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On the Role of Osteoprotegerin/RANK/RANKL System in the Interaction between Prostate Cancer and Bone
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. (Metabola bensjukdomar)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Metastases to bone are observed in around 80% of prostate cancer patients and represent the most critical complication of advanced prostate cancer. Unlike other solid tumors that are associated with osteolytic bone metastases, prostate cancer bone metastases stimulate osteoblastic activity with sclerosis in the bone lesions as a consequence. Osteoprotegerin (OPG) is part of a system with three proteins that play a key role in bone remodeling; namely OPG, RANK and RANKL. RANKL regulates osteoclast activity by binding to RANK on the osteoclasts surface, and this interaction is interrupted by OPG. OPG also plays a role in the lifecycle of tumor cells by blocking TNF-related apoptosis-inducing ligand (TRAIL) making it possible for them to evade cell death. The aim of this thesis was to investigate the interaction between the OPG/RANK/RANKL system and prostate cancer.

Data showed that there was production of OPG from prostate cancer cell lines in vitro. This expression was under the influence of cytokines that are present in the microenvironment of bone. Further, there was documented a previously unnoticed cell surface expression of RANKL. Co-culturing the prostate cancer with human osteoblasts increased the expression of RANKL.

To connect these findings with in vivo studies, OPG-gene single nucleotide polymorphisms (SNP) were investigated. To evaluate OPG SNPs association with bone, a cohort of elderly men was used. OPG SNPs was shown to be correlated to bone mineral density at hip and spine. There was also an association to fragility fractures. Then there was examined the association of the same SNPs to the incidence of prostate cancer but after a four-year follow-up there was no association to the genetic variants.

To summarize this research, we hereby present data that the OPG/RANK/RANKL system might be relevant for prostate cancer growth in bone, and for the skeletal related morbidity in this disease. Future in vitro and in vivo studies will demonstrate the relative importance of this crosstalk, and whether pharmacological interference with the system might be used as a therapeutic tool aiming to decrease skeletal morbidity and possibly also prolong survival in prostate cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 723
Keyword [en]
metastases, bone, prostate cancer, osteoprotegerin, RANKL, osteoporosis, genetics, polymorphisms
National Category
Orthopedics
Research subject
Orthopaedics
Identifiers
URN: urn:nbn:se:uu:diva-160751ISBN: 978-91-554-8215-2 (print)OAI: oai:DiVA.org:uu-160751DiVA: diva2:452639
Public defence
2011-12-09, Rosénsalen, Ingång 95/96, nbv, Barnsjukhuset, Akademiska sjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-11-18 Created: 2011-10-31 Last updated: 2011-11-23Bibliographically approved
List of papers
1. Osteoprotegerin secretion from prostate cancer is stimulated by cytokines,in vitro.
Open this publication in new window or tab >>Osteoprotegerin secretion from prostate cancer is stimulated by cytokines,in vitro.
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2002 (English)In: Biochem Biophys Res Commun, Vol. 293, 451- p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-65096 (URN)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2011-11-23
2. Expression of RANK-ligand in prostate cancer cell lines
Open this publication in new window or tab >>Expression of RANK-ligand in prostate cancer cell lines
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2009 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 69, no 1, 151-155 p.Article in journal (Refereed) Published
Abstract [en]

The molecular mediators of bone remodelling, receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK) and osteoprotegerine (OPG), are believed to be involved in the cellular mechanisms by which tumours metastasize to bone. RANKL is a potent stimulator of osteoclastic bone resorption and is expressed in a variety of tumour cells. We have investigated if the membrane bound form of RANKL is expressed in prostate cancer cell lines, and whether this expression might be regulated by the presence of human osteoblasts. Three prostate cancer cell lines were co-cultured with human osteoblast-like cells (hOB) and RANKL expression on cell surface was measured by FACS. We found basal expression of RANKL on the cell surface, and in co-culture with hOBs the number of cells expressing RANKL was increased between 2.5 and 4 times. These data suggest a signalling mechanism between bone cells and prostate cancer cells that might increase bone resorption and thereby promote bone metastases.

