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 J. Nazemi, Mark Pines*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)940-948
Number of pages9
Issue number9
StatePublished - Sep 2008
Externally publishedYes


FundersFunder number
Crosby Family Foundation, Inc.
Cure Alveolar Soft Part Sarcoma International


    Dive into the research topics of 'Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: A novel target for treatment?'. Together they form a unique fingerprint.

    Cite this