planning potential of MCO navigation, this alternative planning approach intends to improve planning efficiency and individual plan quality. Planning was retrospectively performed on 12 brain tumor and 10 post-prostatectomy prostate patients previously treated with MCO-IMRT. For each patient, physicians were provided with a template-based generated Pareto surface of optimal plans to navigate, using the beam angles from the original clinical plans. We compared physician generated plans to clinically delivered plans (created by dosimetrists) in terms of dosimetric differences, physician preferences and planning times. Plan qualities were similar, however physician generated and clinical plans differed in the prioritization of clinical goals. Physician derived prostate plans showed significantly better sparing of the high dose rectum and bladder regions (p(D1) plans indicated higher doses for targets and brainstem (p(D1) plan comparisons physicians preferred the clinical plans more often (brain: 6:3 out of 12, prostate: 2:6 out of 10) (not statistically significant). While times of physician involvement were comparable for prostate planning, the new workflow reduced the average involved time for brain cases by 30%. Planner times were reduced for all cases. Subjective benefits, such as a better understanding of planning situations, were observed by clinicians through the insight into plan optimization and experiencing dosimetric trade-offs. We introduce physician driven planning with MCO for brain and prostate tumors as a feasible planning workflow. The proposed approach standardizes the planning process by utilizing site specific templates and integrates physicians more tightly into treatment planning. Physicians

  2. Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses.

    Science.gov (United States)

    Twu, Olivia; Dessí, Daniele; Vu, Anh; Mercer, Frances; Stevens, Grant C; de Miguel, Natalia; Rappelli, Paola; Cocco, Anna Rita; Clubb, Robert T; Fiori, Pier Luigi; Johnson, Patricia J

    2014-06-03

    The human-infective parasite Trichomonas vaginalis causes the most prevalent nonviral sexually transmitted infection worldwide. Infections in men may result in colonization of the prostate and are correlated with increased risk of aggressive prostate cancer. We have found that T. vaginalis secretes a protein, T. vaginalis macrophage migration inhibitory factor (TvMIF), that is 47% similar to human macrophage migration inhibitory factor (HuMIF), a proinflammatory cytokine. Because HuMIF is reported to be elevated in prostate cancer and inflammation plays an important role in the initiation and progression of cancers, we have explored a role for TvMIF in prostate cancer. Here, we show that TvMIF has tautomerase activity, inhibits macrophage migration, and is proinflammatory. We also demonstrate that TvMIF binds the human CD74 MIF receptor with high affinity, comparable to that of HuMIF, which triggers activation of ERK, Akt, and Bcl-2-associated death promoter phosphorylation at a physiologically relevant concentration (1 ng/mL, 80 pM). TvMIF increases the in vitro growth and invasion through Matrigel of benign and prostate cancer cells. Sera from patients infected with T. vaginalis are reactive to TvMIF, especially in males. The presence of anti-TvMIF antibodies indicates that TvMIF is released by the parasite and elicits host immune responses during infection. Together, these data indicate that chronic T. vaginalis infections may result in TvMIF-driven inflammation and cell proliferation, thus triggering pathways that contribute to the promotion and progression of prostate cancer.

  3. Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits.

    Science.gov (United States)

    Rhie, Suhn Kyong; Guo, Yu; Tak, Yu Gyoung; Yao, Lijing; Shen, Hui; Coetzee, Gerhard A; Laird, Peter W; Farnham, Peggy J

    2016-01-01

    Although technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach toward understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements. Using DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called Tracing Enhancer Networks using Epigenetic Traits that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors. Our studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms

  4. Proliferative activity and branching morphogenesis in the human prostate: a closer look at pre- and postnatal prostate growth

    NARCIS (Netherlands)

    Xue, Y.; Sonke, G.; Schoots, C.; Schalken, J.; Verhofstad, A.; de la Rosette, J.; Smedts, F.

    2001-01-01

    To gain further insight into the molecular cell biologic features of prostate development, we investigated the proliferative activity of prostate epithelial and stromal cells and their topographic relationship with neuroendocrine (NE) cell distribution and regional heterogeneity. Consecutive

  5. Proliferative activity and branching morphogenesis in the human prostate: a closer look at pre- and postnatal prostate growth.

    NARCIS (Netherlands)

    Xue, Y.; Sonke, G.S.; Schoots, C.; Schalken, J.A.; Verhofstad, A.A.J.; Rosette, J.J.M.H.C. de la; Smedts, F.

    2001-01-01

    BACKGROUND: To gain further insight into the molecular cell biologic features of prostate development, we investigated the proliferative activity of prostate epithelial and stromal cells and their topographic relationship with neuroendocrine (NE) cell distribution and regional heterogeneity.

  6. Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction

    Directory of Open Access Journals (Sweden)

    Takahiro Ochiya

    Full Text Available The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.

  7. Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

    Science.gov (United States)

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL

  8. PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

    Science.gov (United States)

    Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

    2018-01-01

    Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

  9. Dynamic density functional theory of solid tumor growth: Preliminary models

    Directory of Open Access Journals (Sweden)

    Arnaud Chauviere

    2012-03-01

    Full Text Available Cancer is a disease that can be seen as a complex system whose dynamics and growth result from nonlinear processes coupled across wide ranges of spatio-temporal scales. The current mathematical modeling literature addresses issues at various scales but the development of theoretical methodologies capable of bridging gaps across scales needs further study. We present a new theoretical framework based on Dynamic Density Functional Theory (DDFT extended, for the first time, to the dynamics of living tissues by accounting for cell density correlations, different cell types, phenotypes and cell birth/death processes, in order to provide a biophysically consistent description of processes across the scales. We present an application of this approach to tumor growth.

  10. Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

    Directory of Open Access Journals (Sweden)

    Tasleem Arif

    2014-01-01

    Full Text Available Alterations in cellular metabolism and bioenergetics are vital for cancer cell growth and motility. Here, the role of the mitochondrial protein voltage-dependent anion channel (VDAC1, a master gatekeeper regulating the flux of metabolites and ions between mitochondria and the cytoplasm, in regulating the growth of several cancer cell lines was investigated by silencing VDAC1 expression using small interfering RNA (siRNA. A single siRNA specific to the human VDAC1 sequence at nanomolar concentrations led to some 90% decrease in VDAC1 levels in the lung A549 and H358, prostate PC-3, colon HCT116, glioblastoma U87, liver HepG2, and pancreas Panc-1 cancer cell lines. VDAC1 silencing persisted 144 hours post-transfection and resulted in profound inhibition of cell growth in cancer but not in noncancerous cells, with up to 90% inhibition being observed over 5 days that was prolonged by a second transfection. Cells expressing low VDAC1 levels showed decreased mitochondrial membrane potential and adenoside triphosphate (ATP levels, suggesting limited metabolite exchange between mitochondria and cytosol. Moreover, cells silenced for VDAC1 expression showed decreased migration, even in the presence of the wound healing accelerator basic fibroblast growth factor (bFGF. VDAC1-siRNA inhibited cancer cell growth in a Matrigel-based assay in host nude mice. Finally, in a xenograft lung cancer mouse model, chemically modified VDAC1-siRNA not only inhibited tumor growth but also resulted in tumor regression. This study thus shows that VDAC1 silencing by means of RNA interference (RNAi dramatically inhibits cancer cell growth and tumor development by disabling the abnormal metabolic behavior of cancer cells, potentially paving the way for a more effective pipeline of anticancer drugs.