Keyword
Co-culture, DU145, FACS, LNCaP, metastases, osteoblasts, PC3, prostate cancer, RANKL
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103165 (URN)10.1080/00365510802460466 (DOI)000263145500025 ()19058084 (PubMedID)
Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2017-12-13Bibliographically approved
3. Polymorphic variations in the gene for osteoprotegerin are associated with bone mineral density and predict fractures in elderly men: Data from Mr OS Sweden.:  
Open this publication in new window or tab >>Polymorphic variations in the gene for osteoprotegerin are associated with bone mineral density and predict fractures in elderly men: Data from Mr OS Sweden.:  
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:  Osteoporosis is a polygenetic disorder where several genes are known to be involved. In this report we investigated the association between polymorphic variations in the gene for osteoprotegerin (OPG) and bone mineral density (BMD) and fragility fractures in elderly men.

Methods: The study was performed in Mr OS Sweden, a cohort consisting of 3014 randomly selected men between 69 and 81 years of age, where at baseline BMD was measured at hip and spine by dual energy X ray absorbtiometry (DXA) and blood samples extracted. DNA was then isolated and the OPG gene was characterised. Prospective fractures, all verified by X-rays, were recorded for 5 years following baseline. Common variants in the 3’ and 5’UTR of the OPG gene was typed using Sequenom technology. 

Results: There was a significant association between common genetic variants in the gene for OPG and BMD at both hip (top SNP rs10955908, p<0.0008) and spine (top SNP rs10955908, p<0.0008) . The differences in BMD related to presence of various OPG alleles were between 0.5-3.5%. There was also an association with fragility fractures with odds ratio for rs6993813 reaching statistical significance (p=0.03) For five other SNPs were tested were the association with fractures did not reach statistical significance (p=0.12 - 0.19).

Conclusion: Polymorphic variations in the gene for OPG are associated with BMD and fragility fractures in elderly men. The data support the view that variation in the OPG gene is a determinant for BMD and fragility fracture risk also in men. 

Keyword
osteoporosis, osteoprotegerin, bone mineral density, fracture, polymorphism
National Category
Orthopedics
Research subject
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-160364 (URN)
Available from: 2011-10-27 Created: 2011-10-23 Last updated: 2011-11-23
4. Polymorphic variations in the gene for osteoprotegerin do not predict prostate cancer incidence: Data from MrOS Sweden.
Open this publication in new window or tab >>Polymorphic variations in the gene for osteoprotegerin do not predict prostate cancer incidence: Data from MrOS Sweden.
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2011 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background

Prostate cancer cells have been shown to produce and secrete osteoprotegerin (OPG), that inhibits tumor cell death by binding to TNF-related anti apoptotic ligand (TRAIL), and also is a key regulator of bone turnover . Bone metastases play a central role in prostate cancer spreading. However, the mechanisms underlying the interaction between bone cells and prostate cancer cells are not known.  The aim of this study was therefore to investigate whether polymorphic variations in the gene for OPG affect prostate cancer incidence, or extra prostatic disease and metastasis.

Methods

The study was performed in the MrOS-Sweden cohort consisting of 3,014 men aged 69-81 years. DNA was collected at the start of the study and the gene for OPG was investigated concerning SNPs previously shown to regulate bone mineral density (BMD), and therefore of biological importance. Data on prostate cancer prevalence at baseline, and incidence during a 3-year follow-up were collected from the Swedish Cancer Register. The association of six OPG polymorphisms with prostate cancer was evaluated.

Results

The association between six OPG polymorphisms and prostate cancer was evaluated. In these analyses there were no significant genotype differences between prostate cancer patients and controls. A tendency for an association between OPG genotypes and more severe disease (p=0.08-0.09) was found however regarding OPG genotypes.

Conclusion

Polymorphic variations in the gene for OPG are not associated with prostate cancer incidence. Our data on staging of prostate cancer at the diagnose according to the TNM system in regard to the variations in the OPG gene gave some tendencies to possible involvement but further studies are required to investigate the potential role of the OPG/RANK/RANKL system in the metastatic skeletal prostate cancer spreading, and growth, in bone.

Publisher
60 p.
Keyword
metastases, bone, prostate, cancer, osteoprotegerin, osteoporosis, RANKL, genetics
National Category
Orthopedics
Research subject
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-160361 (URN)
Available from: 2011-10-31 Created: 2011-10-21 Last updated: 2011-11-23

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