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      Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature

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          Abstract

          Treating metastatic osteosarcoma (OS) remains a challenge in oncology. Current treatment strategies target the primary tumour rather than metastases and have a limited efficacy in the treatment of metastatic disease. Metastatic cells have specific features that render them less sensitive to therapy and targeting these features might enhance the efficacy of current treatment. A detailed study of the biological characteristics and behaviour of metastatic OS cells may provide a rational basis for innovative treatment strategies. The aim of this review is to give an overview of the biological changes in metastatic OS cells and the preclinical and clinical efforts targeting the different steps in OS metastases and how these contribute to designing a metastasis directed treatment for OS.

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          Src kinases as therapeutic targets for cancer.

          Lori C Kim, Lanxi Song, Eric B. Haura (2009)
          Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.
          Article 0 comments Cited 220 times – based on 0 reviews     Review now
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            p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage.

            H. Reinhardt, Aaron S Aslanian, Jacqueline Lees … (2007)
            In response to DNA damage, eukaryotic cells activate ATM-Chk2 and/or ATR-Chk1 to arrest the cell cycle and initiate DNA repair. We show that, in the absence of p53, cells depend on a third cell-cycle checkpoint pathway involving p38MAPK/MK2 for cell-cycle arrest and survival after DNA damage. MK2 depletion in p53-deficient cells, but not in p53 wild-type cells, caused abrogation of the Cdc25A-mediated S phase checkpoint after cisplatin exposure and loss of the Cdc25B-mediated G2/M checkpoint following doxorubicin treatment, resulting in mitotic catastrophe and pronounced regression of murine tumors in vivo. We show that the Chk1 inhibitor UCN-01 also potently inhibits MK2, suggesting that its clinical efficacy results from the simultaneous disruption of two critical checkpoint pathways in p53-defective cells.
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              The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis.

              Chand Khanna, Xiaolin Wan, Seuli Bose … (2004)
              Metastatic cancers, once established, are the primary cause of mortality associated with cancer. Previously, we used a genomic approach to identify metastasis-associated genes in cancer. From this genomic data, we selected ezrin for further study based on its role in physically and functionally connecting the actin cytoskeleton to the cell membrane. In a mouse model of osteosarcoma, a highly metastatic pediatric cancer, we found ezrin to be necessary for metastasis. By imaging metastatic cells in the lungs of mice, we showed that ezrin expression provided an early survival advantage for cancer cells that reached the lung. AKT and MAPK phosphorylation and activity were reduced when ezrin protein was suppressed. Ezrin-mediated early metastatic survival was partially dependent on activation of MAPK, but not AKT. To define the relevance of ezrin in the biology of metastasis, beyond the founding mouse model, we examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with this data, we found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.
              Article 0 comments Cited 164 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : +31-20-4442987 , +31-20-4442357 , bj.vanroyen@vumc.nl
                Journal
                Journal ID (nlm-ta): Clin Exp Metastasis
                Title: Clinical & Experimental Metastasis
                Publisher: Springer Netherlands (Dordrecht )
                ISSN (Print): 0262-0898
                ISSN (Electronic): 1573-7276
                Publication date (Electronic): 2 April 2011
                Publication date PMC-release: 2 April 2011
                Publication date (Print): June 2011
                Volume: 28
                Issue: 5
                Pages: 493-503
                Affiliations
                [1 ]Department of Orthopaedic Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                [2 ]Department of Orthopaedic Surgery, Westfries Gasthuis, Hoorn, The Netherlands
                [3 ]Paediatric Oncology/Haematology, VU University Medical Center, Amsterdam, The Netherlands
                [4 ]VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
                Article
                Publisher ID: 9384
                DOI: 10.1007/s10585-011-9384-x
                PMC ID: 3081058
                PubMed ID: 21461590
                SO-VID: 2037a45e-ea11-4a4d-afe5-969802e665e4
                Copyright © © The Author(s) 2011
                History
                Date received : 15 July 2010
                Date accepted : 18 March 2011
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media B.V. 2011

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: therapy,metastasis,drug resistance,osteosarcoma
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: therapy, metastasis, drug resistance, osteosarcoma

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