  11. Prostate-Specific Membrane Antigen Regulation of Prostate Tumor Growth, Angiogenesis,and Integrin Signal Transduction

    Science.gov (United States)

    2012-07-01

    mothers were maintained in 75% oxygen for five days. After 2.5 days in 75% oxygen, the lactating females were replaced with surrogate dames. Mice were... harmful side effects. To avoid this possibility we treated OIR mice with a single intravitreal injection of 2-PMPA on P14 and measured avascular area three...experiments. Oxygen Induced Retinopathy (OIR) Model Seven day old mice weighing 6g or greater and their lactating mothers were maintained in 75% oxygen

  12. Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.

    Science.gov (United States)

    Pérez-Pérez, María-Jesús; Priego, Eva-María; Bueno, Oskía; Martins, Maria Solange; Canela, María-Dolores; Liekens, Sandra

    2016-10-13

    The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

  13. An Anti-Urokinase Plasminogen Activator Receptor Antibody (ATN-658 Blocks Prostate Cancer Invasion, Migration, Growth, and Experimental Skeletal Metastasis In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Shafaat A. Rabbani

    2010-10-01

    Full Text Available Urokinase plasminogen activator receptor (uPAR is a multidomain protein that plays important roles in the growth, invasion, and metastasis of a number of cancers. In the present study, we examined the effects of administration of a monoclonal anti-uPAR antibody (ATN-658 on prostate cancer progression in vitro and in vivo. We examined the effect of treatment of ATN-658 on human prostate cancer cell invasion, migration, proliferation, and regulation of intracellular signaling pathways. For in vivo studies, PC-3 cells (1 x 106 were inoculated into the right flank of male Balb C nu/nu mice through subcutaneous or through intratibial route (2 x 105 of male Fox Chase severe combined immunodeficient mice to monitor the effect on tumor growth and skeletal metastasis. Treatment with ATN-658 resulted in a significant dose-dependent decrease in PC-3 cell invasion and migration without affecting cell doubling time. Western blot analysis showed that ATN-658 treatment decreased the phosphorylation of serine/threonine protein kinase B (AKT, mitogen-activated protein kinase (MAPK, and focal adhesion kinase (FAK without affecting AKT, MAPK, and FAK total protein expression. In in vivo studies, ATN-658 caused a significant decrease in tumor volume and a marked reduction in skeletal lesions as determined by Faxitron x-ray and micro-computed tomography. Immunohistochemical analysis of subcutaneous and tibial tumors showed a marked decrease in the levels of expression of pAKT, pMAPK, and pFAK, consistent with the in vitro observations. Results from these studies provide compelling evidence for the continued development of ATN-658 as a potential therapeutic agent for the treatment of prostate and other cancers expressing uPAR.

  14. Xanthogranulomatous Prostatitis, a Rare Prostatic Entity

    Directory of Open Access Journals (Sweden)

    Alejandro Noyola

    2017-01-01

    Full Text Available There are several benign prostatic pathologies that can clinically mimic a prostate adenocarcinoma. Xanthogranulomatous prostatitis is a benign inflammatory condition of the prostate and a rare entity. A 47-year old male, with 3 years of lower urinary tract symptoms, with a palpable hypogastric tumor, digital rectal examination: solid prostate, of approximately 60 g. Initial PSA was 0.90 ng/mL. He underwent surgical excision of the lower abdominal nodule and prostatectomy. Histopathology showed xanthogranulomatous prostatitis, without malignancy. Xanthogranulomatous prostatitis is an extremely rare entity that can simulate prostate adenocarcinoma, therefore having a correct histopathological diagnosis is essential.

  15. Phase transitions in tumor growth: IV relationship between metabolic rate and fractal dimension of human tumor cells

    Science.gov (United States)

    Betancourt-Mar, J. A.; Llanos-Pérez, J. A.; Cocho, G.; Mansilla, R.; Martin, R. R.; Montero, S.; Nieto-Villar, J. M.

    2017-05-01

    By the use of thermodynamics formalism of irreversible processes, complex systems theory and systems biology, it is derived a relationship between the production of entropy per unit time, the fractal dimension and the tumor growth rate for human tumors cells. The thermodynamics framework developed demonstrates that, the dissipation function is a Landau potential and also the Lyapunov function of the dynamical behavior of tumor growth, which indicate the directional character, stability and robustness of the phenomenon. The entropy production rate may be used as a quantitative index of the metastatic potential of tumors. The current theoretical framework will hopefully provide a better understanding of cancer and contribute to improvements in cancer treatment.

  16. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    International Nuclear Information System (INIS)

    Liu, Shicheng; Yuan, Yiming; Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi

    2010-01-01

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser 81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [ 3 H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  17. Antitumor action of 3-bromopyruvate implicates reorganized tumor growth regulatory components of tumor milieu, cell cycle arrest and induction of mitochondria-dependent tumor cell death.

    Science.gov (United States)

    Yadav, Saveg; Kujur, Praveen Kumar; Pandey, Shrish Kumar; Goel, Yugal; Maurya, Babu Nandan; Verma, Ashish; Kumar, Ajay; Singh, Rana Pratap; Singh, Sukh Mahendra

    2018-01-15

    Evidences demonstrate that metabolic inhibitor 3-bromopyruvate (3-BP) exerts a potent antitumor action against a wide range of malignancies. However, the effect of 3-BP on progression of the tumors of thymic origin remains unexplored. Although, constituents of tumor microenvironment (TME) plays a pivotal role in regulation of tumor progression, it remains unclear if 3-BP can alter the composition of the crucial tumor growth regulatory components of the external surrounding of tumor cells. Thus, the present investigation attempts to understand the effect of 3-BP administration to a host bearing a progressively growing tumor of thymic origin on tumor growth regulatory soluble, cellular and biophysical components of tumor milieu vis-à-vis understanding its association with tumor progression, accompanying cell cycle events and mode of cell death. Further, the expression of cell survival regulatory molecules and hemodynamic characteristics of the tumor milieu were analysed to decipher mechanisms underlying the antitumor action of 3-BP. Administration of 3-BP to tumor-bearing hosts retarded tumor progression accompanied by induction of tumor cell death, cell cycle arrest, declined metabolism, inhibited mitochondrial membrane potential, elevated release of cytochrome c and altered hemodynamics. Moreover, 3-BP reconstituted the external milieu, in concurrence with deregulated glucose and pH homeostasis and increased tumor infiltration by NK cells, macrophages, and T lymphocytes. Further, 3-BP administration altered the expression of key regulatory molecules involved in glucose uptake, intracellular pH and tumor cell survival. The outcomes of this study will help in optimizing the therapeutic application of 3-BP by targeting crucial tumor growth regulatory components of tumor milieu. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth.

    Science.gov (United States)

    Wolff, Dennis W; Xie, Yan; Deng, Caishu; Gatalica, Zoran; Yang, Mingjie; Wang, Bo; Wang, Jincheng; Lin, Ming-Fong; Abel, Peter W; Tu, Yaping

    2012-04-01

    G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity. Copyright © 2011 UICC.

  19. Effect of serum testosterone and percent tumor volume on extra-prostatic extension and biochemical recurrence after laparoscopic radical prostatectomy

    Directory of Open Access Journals (Sweden)

    Eu Chang Hwang

    2016-01-01

    Full Text Available Several studies have revealed that the preoperative serum testosterone and percent tumor volume (PTV predict extra-prostatic extension (EPE and biochemical recurrence (BCR after radical prostatectomy. This study investigated the prognostic significance of serum testosterone and PTV in relation to EPE and BCR after laparoscopic radical prostatectomy (LRP. We reviewed 520 patients who underwent LRP between 2004 and 2012. PTV was determined as the sum of all visually estimated tumor foci in every section. BCR was defined as two consecutive increases in the postoperative prostate-specific antigen (PSA >0.2 ng ml−1 . The threshold for serum total testosterone was 3.0 ng ml−1 . Multivariate logistic regression was used to define the effect of variables on the risk of EPE and BCR. A low serum testosterone (<3.0 ng ml−1 was associated with a high serum PSA, Gleason score, positive core percentage of the prostate biopsy, PTV, and all pathological variables. On multivariate analysis, similar to previous studies, the serum PSA, biopsy positive core percentage, Gleason score, and pathological variables predicted EPE and BCR. In addition, low serum testosterone (<3.0 ng ml−1 , adjusted OR, 8.52; 95% CI, 5.04-14.4, P= 0.001 predicted EPE and PTV (adjusted OR, 1.02; 95% CI, 1.01-1.05, P= 0.046 predicted BCR. In addition to previous predictors of EPE and BCR, low serum testosterone and PTV are valuable predictors of EPE and BCR after LRP.

