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Columbus, OH, United States

Schneider G.,University of Louisville | Bryndza E.,University of Louisville | Abdel-Latif A.,University of Kentucky | Ratajczak J.,University of Louisville | And 10 more authors.
Molecular Cancer Research

Evidence suggests that bioactive lipids may regulate pathophysiologic functions such as cancer cell metastasis. Therefore, we determined that the bioactive lipid chemoattractants sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) strongly enhanced the in vitro motility and adhesion of human rhabdomyosarcoma (RMS) cells. Importantly, this effect was observed at physiologic concentrations for both bioactive lipids, which are present in biologic fluids, and were much stronger than the effects observed in response to known RMS prometastatic factors such as stromal derived factors-1 (SDF-1/CXCL12) or hepatocyte growth factor/scatter factor (HGF/SF). We also present novel evidence that the levels of S1P and C1P were increased in several organs after γ-irradiation or chemotherapy, which indicates an unwanted prometastatic environment related to treatment. Critically, we found that the metastasis of RMS cells in response to S1P can be effectively inhibited in vivo with the S1P-specific binder NOX-S93 that is based on a high-affinity Spiegelmer. These data indicate that bioactive lipids play a vital role in dissemination of RMS and contribute to the unwanted side effects of radio/chemotherapy by creating a prometastatic microenvironment. © 2013 American Association for Cancer Research. Source

Tarnowski M.,University of Louisville | Tarnowski M.,Pomeranian Medical University | Schneider G.,University of Louisville | Amann G.,Medical University of Vienna | And 7 more authors.
International Journal of Oncology

The involvement of the Ras superfamily of GTPases in the pathogenesis of rhabdomysarcoma (RMS) is not well understood. While mutant H-Ras leads to embryonal RMS (ERMS) formation in experimental animals and in Costello syndrome patients, no data exists on the potential role of Ras GTPases in the pathogenesis of alveolar RMS (ARMS). To address this issue better, we focused on the role of the GTP exchange factor RasGRF1 in this process. We observed that, in comparison to normal skeletal muscle cells, RasGRF1 mRNA is upregulated in the majority of human ARMS cell lines and subsequently confirmed its high expression in patient samples. By employing confocal microscopy analysis, we observed RasGRF1 accumulation in cell filopodia, which suggests its involvement in ARMS cell migration. Furthermore, we observed that RasGRF1 becomes phosphorylated in ARMS after stimulation by several pro-metastatic factors, such as SDF-1 and HGF/SF, as well as after exposure to growth-promoting Igf-2 and insulin. More importantly, activation of RasGRF1 expression correlated with activation of p42/44 MAPK and AKT. When the expression of RasGRF1 was down-regulated in ARMS cells by an shRNA strategy, these RasGRF1-kd RMS cells did not respond to stimulation by SDF-1, HGF/SF, Igf-2 or insulin by phosphorylation of p42/44 MAPK and AKT and lost their chemotactic responsiveness; however, their adhesion was not affected. We also observed that RasGRF1-kd ARMS cells proliferated at a very low rate in vitro, and, more importantly, after inoculation into immunodeficient SCID/beige inbred mice they formed significantly smaller tumors. We conclude that RasGRF1 plays an important role in ARMS pathogenesis and is a new potential therapeutic target to inhibit ARMS growth. Source

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