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Genin, O., Institute of Animal Science, Volcani Center, Bet Dagan 50250, Israel
Rechavi, G., Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Nagler, A., Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Ben-Itzhak, O., Department of Pathology, Rambam Medical Center, Technion-Israel Institute of Technology, Haifa, Israel
Nazemi, K.J., Division of Pediatric Hematology/Oncology, Doernbecher Children's Hospital, Oregon Health and Science University, CDRC-P, Portland, OR 97239, United States
Pines, M., Institute of Animal Science, Volcani Center, Bet Dagan 50250, Israel, Institute of Animal Sciences, Volcani Center, P.O. Box 6, Bet Dagan, 50250, Israel
Alveolar soft-part sarcoma (ASPS) is a rare neoplasm with chromosomal translocation that results in ASPL-TFE3 fusion. It is a slow-growing lesion associated with a high incidence of pulmonary and brain metastases indicating poor survival. We demonstrated that the ASPS metastases include also stromal myofibroblasts. These cells proliferate, express smooth-muscle genes, and synthesize extracellular matrix proteins, all of which are characteristics of activated myofibroblasts. The tumor cells also exhibited stromal components such as transforming growth factor beta (TGFβ)-dependent, hypoxia-regulated cytoglobin (stellate cell activation association protein, cytg/ STAP) and prolyl 4-hydroxylase, a collagen cross-linking enzyme. The pulmonary ASPS myofibroblasts synthesize serum response factor (SRF), a repressor of Smad3-mediated TGFβ signaling essential for myofibroblast differentiation and Smad3. The phosphorylated active Smad3 was found mostly in the tumor cells. The brain tumor cells express cytg/STAP, but in contrast to the lung metastases, they also express SRF, Smad3, and phospho-Smad3. Halofuginone, an inhibitor of myofibroblasts' activation and Smad3 phosphorylation, inhibited tumor development in xenografts derived from renal carcinoma cells harboring a reciprocal ASPL-TFE3 fusion transcript. This inhibition was associated with the inhibition of TGF(3/SRF signaling, with the inhibition of myofibroblasts' activation, and with the complete loss in TFE3 synthesis by the tumor cells. These results suggest that the myofibroblasts may serve as a novel target for treatment of ASPS metastases. Copyright © 2008 Neoplasia Press, Inc. All rights reserved.
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Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: A novel target for treatment?
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Genin, O., Institute of Animal Science, Volcani Center, Bet Dagan 50250, Israel
Rechavi, G., Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Nagler, A., Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
Ben-Itzhak, O., Department of Pathology, Rambam Medical Center, Technion-Israel Institute of Technology, Haifa, Israel
Nazemi, K.J., Division of Pediatric Hematology/Oncology, Doernbecher Children's Hospital, Oregon Health and Science University, CDRC-P, Portland, OR 97239, United States
Pines, M., Institute of Animal Science, Volcani Center, Bet Dagan 50250, Israel, Institute of Animal Sciences, Volcani Center, P.O. Box 6, Bet Dagan, 50250, Israel
Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: A novel target for treatment?
Alveolar soft-part sarcoma (ASPS) is a rare neoplasm with chromosomal translocation that results in ASPL-TFE3 fusion. It is a slow-growing lesion associated with a high incidence of pulmonary and brain metastases indicating poor survival. We demonstrated that the ASPS metastases include also stromal myofibroblasts. These cells proliferate, express smooth-muscle genes, and synthesize extracellular matrix proteins, all of which are characteristics of activated myofibroblasts. The tumor cells also exhibited stromal components such as transforming growth factor beta (TGFβ)-dependent, hypoxia-regulated cytoglobin (stellate cell activation association protein, cytg/ STAP) and prolyl 4-hydroxylase, a collagen cross-linking enzyme. The pulmonary ASPS myofibroblasts synthesize serum response factor (SRF), a repressor of Smad3-mediated TGFβ signaling essential for myofibroblast differentiation and Smad3. The phosphorylated active Smad3 was found mostly in the tumor cells. The brain tumor cells express cytg/STAP, but in contrast to the lung metastases, they also express SRF, Smad3, and phospho-Smad3. Halofuginone, an inhibitor of myofibroblasts' activation and Smad3 phosphorylation, inhibited tumor development in xenografts derived from renal carcinoma cells harboring a reciprocal ASPL-TFE3 fusion transcript. This inhibition was associated with the inhibition of TGF(3/SRF signaling, with the inhibition of myofibroblasts' activation, and with the complete loss in TFE3 synthesis by the tumor cells. These results suggest that the myofibroblasts may serve as a novel target for treatment of ASPS metastases. Copyright © 2008 Neoplasia Press, Inc. All rights reserved.
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