| 1. |
- Valta, Maija P., et al.
(författare)
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FGF-8b Induces Growth and Rich Vascularization in an Orthotopic PC-3 Model of Prostate Cancer
- 2009
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Ingår i: Journal of Cellular Biochemistry. - : Wiley. - 0730-2312 .- 1097-4644. ; 107:4, s. 769-784
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Tidskriftsartikel (refereegranskat)abstract
- Fibroblast growth factor 8 (FGF-8) is expressed at an increased level in a high proportion of prostate cancers and it is associated with a poor prognosis of the disease. Our aim was to study the effects of FGF-8b on proliferation of PC-3 prostate cancer cells and growth of PC-3 tumors, and to identify FGF-8b-associated molecular targets. Expression of ectopic FGF-8b in PC-3 cells caused a 1.5-fold increase in cell proliferation in vitro and a four- to fivefold increase in the size of subcutaneous and orthotopic prostate tumors in nude mice. Tumors expressing FGF-8b showed a characteristic morphology with a very rich network of capillaries. This was associated with increased spread of the cancer cells to the lungs as measured by RT-qPCR of FGF-8b mRNA. Microarray analyses revealed significantly altered, up- and downregulated, genes in PC-3 cell cultures (169 genes) and in orthotopic PC-3 tumors (61 genes). IPA network analysis of the upregulated genes showed the strongest association with development, cell proliferation (CRIP1, SHC1), angiogenesis (CCL2, DDAH2), bone metastasis (SPP1), cell-to-cell signaling and energy production, and the downregulated genes associated with differentiation (DKK-1, VDR) and cell death (CYCS). The changes in gene expression were confirmed by RT-qPCR. In conclusion, our results demonstrate that FGF-8b increases the growth and angiogenesis of orthotopic prostate tumors. The associated gene expression signature suggests potential mediators for FGF-8b actions on prostate cancer progression and metastasis. J. Cell. Biochem. 107: 769-784, 2009. (C) 2009 Wiley-Liss, Inc.
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| 2. |
- Gerdhem, Paul, et al.
(författare)
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Associations between homocysteine, bone turnover, BMD, mortality, and fracture risk in elderly women
- 2007
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 22:1, s. 127-134
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Tidskriftsartikel (refereegranskat)abstract
- Homocysteine has been suggested to be a risk factor for fracture, but the causal relationship is not clear. In 996 women from the OPRA study, high homocysteine level was associated with high bone marker levels and low BMD at baseline. During a mean 7-year follow-up, high homocysteine level was associated with mortality, but no clear association to fracture risk existed.
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| 3. |
- Härkönen, Pirkko, et al.
(författare)
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Monocyte-macrophage system as a target for estrogen and selective estrogen receptor modulators.
- 2006
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1089:Nov, s. 218-227
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Tidskriftsartikel (refereegranskat)abstract
- Postmenopausal decline of estrogen production is associated with development of several degenerative disorders such as osteoporosis, neuroinflammatory diseases and vascular wall degeneration. These are associated with the activation of the cells of the monocyte-macrophage system in a context-dependent manner. Estrogen regulates differentiation, maturation and function of many cell types in this system directly or indirectly via other cells by autocrine/paracrine mechanisms. Estrogen effects on the monocyte-macrophage system are primarily repressive. Most of these effects are mediated by repression of expression of genes for cytokines or modulation of other inflammatory mediators by the estrogen receptor (ER)-dependent or nongenomic pathways. The ER-dependent mechanisms mostly involve modulation of the nuclear factor kappa B (NF-kappaB) pathway for transcriptional regulation of cytokine or other mediator genes. In the context of hormone-regulated cancer, estrogen can influence production of cytokines or other inflammatory mediators by both tumor cells and tumor-invading macrophages. The interactions of breast and prostate cancer cells with tumor-associated macrophages (TAMs) may play an important role in tumor progression and even in the development of resistance to hormonal treatment. Regulation of the monocyte-macrophage system by estrogen and cross-talk between the ER and cytokine-mediated pathways provides multiple novel targets for development of selective ER modulator (SERM) molecules for prevention and treatment of postmenopausal degenerative and neoplastic diseases.
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| 4. |
- Ivaska, Kaisa, et al.
(författare)
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Bone Turnover Markers and Prediction of Fracture: A Prospective Follow-Up Study of 1040 Elderly Women for a Mean of 9 Years
- 2010
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 25:2, s. 393-403
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is characterized by compromised bone mass and strength, predisposing to an increased risk of fracture. Increased bone metabolism has been suggested to be a risk factor for fracture. The aim of this study was to evaluate whether baseline bone turnover markers are associated with long-term incidence of fracture in a population-based sample of 1040 women who were 75 years old (Malmo OPRA study). Seven bone markers (S-TRACP5b, S-CTX-1, S-OC[1-49], S-TotaIOC, S-cOC, S-boneALP, and urinary osteocalcin) were measured at baseline and 1-year follow-up visit. During the mean follow-up of 9.0 years (range 7.4-10.9), 363 women sustained at least one fracture of any type, including 116 hip fractures and 103 clinical vertebral fractures. High S-TRACP5b and S-CTX-1 levels were associated with increased risk of any fracture with hazard ratios [HRs (95% confidence interval)] of 1.16 (1.04-1.29) and 1.13 (1.01-1.27) per SD increase, respectively. They also were associated with increased risk of clinical vertebral fracture with HRs of 1.22 (1.01-1.48) and 1.32 (1.05-1.67), respectively. Markers were not associated with risk for hip fracture. Results were similar when we used resorption markers, including urinary osteocalcin, measured at the 1-year visit or an average of the two measurements. The HRs were highest for any fracture in the beginning of the follow-up period, 2.5 years from baseline. For vertebral fractures, the association was more pronounced and lasted for a longer period of time, at least for 5 years. In conclusion, elevated levels of S-TRACP5b, S-CTX-1, and urinary osteocalcin are associated with increased fracture risk for up to a decade in elderly women. (C) 2010 American Society for Bone and Mineral Research.
