Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma.
Osteosarcoma is a cancer of pathological bone remodeling with high mortality and severe comorbidity. New therapies are urgently needed. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, has been suggested to stimulate proliferation and invasion of osteosarcoma cells in vitro, thus representing a potential therapeutic target. In this study, inhibition of the activin receptor signaling pathway was explored as a therapy for osteosarcoma. In a murine intratibial osteosarcoma xenograft model, two types of inhibitors were tested: (a) a soluble activin type IIA decoy receptor (ActRIIA-mFc), or (b) a modified variant of follistatin (FSTΔHBS -hFc), either alone or in combination with a bisphosphonate. Both inhibitors reduced primary tumor development by nearly 50% compared to vehicle treatment. When ActRIIA-mFc was combined with bisphosphonate, the effect on tumor size became even more pronounced (78% reduction vs. vehicle). Moreover, FSTΔHBS -hFc increased body weight in the face of tumor progression (14% increase vs. vehicle), and ActRIIA-mFc reduced the number of lung metastases when combined with bisphosphonate. The present study demonstrates a novel approach to treating osteosarcoma and encourages further investigation of inhibition of the activin receptor signaling pathway as an intervention against the disease.
['Meier|Daniela|D|', 'Lodberg|Andreas|A|0000-0001-9261-8753', 'Gvozdenovic|Ana|A|0000-0002-6013-0355', 'Pellegrini|Giovanni|G|', 'Neklyudova|Olga|O|', 'Born|Walter|W|', 'Fuchs|Bruno|B|', 'Eijken|Marco|M|', 'M Botter|Sander|S|0000-0003-1695-1700']
D030301:Activin Receptors, Type II D000818:Animals D000970:Antineoplastic Agents D000971:Antineoplastic Combined Chemotherapy Protocols D050071:Bone Density Conservation Agents D001859:Bone Neoplasms D016723:Bone Remodeling D045744:Cell Line, Tumor D004164:Diphosphonates D038681:Follistatin D006801:Humans D007141:Immunoglobulin Fc Fragments D007074:Immunoglobulin G D016513:Mice, SCID D009336:Necrosis D012516:Osteosarcoma D011993:Recombinant Fusion Proteins D015398:Signal Transduction D013977:Tibia D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
osteosarcoma pathological bone remodeling follistatin activin type II receptor zoledronic acid