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  • prostate cancer  (15)
  • 1
    ISSN: 1573-7276
    Keywords: Keywords ; insulin-like growth factor I ; osteoblastic metastasis ; prostate cancer ; transforming growth factor b1 ; urokinase-type plasminogen activator
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We analysed the glucocorticoid receptor (GR) function and its ability to modulate cell-cell interactions between the PA-III rat prostate cancer and UMR 106 osteoblast-like rat osteosarcoma cells as an in vitro model for studying GR function in PA-III cell-induced tumor and blastic reaction in rat bone. Intact GR was detected by ligand binding assays, DNA band-shift, and GR trans-activation analysis of PA-III and UMR 106 cells transiently transfected with the mouse mammary tumor virus thymidine kinase-chloramphenicol acetyltransferase reporter gene. Dexamethasone and transforming growth factor beta 1 (TGFb1) inhibited the growth of PA-III and UMR 106 cells. Dexamethasone's inhibition of PA-III and UMR 106 cells was reversed by anti-TGFb1 antibody and exogenous insulin-like growth factor I (IGF-I). Exogenous IGF-I, urokinase-type plasminogen activator (uPA), UMR 106 conditioned media (CM) and PA-III CM stimulated the proliferation of PA-III and UMR 106 cells. The mitogenic activity exerted by uPA and PA-III CM in UMR 106 cells was completely neutralized by anti-IGF-I specific antibody. In addition, dexamethasone up-regulated TGFb1 mRNA and down-regulated uPA mRNA expression in PA-III cells without affecting TGFb1 and uPA mRNA expression in UMR 106 cells. These data suggested that TGFb1, uPA, and IGF-I mediate at least in part cell-cell interactions and GR function in PA-III prostate cancer and UMR 106 osteosarcoma cells.
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  • 2
    ISSN: 1573-7276
    Keywords: molecular staging ; nested rt-PCR ; prostate cancer ; PSA ; PSM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We performed repetitive molecular staging using, nested rt-PCR for PSA and PSM at the peripheral blood (PB) and bone marrow (BM) of patients with prostate cancer (Pr.Ca) and benign prostate hyperplasia (BPH) after transrectal ultrasonography-guided biopsy (TRUS-B; 6–9 biopsies/patient), Pr.Ca patients after radical prostatectomy (RP), and Pr.Ca patients with diffuse bony metastases. All BPH patients (N = 20) tested negative at BM. Of the 2 who tested positive at PB 2 weeks after TRUS-B tested negative 8 weeks after TRUS-B. Of the 17 Pr.Ca, 7 (41.2%) tested positive at PB for PSA and PSM 2 weeks after TRUS-B while only 4 (23.5%) of them tested positive at repetitive analysis 8 weeks after TRUS-B. Two (11.8%) of the 17 Pr.Ca patients had positive analysis at BM for PSA and PSM 2 and 8 weeks after TRUS-B. Of 12 Pr.Ca patients with negative pre-operative molecular staging, 7 (58.3%) tested positive at PB for PSA and PSM 2 months post-RP but only 3 (25%) of them re-tested positive 12 months post-RP. Of these 12 Pr.Ca, 4 (33.3%) tested positive at BM for PSA and PSM 2 months post-RP while none re-tested positive 12 months post-RP. All Pr.Ca (N = 20) with diffuse bony lesions tested positive at BM. At PB, 6 of them (30%) tested negative for both PSA and PSM. Our data suggest that nested rt-PCR for PSA and PSM at PB is affected by TRUS-B and RP, while such analysis at BM concerted diffuse bony disease.
