Myofibroblasts in Pulmonary and Brain Metastases of Alveolar Soft-Part Sarcoma: A Novel Target for Treatment?

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2008-09, Vol.10 (9), p.940-948
• Main Authors: Genin, Olga, Rechavi, Gideon, Nagler, Arnon, Ben-Itzhak, Ofer, Nazemi, Kellie J., Pines, Mark
• Format: Article
• Language: English
• Subjects: Adolescent; Brain Neoplasms - secondary; Cytoglobin; Female; Fibroblasts - metabolism; Globins - metabolism; Humans; Lung Neoplasms - secondary; Male; Muscle Neoplasms - pathology; Myoblasts - metabolism; Oncogene Proteins, Fusion; Procollagen-Proline Dioxygenase - metabolism; Sarcoma, Alveolar Soft Part - genetics; Serum Response Factor - metabolism; Smad3 Protein - metabolism; Young Adult
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.08456

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 pro-liferate, 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 TGFβ/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.