title: Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: a novel target for treatment?
abstract: 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 (TGFbeta)-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 TGFbeta 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 TGFbeta/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.
authors: Institute of Animal Science, the Volcani Center, Bet Dagan 50250, Israel.
authors: Olga
authors: O
authors: Genin
authors: Gideon
authors: G
authors: Rechavi
authors: Arnon
authors: A
authors: Nagler
authors: Ofer
authors: O
authors: Ben-Itzhak
authors: Kellie J
authors: KJ
authors: Nazemi
authors: Mark
authors: M
authors: Pines
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000556:secondary*; D000078842:Cytoglobin; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005914:Globins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000556:secondary*; D008297:Male; D019042:Muscle Neoplasms / Q000473:pathology*; D032446:Myoblasts / Q000378:metabolism; D015514:Oncogene Proteins, Fusion; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D018234:Sarcoma, Alveolar Soft Part / Q000235:genetics*; D026362:Serum Response Factor / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism*; D055815:Young Adult
chemical_list: C422743:ASPSCR1 protein, human; C000627265:CYGB protein, human; D000078842:Cytoglobin; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; C497790:SMAD3 protein, human; D026362:Serum Response Factor; D051900:Smad3 Protein; D005914:Globins; D011393:Procollagen-Proline Dioxygenase