  20. SU-D-207A-03: Potential Role of BOLD MRI in Discrimination of Aggressive Tumor Habitat in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ford, J; Lopez, C; Tschudi, Y; Breto, A; Padgett, K; Pollack, A; Stoyanova, R [University of Miami Miller School of Medicine, Miami, FL (United States)

    2016-06-15

    Purpose: To determine whether blood oxygenation level dependent (BOLD) MRI signal measured in prostate cancer patients, in addition to quantitative diffusion and perfusion parameters from multiparametric (mp)MRI exams, can help discriminate aggressive and/or radioresistant lesions. Methods: Several ongoing clinical trials in our institution require mpMRI exam to determine eligibility (presence of identifiable tumor lesion on mpMRI) and prostate volumes for dose escalation. Upon consent, patients undergo fiducial markers placement and a T2*-weighted imaging at the time of CT sim to facilitate the fusion. In a retrospective analysis eleven clinical trial patients were identified who had undergone mpMRI on GE 3T magnet, followed by T2*-weighted imaging (time-period mean±SD = 48±20 days) using a consistent protocol (gradient echo, TR/TE=30/11.8ms, flip angle=12, matrix=256×256×75, voxel size=1.25×1.25×2.5mm). ROIs for prostate tumor lesions were automatically determined using ADC threshold ≤1200 µm2/s. Although the MR protocol was not intended for BOLD analysis, we utilized the T2*-weighted signal normalized to that in nearby muscle; likewise, T2-weighted lesion signal was normalized to muscle, following rigid registration of the T2 to T2* images. The ratio of these normalized signals, T2*/T2, is a measure of BOLD effect in the prostate tumors. Perfusion parameters (Ktrans, ve, kep) were also calculated. Results: T2*/T2 (mean±SE) was found to be substantially lower for Gleason score (GS) 8&9 (0.82±0.04) compared to GS 7 (1.08±0.07). A k-means cluster analysis of T2*/T2 versus kep = Ktrans/ve revealed two distinct clusters, one with higher T2*/T2 and lower kep, containing only GS 7 lesions, and another with lower T2*/T2 and higher kep, associated with tumor aggressiveness. This latter cluster contained all GS 8&9 lesions, as well as some GS 7. Conclusion: BOLD MRI, in addition to ADC and kep, may play a role (perhaps orthogonal to Gleason score) in

  1. Possible autocrine loop of the epidermal growth factor system in patients with benign prostatic hyperplasia treated with finasteride: a placebo-controlled randomized study

    DEFF Research Database (Denmark)

    Tørring, N.; Møller-Ernst Jensen, K.; Lund, L.

    2002-01-01

    To analyse the expression of the epidermal growth factor (EGF) system in prostate tissue and secretions obtained from patients with benign prostatic hyperplasia (BPH) treated with or without finasteride (which primarily targets the androgen-sensitive secretory epithelial cells in the prostate......, with little effect on basal epithelial and stromal cells)....

  2. Strategies to reduce the systematic error due to tumor and rectum motion in radiotherapy of prostate cancer

    International Nuclear Information System (INIS)

    Hoogeman, Mischa S.; Herk, Marcel van; Bois, Josien de; Lebesque, Joos V.

    2005-01-01

    carried out later in the treatment (based on the data of more scans) the overall reduction was less. For the rectum, the first strategy performed best at the upper anterior side, where a reduction of the anterior-posterior displacement of 30% could be achieved. The systematic error could be reduced by 43% for the whole rectum by using the data of 4 repeat CT scans and the planning CT scan. Conclusions: Both the pre-treatment as well as the adaptive correction strategy reduced the systematic error in the prostate position and rectum position and shape. A smaller systematic error makes it possible to safely reduce the margin around the clinical tumor volume, so that normal tissues can be spared or the prescription dose can be escalated

  3. In Vivo Imaging of Prostate Cancer Tumors and Metastasis Using Non-Specific Fluorescent Nanoparticles in Mice

    Directory of Open Access Journals (Sweden)

    Coralie Genevois

    2017-12-01

    Full Text Available With the growing interest in the use of nanoparticles (NPs in nanomedicine, there is a crucial need for imaging and targeted therapies to determine NP distribution in the body after systemic administration, and to achieve strong accumulation in tumors with low background in other tissues. Accumulation of NPs in tumors results from different mechanisms, and appears extremely heterogeneous in mice models and rather limited in humans. Developing new tumor models in mice, with their low spontaneous NP accumulation, is thus necessary for screening imaging probes and for testing new targeting strategies. In the present work, accumulation of LipImageTM 815, a non-specific nanosized fluorescent imaging agent, was compared in subcutaneous, orthotopic and metastatic tumors of RM1 cells (murine prostate cancer cell line by in vivo and ex vivo fluorescence imaging techniques. LipImageTM 815 mainly accumulated in liver at 24 h but also in orthotopic tumors. Limited accumulation occurred in subcutaneous tumors, and very low fluorescence was detected in metastasis. Altogether, these different tumor models in mice offered a wide range of NP accumulation levels, and a panel of in vivo models that may be useful to further challenge NP targeting properties.

  4. Preliminary experience on the use of the Adnatest® system for detection of circulating tumor cells in prostate cancer patients.

    Science.gov (United States)

    Todenhöfer, Tilman; Hennenlotter, Jörg; Feyerabend, Susan; Aufderklamm, Stefan; Mischinger, Johannes; Kühs, Ursula; Gerber, Valentina; Fetisch, Jasmin; Schilling, David; Hauch, Siegfried; Stenzl, Arnulf; Schwentner, Christian

    2012-08-01

    The Adnatest® system combines immunomagnetic enrichment of epithelial cells with polymerase chain reaction for prostate cancer (PC)-specific transcripts for the detection circulating tumor cells (CTCs). We evaluated the Adnatest® in patients with castration-resistant PC receiving docetaxel chemotherapy. CTCs were assessed in 16 patients with castration-resistant PC before cycles one and three of chemotherapy. Furthermore, markers of stem cells and epithelial-mesenchymal transition were assessed. Treatment response was assessed by imaging and prostate-specific antigen measurements. Before chemotherapy, 11 patients were Adnatest®-positive whereas five patients were Adnatest®-positive before cycle three. A positive Adnatest® correlated with radiological progression (p=0.02). Rates of disease progression in epidermal growth factor receptor (EGFR)-positive and -negative patients were 100% and 7.7% (p=0.03). In this preliminary study, the Adnatest® detected CTCs in a considerable proportion of patients with castration-resistant PC. First data on certain markers (EGFR and aldehyd dehydrogenase 1) encourage future studies investigating transcripts predicting treatment response.

  5. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  6. The development of fluoroandrogens and fluoroprogestins as potential imaging agents for receptor-positive prostate and breast tumors

    International Nuclear Information System (INIS)

    Brandes, S.J.; Katzenellenbogen, J.A.

