BioProject

Alveolar soft part sarcoma (ASPS) is a slowly growing but highly metastatic sarcoma that affects adolescents and young adults. More...

Alveolar soft part sarcoma (ASPS) is a slowly growing but highly metastatic sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and abundant vascular network that is responsible for metastatic activities at the initial stage. Here we have generated a new ex vivo mouse model for ASPS that well recapitulates angiogenic and metastatic phenotypes. In mouse ASPS the tumor cells frequently show tumor intravasation, and the intravascular tumor cells were present as organoid structures covered with hemangiopericytes, which is also the case in human ASPS. High expression of GPNMB, a transcriptional target of ASPSCR1-TFE3, was observed at the intravasation. ASPS tumor cells showed the enhanced activity of transendothelial migration and the activity was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, one of key steps in cancer metastasis. The present model also enabled to evaluate the function of TFE/MITF family transcription factors, and ASPSCR1-TFEB also possessed definitive but less oncogenic activity than that of ASPSCR1-TFE3. Collectively, our new mouse model is a useful tool to understand oncogenic, angiogenic and metastatic mechanisms of ASPS, to identify important motif within the ASPSCR1-TFE3 fusion protein and to provide a novel therapeutic strategy. We used microarrays to detail the global programme of gene expression in mouse ASPS. Overall design: Murine embryonic mesenchymal cells were transduced with the ASPSCR1-TFE3 retrovirus and transplanted into nude mice. Tumor developed as a subcutaneous mass and histological examination was performed to confirm the ASPS phenotypes. Individual tumor tissues were subjected to microarray analyses. Mixture of mouse normal tissues (bone marrow, brain, colon, heart, kidney, liver, lung, ovary, skin, skeletal muscle) was used as a control. Less...