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      Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone

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          Abstract

          Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.

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          The online version of this article (doi:10.1007/s10585-017-9848-8) contains supplementary material, which is available to authorized users.

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          Most cited references 32

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          The insulin and insulin-like growth factor receptor family in neoplasia: an update.

          Although several early phase clinical trials raised enthusiasm for the use of insulin-like growth factor I receptor (IGF1R)-specific antibodies for cancer treatment, initial Phase III results in unselected patients have been disappointing. Further clinical studies may benefit from the use of predictive biomarkers to identify probable responders, the use of rational combination therapies and the consideration of alternative targeting strategies, such as ligand-specific antibodies and receptor-specific tyrosine kinase inhibitors. Targeting insulin and IGF signalling also needs to be considered in the broader context of the pathophysiology that relates obesity and diabetes to neoplasia, and the effects of anti-diabetic drugs, including metformin, on cancer risk and prognosis. The insulin and IGFI receptor family is also relevant to the development of PI3K-AKT pathway inhibitors.
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            Cancer to bone: a fatal attraction.

            When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour-bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases.
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              Matrix-embedded cells control osteoclast formation

              Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of NFκB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors. However, RANKL is expressed by a variety of cell types and it is unclear which of them are essential sources for osteoclast formation. Here we have used a conditional mouse RANKL allele and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.
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                Author and article information

                Contributors
                +46-90-7853752 , pernilla.wikstrom@umu.se
                Journal
                Clin Exp Metastasis
                Clin. Exp. Metastasis
                Clinical & Experimental Metastasis
                Springer Netherlands (Dordrecht )
                0262-0898
                1573-7276
                26 April 2017
                26 April 2017
                2017
                : 34
                : 3
                : 261-271
                Affiliations
                [1 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Radiation Sciences, Oncology, , Umeå University, ; Umeå, Sweden
                [2 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Medical Biosciences, Pathology, , Umeå University, ; Umeå, Sweden
                [3 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Molecular Periodontology, , Umeå University, ; Umeå, Sweden
                [4 ]ISNI 0000 0000 9919 9582, GRID grid.8761.8, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, , Sahlgrenska Academy at University of Gothenburg, ; Gothenburg, Sweden
                Article
                9848
                10.1007/s10585-017-9848-8
                5442252
                28447314
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: 2015-02393
                Award ID: 2015-02638
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002794, Cancerfonden;
                Award ID: CAN 2013/845
                Award ID: CAN 2013/1324
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004886, Cancer Research Foundation in Northern Sweden;
                Funded by: FundRef http://dx.doi.org/10.13039/501100002960, Västerbotten Läns Landsting;
                Categories
                Research Paper
                Custom metadata
                © Springer Science+Business Media Dordrecht 2017

                Oncology & Radiotherapy

                igf-1r, bone metastasis, apoptosis, proliferation, immune response, runx2, trap

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