    1986-01-01

    The assay of progesterone receptor (PR) concentration in breast tumors and androgen receptor (AR) concentration in prostate tumors enables hormone responsive neoplasms to be distinguished from those that are non-responsive. In principle, a positron-emitting progestin or androgen with suitably high affinity and selectivity for PR and AR, respectively, and an adequately high specific activity might provide a means for imaging receptor-positive tumors and quantifying their receptor content in vivo. The use of fluorine-18 as a radiolabel, coupled with the use of positron emission transaxial tomography, appears to be a most favorable approach in the development of receptor binding radiopharmaceuticals for in vivo imaging. Therefore, we have begun a systematic investigation of the development of fluorine-substituted androgens and progestins that might be prepared in F-18 labeled form as probes for AR and PR. (author)

  7. Differential role of PTEN in transforming growth factor β (TGF-β) effects on proliferation and migration in prostate cancer cells.

    Science.gov (United States)

    Kimbrough-Allah, Mawiyah N; Millena, Ana C; Khan, Shafiq A

    2018-04-01

    Transforming growth factor-β (TGF-β) acts as a tumor suppressor in normal epithelial cells but as a tumor promoter in advanced prostate cancer cells. PI3-kinase pathway mediates TGF-β effects on prostate cancer cell migration and invasion. PTEN inhibits PI3-kinase pathway and is frequently mutated in prostate cancers. We investigated possible role(s) of PTEN in TGF-β effects on proliferation and migration in prostate cancer cells. Expression of PTEN mRNA and proteins were determined using RT-PCR and Western blotting in RWPE1 and DU145 cells. We also studied the role of PTEN in TGF-β effects on cell proliferation and migration in DU145 cells after transient silencing of endogenous PTEN. Conversely, we determined the role of PTEN in cell proliferation and migration after over-expression of PTEN in PC3 cells which lack endogenous PTEN. TGF-β1 and TGF-β3 had no effect on PTEN mRNA levels but both isoforms increased PTEN protein levels in DU145 and RWPE1 cells indicating that PTEN may mediate TGF-β effects on cell proliferation. Knockdown of PTEN in DU145 cells resulted in significant increase in cell proliferation which was not affected by TGF-β isoforms. PTEN overexpression in PC3 cells inhibited cell proliferation. Knockdown of endogenous PTEN enhanced cell migration in DU145 cells, whereas PTEN overexpression reduced migration in PC3 cells and reduced phosphorylation of AKT in response to TGF-β. We conclude that PTEN plays a role in inhibitory effects of TGF-β on cell proliferation whereas its absence may enhance TGF-β effects on activation of PI3-kinase pathway and cell migration. © 2018 Wiley Periodicals, Inc.

  8. Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data

    Directory of Open Access Journals (Sweden)

    Fernandez Pedro L

    2005-08-01

    Full Text Available Abstract Background We use an approach based on Factor Analysis to analyze datasets generated for transcriptional profiling. The method groups samples into biologically relevant categories, and enables the identification of genes and pathways most significantly associated to each phenotypic group, while allowing for the participation of a given gene in more than one cluster. Genes assigned to each cluster are used for the detection of pathways predominantly activated in that cluster by finding statistically significant associated GO terms. We tested the approach with a published dataset of microarray experiments in yeast. Upon validation with the yeast dataset, we applied the technique to a prostate cancer dataset. Results Two major pathways are shown to be activated in organ-confined, non-metastatic prostate cancer: those regulated by the androgen receptor and by receptor tyrosine kinases. A number of gene markers (HER3, IQGAP2 and POR1 highlighted by the software and related to the later pathway have been validated experimentally a posteriori on independent samples. Conclusion Using a new microarray analysis tool followed by a posteriori experimental validation of the results, we have confirmed several putative markers of malignancy associated with peptide growth factor signalling in prostate cancer and revealed others, most notably ERRB3 (HER3. Our study suggest that, in primary prostate cancer, HER3, together or not with HER4, rather than in receptor complexes involving HER2, could play an important role in the biology of these tumors. These results provide new evidence for the role of receptor tyrosine kinases in the establishment and progression of prostate cancer.

  9. Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice.

    Science.gov (United States)

    Sun, Xiujie; Gupta, Kshama; Wu, Bogang; Zhang, Deyi; Yuan, Bin; Zhang, Xiaowen; Chiang, Huai-Chin; Zhang, Chi; Curiel, Tyler J; Bendeck, Michelle P; Hursting, Stephen; Hu, Yanfen; Li, Rong

    2018-02-23

    Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1- KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro , and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Alerting the immune system via stromal cells is central to the prevention of tumor growth

    DEFF Research Database (Denmark)

    Navikas, Shohreh

    2013-01-01

    Anticancer immunotherapies are highly desired. Conversely, unwanted inflammatory or immune responses contribute to oncogenesis, tumor progression, and cancer-related death. For non-immunogenic therapies to inhibit tumor growth, they must promote, not prevent, the activation of anticancer immune...

  11. Effect of Depleting Tumor-Associated Macrophages on Breast Cancer Growth and Response to Chemotherapy

    National Research Council Canada - National Science Library

    Tsan, Min-Fu

    2004-01-01

    Tumor-associated macrophages (TAM) may comprise up to 50% of the tumor mass in breast cancer and are capable of producing estrogen and angiogenic cytokines that regulate the growth and angiogenesis of breast cancer...

  12. Effect of Depleting Tumor-Associated Macrophages on Breast Cancer Growth and Response to Chemotherapy

    National Research Council Canada - National Science Library

    Tsan, Min-Fu; Gao, Baochong

    2005-01-01

    Tumor-associated macrophages may comprise up to 50% of the tumor mass in breast cancer and are capable of producing estrogen and angiogenic cytokines that regulate the growth and angiogenesis of breast cancer...

  13. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.

    Directory of Open Access Journals (Sweden)

    Marie Lundholm

    Full Text Available Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

  14. Image-guided diagnosis of prostate cancer can increase detection of tumors

    Science.gov (United States)

    In the largest prospective study to date of image-guided technology for identifying suspicious regions of the prostate to biopsy, researchers compared the ability of this technology to detect high-risk prostate cancer with that of the current standard of

  15. The novel tumor-suppressor Mel-18 in prostate cancer: its functional polymorphism, expression and clinical significance.

    Science.gov (United States)

    Wang, Wei; Yuasa, Takeshi; Tsuchiya, Norihiko; Ma, Zhiyong; Maita, Shinya; Narita, Shintaro; Kumazawa, Teruaki; Inoue, Takamitsu; Tsuruta, Hiroshi; Horikawa, Yohei; Saito, Mitsuru; Hu, Weilie; Ogawa, Osamu; Habuchi, Tomonori

    2009-12-15

    Mel-18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel-18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel-18 genotyping was analyzed using a PCR-RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel-18 expression was diminished in high grade and high stage prostate cancers. Moreover, patients with positive Mel-18 expression had significantly longer PSA recurrence-free survival than patients negative for Mel-18 expression (p=0.038). A Mel-18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel-18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT-PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel-18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p=0.022) and 2.271 (p=0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer-specific survival with an HR of 4.658 (p=0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel-18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients. Copyright (c) 2009 UICC.

  16. Does Local Recurrence of Prostate Cancer After Radiation Therapy Occur at the Site of Primary Tumor? Results of a Longitudinal MRI and MRSI Study

    International Nuclear Information System (INIS)

    Arrayeh, Elnasif; Westphalen, Antonio C.; Kurhanewicz, John; Roach, Mack; Jung, Adam J.; Carroll, Peter R.; Coakley, Fergus V.

