Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: a novel target for treatment?

Olga Genin, Gideon Rechavi, Arnon Nagler, Ofer Ben-Itzhak, Kellie Nazemi and Mark Pines

Year 2008, Volume 10, Issue 9

Abstract

Alveolar soft-part sarcoma (ASPS) is a rare neoplasm with chromosomal translocation results in ASPL-TFE3 fusion. ASPS 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 ECM proteins all of which are characteristic of activated myofibroblasts. The tumor cells also exhibited stromal components such as TGFƒÒ-dependent, hypoxia-regulated cytoglobin (cygb/STAP) and prolyl-4 hydroxylase, a collagen cross-linking enzyme. The pulmonary ASPS myofibroblasts synthesize serum response factor (SRF), a repressor of Smad3-mediated TGFƒÒ 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 inhibition of TGFƒÒ/SRF signaling, with inhibition of myofibroblasts activation and with 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.

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