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  • 3
    ISSN: 1573-7276
    Keywords: focal adhesion kinase ; prostate cancer ; genistein ; integrin ; cell adhesion ; tyrosine kinase inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has previously been shown that changes in the activity of focal adhesion kinase (FAK), and its binding to β-1-integrin, accompany genistein-induced adhesion of prostate cells. Consumption of genistein world wide is associated with a lower incidence of metastatic prostate cancer. Early human clinical trials of genistein are under way to evaluate genistein's potential causal role in this regard. Though an important cell adhesion-associated signaling molecule, FAK’s role in regulating prostate cell adhesion was not clear. Elucidation of this process would provide important information relating to both biology and potential clinical endpoints. It was hypothesized that FAK activation and complex formation are temporally related in prostate cells, and can thus be separated. Significant activation of FAK was demonstrated when cells adhered to fibronectin, as compared to poly-l-lysine, thus demonstrating that β-1-integrin plays a significant role in activating FAK. Neither FAK activation, nor FAK-integrin complex formation, required β-1-integrin ligand. However, disruption of the cellular cytoskeleton by cytochalasin D prevented FAK activation, but did not block genistein-induced complex formation. In the face of a disrupted cytoskeleton, signaling through FAK could not be restored through either integrin cross linking, or re-establishment of tensile forces via attachment to solid matrix. These studies demonstrate that FAK-β-1-integrin complex formation does not require FAK activation, suggesting that it is an early event in prostate cell adhesion. An intact cytoskeleton is necessary for FAK activation. The functional importance of β-1-integrin in prostate cells is demonstrated. Current findings support plans to test genistein in prostate cancer.
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  • 4
    ISSN: 1573-7276
    Keywords: membrane vesicles ; prostate cancer ; tumor invasion ; urokinase plasminogen activator
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of a cell to modify the extracellular matrix is important in several pathophysiological alterations including tumorigenesis. Cell transformation is accompanied by changes in the surrounding stroma as a result of the action of specific proteases such as the urokinase plasminogen activator (uPA), which has been associated with invasive potential in many tumor types. In this study, we analyzed the release of vesicle-associated uPA by the aggressive prostatic carcinoma cell line PC3 and the implications of this release for the invasive behaviour of prostatic tumor cells. Zymography and Western blot analysis revealed the presence of vesicle-associated uPA in the high-molecular weight form. Vesicles adhered to and degraded both collagen IV and reconstituted basal membrane (Matrigel), and plasminogen enhanced the degradation in a dose-dependent manner. Addition of membrane vesicles shed by PC3 cells to cultures of the poorly invasive prostate cancer cell line LnCaP enhanced the adhesive and invasive capabilities of the latter, suggesting a mechanism involving substrate recognition and degradation. Together, these findings indicate that membrane vesicles can promote tumor invasion and point to the important role of vesicle-associated uPA in the extracellular compartment.
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  • 5
    ISSN: 1573-7276
    Keywords: angiogenesis ; cyclooxygenase-2 ; cobalt chloride-simulated hypoxia ; metastasis ; NS398 ; prostaglandin E2 ; prostate cancer ; vascular endothelial growth factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoCl2)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP 〉 PC-3 〉 PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoCl2-simulated hypoxia. CoCl2 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with CoCl2. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5-fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by CoCl2 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by CoCl2 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoCl2-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and sustained elevation of PGE2 synthesis in a human metastatic prostate cancer cell line, and suggest that COX-2 activity, reflected by PGE2 production, is involved in hypoxia-induced VEGF expression, and thus, modulates prostatic tumor angiogenesis.