    2012-01-01

    Purpose: To determine if local recurrence of prostate cancer after radiation therapy occurs at the same site as the primary tumor before treatment, using longitudinal magnetic resonance (MR) imaging and MR spectroscopic imaging to assess dominant tumor location. Methods and Materials: This retrospective study was HIPAA compliant and approved by our Committee on Human Research. We identified all patients in our institutional prostate cancer database (1996 onward) who underwent endorectal MR imaging and MR spectroscopic imaging before radiotherapy for biopsy-proven prostate cancer and again at least 2 years after radiotherapy (n = 124). Two radiologists recorded the presence, location, and size of unequivocal dominant tumor on pre- and postradiotherapy scans. Recurrent tumor was considered to be at the same location as the baseline tumor if at least 50% of the tumor location overlapped. Clinical and biopsy data were collected from all patients. Results: Nine patients had unequivocal dominant tumor on both pre- and postradiotherapy imaging, with mean pre- and postradiotherapy dominant tumor diameters of 1.8 cm (range, 1–2.2) and 1.9 cm (range, 1.4–2.6), respectively. The median follow-up interval was 7.3 years (range, 2.7–10.8). Dominant recurrent tumor was at the same location as dominant baseline tumor in 8 of 9 patients (89%). Conclusions: Local recurrence of prostate cancer after radiation usually occurs at the same site as the dominant primary tumor at baseline, suggesting supplementary focal therapy aimed at enhancing local tumor control would be a rational addition to management.

  17. Contribution of Interstitial Deletion of 21q22.2-3 per se to Prostate Cancer Progression in Tumors Harboring TMPRSS2-ERG Translocations

    Science.gov (United States)

    2015-12-01

    harboring TMPRSS2- ERG translocations PRINCIPAL INVESTIGATOR: Yan Dong CONTRACTING ORGANIZATION: Tulane University New Orleans, LA 70112...0485 to prostate cancer progression in tumors harboring TMPRSS2- ERG translocations 5b. GRANT NUMBER W81XWH-14-1-0485 5c. PROGRAM ELEMENT NUMBER...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT TMPRSS2- ERG gene fusions are present in close to 50% of human prostate cancers. Approximately half of the

  18. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Qingwen [Shanghai Chest Hospital, Shanghai 200433 (China); State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Jiang, Songmin [State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433 (China); Han, Baohui [Shanghai Chest Hospital, Shanghai 200433 (China); Sun, Tongwen [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China); Li, Zhengnan; Zhao, Lina; Gao, Qiang [College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457 (China); Sun, Jialin, E-mail: jialin_sun@126.com [Wuhan Junyu Innovation Pharmaceuticals, Inc., Wuhan 430079 (China)

    2012-11-02

    Highlights: Black-Right-Pointing-Pointer We construct and purify a fusion protein VEGF-SEA. Black-Right-Pointing-Pointer VEGF-SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. Black-Right-Pointing-Pointer T cells driven by VEGF-SEA were accumulated around tumor cells bearing VEGFR by mice image model. Black-Right-Pointing-Pointer VEGF-SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. Black-Right-Pointing-Pointer The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15 {mu}g, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4{sup +} and CD8{sup +} T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  19. Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor–superantigen conjugate

    International Nuclear Information System (INIS)

    Sun, Qingwen; Jiang, Songmin; Han, Baohui; Sun, Tongwen; Li, Zhengnan; Zhao, Lina; Gao, Qiang; Sun, Jialin

    2012-01-01

    Highlights: ► We construct and purify a fusion protein VEGF–SEA. ► VEGF–SEA strongly repressed the growth of murine solid sarcoma 180 (S180) tumors. ► T cells driven by VEGF–SEA were accumulated around tumor cells bearing VEGFR by mice image model. ► VEGF–SEA can serve as a tumor targeting agent and sequester CTLs into the tumor site. ► The induced CTLs could release the cytokines, perforins and granzyme B to kill the tumor cells. -- Abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF–SEA treated with 15 μg, mean tumor weight: 1.128 g versus 0.252 g, difference = 0.876 g). CD4 + and CD8 + T cells driven by VEGF–SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF–SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.

  20. Prostate cancer incidence and tumor severity in Georgia: descriptive epidemiology, racial disparity, and geographic trends.

    Science.gov (United States)

    Wagner, Sara E; Bauer, Sarah E; Bayakly, A Rana; Vena, John E

    2013-01-01

    Limited research has been conducted to describe the geographical clustering and distribution of prostate cancer (PrCA) incidence in Georgia (GA). This study describes and compares the temporal and geographic trends of PrCA incidence in GA with a specific focus on racial disparities. GA Comprehensive Cancer Registry PrCA incidence data were obtained for 1998-2008. Directly standardized age-adjusted PrCA incidence rates per 100,000 were analyzed by race, stage, grade, and county. County-level hotspots of PrCA incidence were analyzed with the Getis-Ord Gi* statistic in a geographic information system; a census tract-level cluster analysis was performed with a Discrete Poisson model and implemented in SaTScan(®) software. Significant (p incidence were observed in nine southwestern counties and six centrally located counties among men of both races. Six significant (p incidence rates were detected for men of both races in north and northwest central Georgia. When stratified by race, clusters among white and black men were similar, although centroids were slightly shifted. Most notably, a large (122 km radius) cluster in northwest central Georgia was detected only in whites, and two smaller clusters (0-32 km radii) were detected in Southwest Georgia only in black men. Clusters of high-grade and late-stage tumors were identified primarily in the northern portion of the state among men of both races. This study revealed a pattern of higher incidence and more advanced disease in northern and northwest central Georgia, highlighting geographic patterns that need more research and investigation of possible environmental determinants.

  1. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Giesel, Frederik L.; Vinsensia, M.; Mier, W.; Haberkorn, U.; Kratochwil, C. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Hadaschik, B.; Radtke, J.; Kesch, C. [University Hospital Heidelberg, Department of Urology, Heidelberg (Germany); Cardinale, J.; Schaefer, M.; Neels, O.C.; Kopka, K. [German Cancer Research Center (dkfz), Division of Radiopharmaceutical Chemistry, Heidelberg (Germany); Lehnert, W. [ABX-CRO, Dresden (Germany); Tolstov, Y.; Singer, S. [University Hospital Heidelberg, Section of Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, Heidelberg (Germany); Grabe, N. [University Hospital Heidelberg, Institute of Pathology, Heidelberg (Germany); University Hospital Heidelberg, Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg (Germany); University of Heidelberg, Hamamatsu Tissue Imaging and Analysis Center, Heidelberg (Germany); Duensing, S. [University Hospital Heidelberg, Department of Urology, Heidelberg (Germany); University Hospital Heidelberg, Section of Molecular Urooncology, Department of Urology, Medical Faculty Heidelberg, Heidelberg (Germany)

    2017-04-15

    The prostate-specific membrane antigen (PSMA) targeted positron-emitting-tomography (PET) tracer {sup 68}Ga-PSMA-11 shows great promise in the detection of prostate cancer. However, {sup 68}Ga has several shortcomings as a radiolabel including short half-life and non-ideal energies, and this has motivated consideration of {sup 18}F-labelled analogs. {sup 18}F-PSMA-1007 was selected among several {sup 18}F-PSMA-ligand candidate compounds because it demonstrated high labelling yields, outstanding tumor uptake and fast, non-urinary background clearance. Here, we describe the properties of {sup 18}F-PSMA-1007 in human volunteers and patients. Radiation dosimetry of {sup 18}F-PSMA-1007 was determined in three healthy volunteers who underwent whole-body PET-scans and concomitant blood and urine sampling. Following this, ten patients with high-risk prostate cancer underwent {sup 18}F-PSMA-1007 PET/CT (1 h and 3 h p.i.) and normal organ biodistribution and tumor uptakes were examined. Eight patients underwent prostatectomy with extended pelvic lymphadenectomy. Uptake in intra-prostatic lesions and lymph node metastases were correlated with final histopathology, including PSMA immunostaining. With an effective dose of approximately 4.4-5.5 mSv per 200-250 MBq examination, {sup 18}F-PSMA-1007 behaves similar to other PSMA-PET agents as well as to other {sup 18}F-labelled PET-tracers. In comparison to other PSMA-targeting PET-tracers, {sup 18}F-PSMA-1007 has reduced urinary clearance enabling excellent assessment of the prostate. Similar to {sup 18}F-DCFPyL and with slightly slower clearance kinetics than PSMA-11, favorable tumor-to-background ratios are observed 2-3 h after injection. In eight patients, diagnostic findings were successfully validated by histopathology. {sup 18}F-PSMA-1007 PET/CT detected 18 of 19 lymph node metastases in the pelvis, including nodes as small as 1 mm in diameter. {sup 18}F-PSMA-1007 performs at least comparably to {sup 68}Ga-PSMA-11, but its

  2. Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells

    International Nuclear Information System (INIS)

    Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.; Wilson, George D.; Marples, Brian

    2010-01-01

    Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing γH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2μg/mL], Trinovin [10μg/mL], and Prostate Rx [50 μg/mL]). However, both Trinovin (10μg/mL) and Prostate Rx (6μg/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.