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| 5. |
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| 6. |
- Kallio, Anu, et al.
(författare)
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Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells
- 2008
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 289:1-2, s. 38-48
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Tidskriftsartikel (refereegranskat)abstract
- In the current work, we compared the ability of 17 beta-estradiol (E-2) and the selective estrogen receptor modulators (SERMs), tamoxifen (Tam), raloxifene (Ral) and ospemifene (Osp) to promote the survival of osteoblast-derived cells against etoposide-incluced apoptosis. In order to compare the roles of the two estrogen receptor (ER) isotypes, we created a U2OS human osteosarcoma cell line stably expressing either ERalpha (ER alpha) or ERbeta (ER beta). Transfection with either of the ERs was able to render the U2OS cells sensitive to E-2. We show that E2 opposed etoposide-induced apoptosis and that the effect was mediated via both ER isotypes. The ER isotype selective agonists propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPN) had the same effect in U2OS/ER alpha and U20S/ER beta cells, respectively. Osp also opposed apoptosis at least in U2OS/ERa cells. Tam and Ral were not able to protect against etoposide-induced cell death. In order to evaluate the protective effects of E-2 and Osp upon etoposide challenge, we studied the expression of two E-2-regulated, osteoblast-produced cytokines, IL-6 and OPG in E-2 and SERM-treated U2OS/ER alpha and U2OS/ER beta cells. Etoposide strongly increased expression of IL-6 and decreased that of OPG. E-2 opposed IL-6 increase only in U2OS/ER alpha cells and OPG decrease primarily in ER beta cells. Osp opposed the effect of etoposide on OPG primarily in U2OS/ER beta cells but interestingly, it had little effect on IL-6 expression. E2, PPT, DNP and Osp also inhibited etoposide-induced death and cytokine changes in SAOS-2 osteosarcoma cells expressing endogenous ER alpha and ER beta. Collectively, our results suggest that the osteoblast protective anti-apoptotic effects of E-2 are mediated by both ER alpha and ER beta but those of Osp primarily by ER alpha. In addition, E-2 and Osp opposed the etoposide-induced increase of IL-6 and decrease of OPG which changes would increase osteoclastic activity. These anti-resorptive effects of E-2 and Osp upon etoposide challenge differed from each other and they seemed to be differentially mediated in ER(x and ER beta expressing osteoblast-derived U2OS cells. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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| 7. |
- Tuomela, Johanna, et al.
(författare)
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Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors
- 2009
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. Methods: 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. Results: 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 PC3/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). Conclusion: 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.
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| 8. |
- Virtanen, Sanna S., et al.
(författare)
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Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells
- 2010
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Ingår i: Cell Biology International. - 1095-8355. ; 34:8, s. 815-826
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Tidskriftsartikel (refereegranskat)abstract
- The mevalonate synthesis pathway produces intermediates for isoprenylation of small GTPases, which are involved in the regulation of actin cytoskeleton and cell motility. Here, we investigated the role of the prenylation transferases in the regulation of the cytoskeletal organization and motility of PC-3 prostate cancer cells. This was done by using FTI-277, GGTI-298 or NE-10790, the specific inhibitors of FTase (farnesyltransferase), GGTase (geranylgeranyltransferase)-I and -II, respectively. Treatment of PC-3 cells with GGTI-298 and FTI-277 inhibited migration and invasion in a time- and dose-dependent manner. This was associated with disruption of F-actin organization and decreased recovery of GFP-actin. Immunoblot analysis of various cytoskeleton-associated proteins showed that the most striking change in GGTI-298- and FTI-277-treated cells was a markedly decreased level of total and phosphorylated cofilin, whereas the level of cofilin mRNA was not decreased. The treatment of PC-3 cells with GGTI-298 also affected the dynamics of GFP-paxillin and decreased the levels of total and phosphorylated paxillin. The levels of phosphorylated FAK (focal adhesion kinase) and PAK (p-21-associated kinase)-2 were also lowered by GGTI-298, but levels of paxillin or FAK mRNAs were not affected. In addition, GGTI-298 had a minor effect on the activity of MMP-9. RNAi knockdown of GGTase-I beta inhibited invasion, disrupted F-actin organization and decreased the level of cofilin in PC-3 cells. NE-10790 did not have any effect on PC-3 prostate cancer cell motility or on the organization of the cytoskeleton. In conclusion, our results demonstrate the involvement of GGTase-I- and FTase-catalysed prenylation reactions in the regulation of cytoskeletal integrity and motility of prostate cancer cells and suggest them as interesting drug targets for development of inhibitors of prostate cancer metastasis.
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