Neuronal differentiation of synovial sarcoma and its therapeutic application.
Synovial sarcoma is a rare sarcoma of unknown histologic origin. We previously reported the gene expression profile of synovial sarcoma was closely related to that of malignant peripheral nerve sheath tumors, and the fibroblast growth factor (FGF) signal was one of the main growth signals in synovial sarcoma. Here we further demonstrate the neural origin of synovial sarcoma using primary tumors and cell lines. The expression of neural tissue-related genes was confirmed in synovial sarcoma tumor tissues, but the expression of some genes was absent in synovial sarcoma cell lines. Treatment of synovial sarcoma cell lines with BMP4 or FGF2 enhanced or restored the expression of neural tissue-related genes and induced a neuron-like morphology with positive Tuj-1 expression. Treatment with all-trans-retinoic acid also induced the expression of neural tissue-related genes in association with growth inhibition, which was not observed in other cell lines except a malignant peripheral nerve sheath tumor cell line. A growth-inhibitory effect of all-trans-retinoic acid was also observed for xenografted tumors in athymic mice. The simultaneous treatment with FGF signal inhibitors enhanced the growth-inhibitory effect of all-trans-retinoic acid, suggesting the combination of growth signaling inhibition and differentiation induction could be a potential molecular target for treating synovial sarcoma.
Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Shogoin, Kyoto, Japan.
Tatsuya
T
Ishibe
Tomitaka
T
Nakayama
Tomoki
T
Aoyama
Takashi
T
Nakamura
Junya
J
Toguchida
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D064231:Nestin; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013584:Sarcoma, Synovial / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D016222:Fibroblast Growth Factor 2; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D064231:Nestin; D020800:Receptor, Nerve Growth Factor; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D000072056:Transcription Factor HES-1; D014212:Tretinoin; C499317:Ascl1 protein, mouse; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C489734:Hes1 protein, mouse; C577484:NES protein, human; C577485:Nes protein, mouse; C082927:retinoic acid binding protein I, cellular