  3. Evaluation of aqueous extracts of Taraxacum officinale on growth and invasion of breast and prostate cancer cells.

    Science.gov (United States)

    Sigstedt, Sophia C; Hooten, Carla J; Callewaert, Manika C; Jenkins, Aaron R; Romero, Anntherese E; Pullin, Michael J; Kornienko, Alexander; Lowrey, Timothy K; Slambrouck, Severine Van; Steelant, Wim F A

    2008-05-01

    Ethnotraditional use of plant-derived natural products plays a significant role in the discovery and development of potential medicinal agents. Plants of the genus Taraxacum, commonly known as dandelions, have a history of use in Chinese, Arabian and Native American traditional medicine, to treat a variety of diseases including cancer. To date, however, very few studies have been reported on the anti-carcinogenic activity of Taraxacum officinale (TO). In the present study, three aqueous extracts were prepared from the mature leaves, flowers and roots, and investigated on tumor progression related processes such as proliferation and invasion. Our results show that the crude extract of dandelion leaf (DLE) decreased the growth of MCF-7/AZ breast cancer cells in an ERK-dependent manner, whereas the aqueous extracts of dandelion flower (DFE) and root (DRE) had no effect on the growth of either cell line. Furthermore, DRE was found to block invasion of MCF-7/AZ breast cancer cells while DLE blocked the invasion of LNCaP prostate cancer cells, into collagen type I. Inhibition of invasion was further evidenced by decreased phosphorylation levels of FAK and src as well as reduced activities of matrix metalloproteinases, MMP-2 and MMP-9. This study provides new scientific data on TO and suggests that TO extracts or individual components present in the extracts may be of value as novel anti-cancer agents.

  4. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

    Science.gov (United States)

    Yu, Yue; Lee, Jennifer Suehyun; Xie, Ning; Li, Estelle; Hurtado-Coll, Antonio; Fazli, Ladan; Cox, Michael; Plymate, Stephen; Gleave, Martin; Dong, Xuesen

    2014-01-01

    Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR) was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood. Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels. Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1) and interlukin-6 (IL-6) by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion. Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  5. Identification and characterization of MEL-3, a novel AR antagonist that suppresses prostate cancer cell growth.

    Science.gov (United States)

    Helsen, Christine; Marchand, Arnaud; Chaltin, Patrick; Munck, Sebastian; Voet, Arnout; Verstuyf, Annemieke; Claessens, Frank

    2012-06-01

    Antiandrogens are an important component of prostate cancer therapy as the androgen receptor (AR) is the key regulator of prostate cancer growth and survival. Current AR antagonists, such as bicalutamide and hydroxyflutamide, have a low affinity for the AR and as a result block AR signaling insufficiently. Moreover, many patients develop a resistance for bicalutamide or hydroxyflutamide during therapy or show a clinical improvement after withdrawal of the antiandrogen. New and more effective AR antagonists are needed to ensure follow-up of these patients. We therefore developed a screening system to identify novel AR antagonists from a collection of compounds. MEL-3 [8-(propan-2-yl)-5,6-dihydro-4H-pyrazino[3,2,1-jk]carbazole] was selected as potent inhibitor of the AR and was further characterized in vitro. On different prostate cancer cell lines MEL-3 displayed an improved therapeutic profile compared with bicalutamide. Not only cell growth was inhibited but also the expression of androgen-regulated genes: PSA and FKBP5. Prostate cancer is often associated with mutated ARs that respond to a broadened spectrum of ligands including the current antiandrogens used in the clinic, hydroxyflutamide and bicalutamide. The activity of two mutant receptors (AR T877A and AR W741C) was shown to be reduced in presence of MEL-3, providing evidence that MEL-3 can potentially be a follow-up treatment for bicalutamide- and hydroxyflutamide-resistant patients. The mechanism of action of MEL-3 on the molecular level was further explored by comparing the structure-activity relationship of different chemical derivatives of MEL-3 with the in silico docking of MEL-3 derivatives in the binding pocket of the AR. ©2012 AACR

  6. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model.

    Science.gov (United States)

    Jablonska, Jadwiga; Leschner, Sara; Westphal, Kathrin; Lienenklaus, Stefan; Weiss, Siegfried

    2010-04-01

    Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.

  7. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castrationresistant prostate cancer: a report from the PETRUS prospective study

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-01-01

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. PMID:27391263

  8. Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.

    Science.gov (United States)

    Massard, Christophe; Oulhen, Marianne; Le Moulec, Sylvestre; Auger, Nathalie; Foulon, Stéphanie; Abou-Lovergne, Aurélie; Billiot, Fanny; Valent, Alexander; Marty, Virginie; Loriot, Yohann; Fizazi, Karim; Vielh, Philippe; Farace, Francoise

    2016-08-23

    Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs.Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

  9. Growth/differentiation factor-15: prostate cancer suppressor or promoter?

    Czech Academy of Sciences Publication Activity Database

    Vaňhara, P.; Hampl, A.; Kozubík, Alois; Souček, Karel

    2012-01-01

    Roč. 15, č. 4 (2012), s. 320-328 ISSN 1365-7852 R&D Projects: GA MZd NS9600; GA MZd NS9956 Institutional research plan: CEZ:AV0Z50040702 Institutional support: RVO:68081707 Keywords : MACROPHAGE-INHIBITORY CYTOKINE-1 * GROWTH-DIFFERENTIATION FACTOR-15 * TGF-BETA SUPERFAMILY Subject RIV: BO - Biophysics Impact factor: 2.811, year: 2012

  10. The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth

    International Nuclear Information System (INIS)

    Deronic, Adnan; Leanderson, Tomas; Ivars, Fredrik

    2016-01-01

    Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C hi and Ly6G hi cells, but instead reduced the influx of Ly6C hi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C hi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor

  11. RADIONUCLIDE STUDIES USING TUMOR-SEEKING RADIOPHARMACEUTICALS IN THE DIAGNOSIS OF PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    N. I. Tarassov

    2009-01-01

    Full Text Available Object: to evaluate the efficiency of prostate scintigraphy in the prebioptic diagnosis of prostate cancer (PC.Subjects and methods. Two hundred and two patients with suspected PC underwent comprehensive examination, including 99mTc-technetril prostate scintigraphy and a morphometric study of biopsy material columns. A computer program (official registration certificate No. 2007614475 dated October 24, 2007 was worked out and patented to calculate the intensity of accumulation of radiopharmaceuticals in different portions of the right and left prostate lobes.Results and discussion. When the division index point «pathological focus/background», 1.5; ≤ 1.5, healthy; > 1.5 suspected prostate cancer was used, the sensitivity of prostate scintigraphy was 81.65%; its specificity was 87.1%; the diagnostic effectiveness was 84.37%.Conclusion: The application of prostate scintigraphy can improve indicators for early detection of PC, due to the purposeful detection of the points, enhance the effectiveness of biopsy, and, having more grounds than the early ones, to exclude this disease at the prebioptic stage. The method is noninvasive and can be used to monitor patients with suspected PC.