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  • 6
    ISSN: 1573-7276
    Keywords: MHG ; PB ; prostate cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of the naturally occurring ether lipid, 1-O (2 methoxy) hexadecyl glycerol (MHG), and phenylbutyrate (BP) to inhibit cellular proliferation, anchorage-independent growth and cellular invasion in the human prostate cancer LnCap and DU145 cells was determined. Both MHG and PB inhibited the malignant properties of these prostate cancer cells. The concentrations required to achieve similar inhibitory effect, however, were significantly different for these two agents. MHG inhibited cell growth with equal potency in these cell lines with an IC-50 value of 93 μM for LnCap, and 97 μM for DU145. The IC-50 values for PB were 1.3 mM and 7.3 mM, respectively, for LnCap and DU145 cells. Both MHG and PB (IC-50 concentrations) inhibited the anchorage-independent growth and cellular invasion in these cells. Over 50% inhibition of anchorage-independent growth was achieved for both LnCap and DU145 cells by PB, while a lesser degree of inhibition was achieved with MHG. Both MHG- and PB-treated cells showed a reduced propensity to invade matrigels. Invasion of PB-treated LnCap and DU145 cells was reduced, respectively, by approximate 41 and 30% when compared to untreated control cells, while invasion of MHG-treated LnCap and DU145 cells was reduced to a lesser extent. Because differentiation-inducing agents may possess chemopreventive properties, the use of naturally occurring MHG and nontoxic PB in the chemoprevention of malignant diseases warrants further investigation.
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  • 7
    ISSN: 1573-7276
    Keywords: basement membrane ; cell adhesion ; extracellular matrix ; laminin ; prostate cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cell adhesion and migration are important features in tumor invasion, being mediated in part by integrins (extracellular matrix receptors). Integrins are significantly decreased in human prostate cancer. An exception is α6 integrin (laminin receptor) which persists during prostate tumor progression. We have selected high (DU-H) and low (DU-L) expressors of α6 integrin from a human prostate tumor cell line, DU145, to assess experimentally the importance of α6 integrin in tumor invasion. DU-H cells exhibited a four-fold increased expression of α6 integrin on the surface compared to DU-L cells. Both cell types contained similar amounts of α3 and α5 integrin. The DU-H cells contained α6 subunits complexed with both the β1 and β4 subunits whereas DU-L cells contained α6 complexed only with β4. DU-H cells were three times more mobile on laminin as compared to DU-L, but adhered similarly on laminin. Adhesion and migration were inhibited with anti-α6 antibody. Each subline was injected intraperitoneally into SCID mice to test its invasive potential. Results showed greater invasion of DU-H compared to DU-L cells, with increased expression of a6 integrin on the tumor at the areas of invasion. These data suggest that α6 integrin expression is advantageous for prostate tumor cell invasion.
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  • 8
    ISSN: 1573-7276
    Keywords: heparanase ; invasion ; neurotrophins ; prostate cancer ; p75 neurotrophin receptor (p75NTR)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The role of the neurotrophins (NTs) and their corresponding receptors (NTRs) TrkA, TrkB, TrkC, and p75NTR in neoplasia has received relatively little attention. However, because malignant cell migration within the prostate occurs predominantly by direct extension around prostatic nerves, the presence and possible upregulation of NTs from autocrine/paracrine sources and NTR expression within prostate epithelial tumor cells may be important in metastasis. We have been addressing their expression and interactions in human prostate cancer cell lines (LNCaP, PC-3, and DU145) and their role in prostate cancer invasion. In this study, we demonstrated that nerve growth factor (NGF), the prototypic NT, and NT-4/5 increased in vitro invasion through a reconstituted basement membrane and induced time- and dose-dependent expression of heparanase, a heparan sulfate-specific endo-β-d-glucuronidase, an important molecular determinant of tumor metastasis. The NT effects were most marked in the DU145 brain-metastatic cells and were detected at NT concentrations sufficient to fully saturate both low- and high-affinity NTRs. Additionally, we characterized the molecular expression of NT high-affinity (Trk) and low-affinity (p75NTR) receptors in these cell lines by reverse transcription-polymerase chain reaction. These lines had negligible trkA and trkC expression, although trkB was expressed in the three prostatic tumor cell lines examined. The brain-metastatic DU145 cells were also positive for p75NTR. Our data showed that the NTs and NTRs are important in metastasis and that their expression coincides with transformation to a malignant phenotype capable of invasion along the perineural space and extracapsular metastasis to distant sites. These findings set the stage for more research into this area as related to prostate cancer evolution and may improve therapy for prostate cancer metastasis.
