The decreased metastatic potential of rhabdomyosarcoma cells obtained through MET receptor downregulation and the induction of differentiation

Abstract

Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. The MET receptor has an important role in the biology of RMS, and its overexpression and hyperactivation correlate with the metastatic ability of RMS. Consequently, interfering with MET expression or functionality may constitute a sound strategy for reducing the progression and metastatic potential of RMS. Our study reveals that downregulation of the MET receptor leads to changes in the morphology of ARMS cell in vivo. Tumors acquire a spindle shape that is characteristic of muscle fibers. Inhibition of MET expression or function leads to (i) a decreased expression of the early myogenic marker MyoD, (ii) a decreased ability of ARMS cells to metastasize to bone marrow cavities, (iii) downregulation of CXCR4 receptor expression and (iv) a decreased migration of MET-depleted cells towards gradients of HGF and SDF-1. Finally, we demonstrate that in vitro differentiation of alveolar RMS cells decreases their metastatic behavior by reducing both the expression of the MET and CXCR4 receptors and their migratory response to HGF and SDF-1. These findings suggest that blockers of MET receptor function and inducers of RMS cells differentiation may be clinically useful for reducing the aggressiveness and metastatic potential of RMS and may have significant implications for its treatment.

Tumor-Activated Mesenchymal Stromal Cells Promote Osteosarcoma Stemness and Migratory Potential via IL-6 Secretion

“…Despite this, we could observe IL-6-dependent downregulation of a number of genes involved in migration. The hepatocyte growth factor and its receptor have been described to be associated not only with high tumor grade and poor prognosis of a number of cancers, but also with migration and development of distant metastasis [53, 54]. Moreover, MET and IL-.6 signaling have been reported to upregulate each other’s receptors and cooperatively enhance tissue invasion [55, 56].…”

Mechanisms of impaired differentiation in rhabdomyosarcoma

“…c‐Met is activated by hepatocyte growth factor/scatter factor , which functions to stimulate quiescent muscle precursor cells to re‐enter the cell cycle during postnatal muscle injury. Direct evidence that c‐Met is relevant in aRMS was demonstrated with an shRNA knockdown approach in Rh30 cells, which led to a reduced tumor burden in immunocompromised mice . Histologically, tumors with lower c‐Met expression were characterized as more mature and differentiated, suggesting that c‐Met expression in aRMS functions as a suppressor of differentiation.…”

Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species–Dependent Targeting of Specificity Protein Transcription Factors

“…The importance of Sp transcription factors (TFs) in RMS is primarily due to pro-oncogenic Sp-regulated genes that are themselves drug targets for RMS and these include CXCR4, hepatocyte growth factor receptor (c-MET), insulin-like growth factor 1 receptor (IGF-1R), and platelet-derived growth-factor receptor α (PDGFRα) (14-17). Clinical studies using drugs that specifically target Sp TFs and Sp-regulated genes for treatment of RMS have not yet been reported; however, there is an open phase I/II trial (NCT01610570) evaluating the efficacy of mithramcyin in solid tumors including RMS.…”