  12. RADIONUCLIDE STUDIES USING TUMOR-SEEKING RADIOPHARMACEUTICALS IN THE DIAGNOSIS OF PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    N. I. Tarassov

    2014-08-01

    Full Text Available Object: to evaluate the efficiency of prostate scintigraphy in the prebioptic diagnosis of prostate cancer (PC.Subjects and methods. Two hundred and two patients with suspected PC underwent comprehensive examination, including 99mTc-technetril prostate scintigraphy and a morphometric study of biopsy material columns. A computer program (official registration certificate No. 2007614475 dated October 24, 2007 was worked out and patented to calculate the intensity of accumulation of radiopharmaceuticals in different portions of the right and left prostate lobes.Results and discussion. When the division index point «pathological focus/background», 1.5; ≤ 1.5, healthy; > 1.5 suspected prostate cancer was used, the sensitivity of prostate scintigraphy was 81.65%; its specificity was 87.1%; the diagnostic effectiveness was 84.37%.Conclusion: The application of prostate scintigraphy can improve indicators for early detection of PC, due to the purposeful detection of the points, enhance the effectiveness of biopsy, and, having more grounds than the early ones, to exclude this disease at the prebioptic stage. The method is noninvasive and can be used to monitor patients with suspected PC.

  13. Development of lutetium-labeled bombesin derivates: relationship between structure and diagnostic-therapeutic activity for prostate tumor; Desenvolvimento de derivados da bombesina radiomarcados com lutecio-177: relacao estrutura e potencial diagnostico-terapeutico para tumor de prostata

    Energy Technology Data Exchange (ETDEWEB)

    Pujatti, Priscilla Brunelli

    2009-07-01

    Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor peptide - have been shown to be massively over expressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel series of bombesin derivatives with lutetium-177 and to evaluate the relationship between their structure and diagnostic-therapeutic activity for prostate tumor. The generic structure of studied peptides is DOTA-Phe-(Gly){sub n}-BBN(6-14), where DOTA is the chelator, n is the number of glycine amino acids of Phe-(Gly){sub n} spacer and BBN(6-14) is the bombesin sequence from the amino acid 6 to the amino acid 14. Preliminary studies were done to establish the ideal labeling conditions for obtaining the highest yield of labeled bombesin derivatives, determined by instant thin layer chromatography (ITLC-SG) and high performance liquid chromatography (HPLC). The stability of the preparations was evaluated either after storing at 2-8 degree C or incubation in human serum at 37 degree C and the partition coefficient was determined in n:octanol:water. In vivo studies were performed in both healthy Balb-c and Nude mice bearing PC-3 xenografts, in order to characterize the biological properties of labeled peptides. In vitro studies involved the evaluation of cold bombesin derivatives effect in PC-3 cells proliferation. Bombesin derivatives were successfully labeled with high yield at optimized conditions and exhibited high stability at 4 degree C. The analysis of

  14. DWI-associated entire-tumor histogram analysis for the differentiation of low-grade prostate cancer from intermediate-high-grade prostate cancer.

    Science.gov (United States)

    Wu, Chen-Jiang; Wang, Qing; Li, Hai; Wang, Xiao-Ning; Liu, Xi-Sheng; Shi, Hai-Bin; Zhang, Yu-Dong

    2015-10-01

    To investigate diagnostic efficiency of DWI using entire-tumor histogram analysis in differentiating the low-grade (LG) prostate cancer (PCa) from intermediate-high-grade (HG) PCa in comparison with conventional ROI-based measurement. DW images (b of 0-1400 s/mm(2)) from 126 pathology-confirmed PCa (diameter >0.5 cm) in 110 patients were retrospectively collected and processed by mono-exponential model. The measurement of tumor apparent diffusion coefficients (ADCs) was performed with using histogram-based and ROI-based approach, respectively. The diagnostic ability of ADCs from two methods for differentiating LG-PCa (Gleason score, GS ≤ 6) from HG-PCa (GS > 6) was determined by ROC regression, and compared by McNemar's test. There were 49 LG-tumor and 77 HG-tumor at pathologic findings. Histogram-based ADCs (mean, median, 10th and 90th) and ROI-based ADCs (mean) showed dominant relationships with ordinal GS of Pca (ρ = -0.225 to -0.406, p Histogram 10th ADCs had dominantly high Az (0.738), Youden index (0.415), and positive likelihood ratio (LR+, 2.45) in stratifying tumor GS against mean, median and 90th ADCs, and ROI-based ADCs. Histogram mean, median, and 10th ADCs showed higher specificity (65.3%-74.1% vs. 44.9%, p histogram analysis had higher specificity, Az, Youden index, and LR+ for differentiation of PCa Gleason grade than ROI-based approach.

  15. Numerical modelling of the influence of stromal cells on tumor growth and angiogenesis

    Science.gov (United States)

    Sakiyama, Nobuyuki; Nagayama, Katsuya

    2018-01-01

    According to the statistics provided by the Ministry of Health, Labor and Welfare the death of one in 3.5 Japanese people is attributed to tumor highlighting the need for active research on malignant tumors. Early detection can be cited as a countermeasure against malignant tumors, but it is often difficult to observe the growth process, and thorough understanding of the phenomena will aid in more efficient detection of such tumors. A malnourished benign tumor may create new blood vessels from existing ones and proliferate abnormally by absorbing nutrients from these newly created blood vessels to become malignant. Different factors influence the shape of tumors and shape is an important factor in evaluating their malignancy. Because interstitial cells greatly influence tumor growth, investigating the influence of stromal cells on tumor growth will help in developing a better understanding of the phenomenon.

  16. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth

    Science.gov (United States)

    Yin, Yuan; Cai, Xing; Chen, Xi; Liang, Hongwei; Zhang, Yujing; Li, Jing; Wang, Zuoyun; Chen, Xiulan; Zhang, Wen; Yokoyama, Seiji; Wang, Cheng; Li, Liang; Li, Limin; Hou, Dongxia; Dong, Lei; Xu, Tao; Hiroi, Takachika; Yang, Fuquan; Ji, Hongbin; Zhang, Junfeng; Zen, Ke; Zhang, Chen-Yu

    2014-01-01

    An increased population of CD4+CD25highFoxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles (MVs). In targeted mouse peripheral CD4+ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog (PTEN) and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides (ASOs) into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion. PMID:25223704

  17. Prostate cancer

    International Nuclear Information System (INIS)

    Bey, P.; Beckendorf, V.; Stines, J.

    2001-01-01

    Radiation therapy of prostate carcinoma with a curative intent implies to treat the whole prostate at high dose (at least 66 Gy). According to clinical stage, PSA level, Gleason's score, the clinical target volume may include seminal vesicles and less often pelvic lymph nodes. Microscopic extra-capsular extension is found in 15 to 60% of T1-T2 operated on, specially in apex tumors. On contrary, cancers developing from the transitional zone may stay limited to the prostate even with a big volume and with a high PSA level. Zonal anatomy of the prostate identifies internal prostate, including the transitional zone (5% of the prostate in young people). External prostate includes central and peripheral zones. The inferior limit of the prostate is not lower than the inferior border of the pubic symphysis. Clinical and radiological examination: ultrasonography, nuclear magnetic resonance (NMR), CT-scan identify prognostic factors as tumor volume, capsule effraction, seminal vesicles invasion and lymph node extension. The identification of the clinical target volume is now done mainly by CT-Scan which identifies prostate and seminal vesicles. NMR could be helpful to identify more precisely prostate apex. The definition of margins around the clinical target volume has to take in account daily reproducibility and organ motion and of course the maximum tolerable dose for organs at risk. (authors)

  18. Investigation of the Candidate Tumor Suppressor Gene prk in Prostate Cancer

    National Research Council Canada - National Science Library

    Dai, Wei

    2002-01-01

    .... We have proposed to characterize the genetic and epigenetic basis of aberrant PLK3 transcripts detected in prostate cancer, their prevalence and possible clinical relevance, to test the functional...