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  • 9
    ISSN: 1573-7276
    Keywords: angiogenesis ; bone metastasis ; endothelium ; mouse model ; prostate cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Using the SCID-human model, we recently found that human circulating prostate cancer cells formed tumors in human bone but not mouse bone (Nemeth et al. Cancer Res 1999; 59: 1987–93). It is possible that this tissue preference was mediated by interaction between human tumor cells and human endothelial cells within the implanted bone tissue. We sought to determine the relative amounts of human and mouse vasculature within human bone implants and resulting prostate cancer bone tumors in the SCID-human model. Paraffin sections of plain bone implants or PC3 or LNCaP human bone tumors were double stained for factor VIII (all vessels) and human CD31 (human vessels) followed by fluorescent secondary reagents. At 4 weeks post implantation (when cancer cells are typically introduced), the vasculature within human bone fragments remained primarily human (84.5%), and this pattern persisted to at least 10 weeks (91.6% human). Injection of PC3 cells into the bone resulted in an increase in mouse-derived vessels, however the majority (58%) of the vessels remained human even after the formation of large bone tumors. LNCaP bone tumors were highly angiogenic, and there was a sharp decline in the proportion of vessels which were antigenically human (36.8%), suggesting recruitment of mouse endothelial cells during the angiogenic process. Nonetheless, the persistence of human vasculature suggests the SCID-human model can be used to study the interaction between bone-seeking tumor cells, such as prostate cancer, and human bone endothelium in vivo, and to test potential therapeutic strategies which may depend on the presence of human vessels.
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  • 10
    ISSN: 1573-7276
    Keywords: bone metastasis ; chemoprevention ; prostate cancer ; retinoids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on prostate cancer metastasis in vivo were evaluated in the mouse prostate reconstitution (MPR) model. MPRs were produced by infection of either heterozygous (+/−) or nullizygous (−/−) p53-mutant fetal prostatic epithelial cells with the recombinant retrovirus Zipras/myc 9. Previous studies have documented that loss of p53 function potentiates metastasis in this model system. MPRs were grafted into homozygous (+/+) p53 male mice, fed a 4-HPR containing diet or a control diet and maintained until the status of tumor progression dictated sacrifice. Under these experimental conditions, treatment with 4-HPR did not have a significant effect on primary tumor wet weight for either p53 +/− or p53 −/− MPRs. For, p53 +/− MPRs the animals fed the 4-HPR diet had a slight improvement in survival and a significant reduction in the number of mesenteric metastases (P=0.0477, t-test). Notably, in p53 +/− MPRs the incidence of metastasis to lumbar spine and sternum was 92% in the control animals compared to 54% in the 4-HPR treated animals (P=0.035, χ2-test). In p53 −/− MPRs there was a trend toward a reduction in the number of soft tissue metastases to lung and liver in the 4-HPR group relative to the control diet group and a statistically significant reduction in the incidence of metastasis to bone was demonstrated in that 50% of control animals versus 30% of 4-HPR treated p53 −/− animals harbored bone metastases (P=0〈0.05, χ2-test). Cell lines were established from portions of the primary tumor and from selected metastatic deposits in each experimental group. Clonal analysis, by retroviral integration pattern, indicated increased clonal diversity in both the primary tumors and metastasis-derived cell lines from 4-HPR treated animals relative to the control animals. In vitro treatment with 4-HPR did not reveal discriminating differences between cell lines derived from primary tumors and bone metastases or control and treatment groups in regard to growth arrest or apoptotic responses. Overall these studies indicate limited anti-tumor and anti-metastatic activity in this highly aggressive in vivo mouse model of prostate cancer, yet 4-HPR treatment significantly suppressed the development of bone metastases in p53 +/− and p53 −/− MPRs revealing a novel and potentially clinically useful activity of this retinoid.
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