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• W3204551957 abstract "297 Rhabdomyosarcomas (RMS) and neuroblastomas (NBS) - small round blue-cell tumors -originate in skeletal muscle satellite and neuroectodermal stem cells respectively and frequently metastasize/infiltrate bone marrow (BM). We have recently demonstrated that the stromal-derived factor (SDF)-1-CXCR4 axis plays a pivotal role in RMS and NBS metastases to BM (Blood 2002:100, 2597). However, our recent studies with the CXCR4 antagonist T140 suggest involvement of other factor(s) besides SDF-1 that direct the metastasis of these cells. Based on the fact that Leukemia Inhibitory Factor (LIF), the gp-130 receptor signaling cytokine, plays an important role in trafficking of normal muscle and neural stem cells and the development of muscle and neural tissue, we hypothesized that LIF could be another chemoattractant that is involved in directing metastasis of RMS and NBS cells to the bones. Supporting this notion we found that LIF is secreted by BM stroma cells and LIF-R (a gp130 receptor family member) is expressed at the mRNA/protein level on several human RMS and NBS cell lines as well as in cells isolated from patients (n=24). Furthermore, in these cells the LIF-LIF-R axis regulated phosphorylation of MAPKp42/44, PI-3K-AKT, and JAK-STAT pathways, activation/co-localization of FAK and Paxillin, stress fiber formation, chemotaxis, adhesion and secretion of several pro-angiopoietic factors. Subsequently, we compared the biological effects of LIF to those of SDF-1 and observed that, compared to SDF-1, LIF i) is the more potent stimulator of cell adhesion, ii) increases survival and proliferation of RMS cells, and iii) protects RMS/NBS cells from some cytostatics. To compare the biological effects of both axes in vivo we focused on the ARMS cell line RH30 (highly responsive to SDF-1 and LIF) and selected cells that responded to SDF-1 but not LIF (RH30-S) and to LIF but not SDF-1 (RH30-L) by using repetitive chemotaxis to SDF-1 or LIF. We found that RH30-L cells, as compared to RH30-S cells, responded worse in chemotactic assay to BM-derived conditioned media; however, they adhered much better to BM stroma. When both cell populations (RH30-S and RH30-L), together with the parental RH30 cells, were tested in vivo for their seeding potential in various organs in RAG2 immunodeficient mice, we found that RH30-L cells seeded better to BM, liver and lymph nodes than RH30-S cells. More important, the metastatic potential of RH30 cells was significantly reduced only when the inhibitors of both receptors, (T140 for LIF-R and gp130 blocking antibody for CXCR4) were employed together. In conclusion, we present evidence for the first time that LIF-LIF-R may direct metastasis and enhance the invasive potential of human solid tumor cells. Hence molecular targeting of the LIF-LIF-R axis, along with the SDF-1-CXCR4 axis, may become a new antimetastatic strategy to inhibit BM involvement in pediatric sarcomas." @default.
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• W3204551957 date "2006-04-15" @default.
• W3204551957 modified "2023-09-23" @default.
• W3204551957 title "Leukemia Inhibitory Factor (LIF): An unexpected regulator of metastasis of rhabdomyosarcoma and neuroblastoma to bone marrow" @default.
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