  19. Rapid In Vivo Validation of Tumor Suppressor Gene Function in Prostate Cancer Progression

    Science.gov (United States)

    2016-07-01

    identification of the best sgRNA sequences and accelerated our ability to move to the in vivo studies proposed in Aim2. Our goal was to use CRISPR / Cas ...and to initiate prostate cancer in the mouse after injection of lentiviral particles expressing CRISPR / Cas components and Cre recombinase. Our initial...in vivo Our goal was to use CRISPR / Cas lentiviral transduction of the adult prostate to inactivate p53 or Rb. We aimed to recapitulate the effects of

  20. HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

    Science.gov (United States)

    Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

    2016-08-01

    The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Characteristics Studies of 125I- and total PSA antibody's Binding with prostate specific antigen (PSA) in Human Uterus Tumors

    International Nuclear Information System (INIS)

    Al-Mudaffar, S.; Al-Salihi, J.

    2005-01-01

    Two groups of uterus tumors (benign and malignant) postmenopausal patients were used to investigate the presence of prostate specific antigen (PSA). Preliminary experiments were performed to follow the binding of '1 25 I-anti total PSA antibody with PSA in uterus tissues homogenates of the two groups with their corresponding antigen and found to be (8.8,7.1%) for benign and malignant tumors, respectively. An Immuno Radio Metric Assay (IRMA) procedure was developed for measuring PSA in benign and malignant uterus tumors homogenates. The optimum conditions of the binding of 125 I-anti total PSA antibody with PSA were as follows: PSA concentration (150,200 μg protein),tracer antibody concentration (125,250 μg protein), p H (7.6,7.2), temp (15,25?C) and time (1.5 hrs) for postmenopausal benign and malignant uterus tumors tissue homogenates, respectively. The use of different concentrations of Na + and Mg 2+ ions were shown to cause an increase in the binding at concentration of (125,75 mΜ) of Na 1+ ions (75,225 mΜ) of Mg 2+ ions for benign and malignant uterus tumors homogenates, respectively, while the use of different concentrations of urea and polyethylene glycol (PEG) Caused a decrease in the binding with the increase in the concentration of each of urea and PEG in the both cases

  2. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth.

    Science.gov (United States)

    Cramer, Shira L; Saha, Achinto; Liu, Jinyun; Tadi, Surendar; Tiziani, Stefano; Yan, Wupeng; Triplett, Kendra; Lamb, Candice; Alters, Susan E; Rowlinson, Scott; Zhang, Yan Jessie; Keating, Michael J; Huang, Peng; DiGiovanni, John; Georgiou, George; Stone, Everett

    2017-01-01

    Cancer cells experience higher oxidative stress from reactive oxygen species (ROS) than do non-malignant cells because of genetic alterations and abnormal growth; as a result, maintenance of the antioxidant glutathione (GSH) is essential for their survival and proliferation. Under conditions of elevated ROS, endogenous L-cysteine (L-Cys) production is insufficient for GSH synthesis. This necessitates uptake of L-Cys that is predominantly in its disulfide form, L-cystine (CSSC), via the xCT(-) transporter. We show that administration of an engineered and pharmacologically optimized human cyst(e)inase enzyme mediates sustained depletion of the extracellular L-Cys and CSSC pool in mice and non-human primates. Treatment with this enzyme selectively causes cell cycle arrest and death in cancer cells due to depletion of intracellular GSH and ensuing elevated ROS; yet this treatment results in no apparent toxicities in mice even after months of continuous treatment. Cyst(e)inase suppressed the growth of prostate carcinoma allografts, reduced tumor growth in both prostate and breast cancer xenografts and doubled the median survival time of TCL1-Tg:p53 -/- mice, which develop disease resembling human chronic lymphocytic leukemia. It was observed that enzyme-mediated depletion of the serum L-Cys and CSSC pool suppresses the growth of multiple tumors, yet is very well tolerated for prolonged periods, suggesting that cyst(e)inase represents a safe and effective therapeutic modality for inactivating antioxidant cellular responses in a wide range of malignancies.

  3. Efficacy of c-Met inhibitor for advanced prostate cancer

    International Nuclear Information System (INIS)

    Tu, William H; Zhu, Chunfang; Clark, Curtis; Christensen, James G; Sun, Zijie

    2010-01-01

    Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer

  4. Larger Maximum Tumor Diameter at Radical Prostatectomy Is Associated With Increased Biochemical Failure, Metastasis, and Death From Prostate Cancer After Salvage Radiation for Prostate Cancer

    International Nuclear Information System (INIS)

    Johnson, Skyler B.; Hamstra, Daniel A.; Jackson, William C.; Zhou, Jessica; Foster, Benjamin; Foster, Corey; Song, Yeohan; Li, Darren; Palapattu, Ganesh S.; Kunju, Lakshmi; Mehra, Rohit; Sandler, Howard; Feng, Felix Y.

    2013-01-01

    Purpose: To investigate the maximum tumor diameter (MTD) of the dominant prostate cancer nodule in the radical prostatectomy specimen as a prognostic factor for outcome in patients treated with salvage external beam radiation therapy (SRT) for a rising prostate-specific antigen (PSA) value after radical prostatectomy. Methods and Materials: From an institutional cohort of 575 patients treated with SRT, data on MTD were retrospectively collected. The impact of MTD on biochemical failure (BF), metastasis, and prostate cancer-specific mortality (PCSM) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards models. Results: In the 173 patients with MTD data available, median follow-up was 77 months (interquartile range, 47-104 months) after SRT, and median MTD was 18 mm (interquartile range, 13-22 mm). Increasing MTD correlated with increasing pT stage, Gleason score, presence of seminal vesicle invasion, and lymph node invasion. Receiver operating characteristic curve analysis identified MTD of >14 mm to be the optimal cut-point. On univariate analysis, MTD >14 mm was associated with an increased risk of BF (P=.02, hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8), metastasis (P=.002, HR 4.0, 95% CI 2.1-7.5), and PCSM (P=.02, HR 8.0, 95% CI 2.9-21.8). On multivariate analysis MTD >14 mm remained associated with increased BF (P=.02, HR 1.9, 95% CI 1.1-3.2), metastasis (P=.02, HR 3.4, 95% CI 1.2-9.2), and PCSM (P=.05, HR 9.7, 95% CI 1.0-92.4), independent of extracapsular extension, seminal vesicle invasion, positive surgical margins, pre-RT PSA value, Gleason score, and pre-RT PSA doubling time. Conclusions: For patients treated with SRT for a rising PSA value after prostatectomy, MTD at time of radical prostatectomy is independently associated with BF, metastasis, and PCSM. Maximum tumor diameter should be incorporated into clinical decision making and future clinical risk assessment tools for those patients

  5. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    Energy Technology Data Exchange (ETDEWEB)

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  6. Modified model of VX2 tumor overexpressing vascular endothelial growth factor.

    Science.gov (United States)

    Pascale, Florentina; Ghegediban, Saida-Homayra; Bonneau, Michel; Bedouet, Laurent; Namur, Julien; Verret, Valentin; Schwartz-Cornil, Isabelle; Wassef, Michel; Laurent, Alexandre

    2012-06-01

    To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control