Rhabdomyosarcomas (RMS) and neuroblastomas (NBS) are tumors that originate in skeletal muscle and neural tissue respectively, and frequently metastasize/infiltrate bone marrow (BM). We have recently demonstrated a crucial role for the stromal-derived factor (SDF)-1- CXCR4 axis in RMS and NBS metastases to BM (
). However, our recent studies with the CXCR4 antagonist T140 suggest involvement of other factor(s) besides SDF-1 that direct the motility/metastasis of these cells. Based on the fact that the gp-130 receptor signaling cytokine Leukemia Inhibitory Factor (LIF) plays an important role in trafficking of normal muscle and neural cells and the development of muscle and neural tissue we hypothesized that LIF could be this missing chemoattractant that is involved in directing metastasis of RMS and NBS cells to the BM environment. 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 protein level on several human RMS and NBS cell lines as determined by FACS analysis. Next, we found that LIF-R is functional on RMS and NBS cells, mediates phosphorylation of MAPKp42/44, PI-3K-AKT, and JAK-STAT pathways and activation of small GTP-ase - Rac-1, and both RMS and NBS cells are chemoattracted by LIF. Furthermore, LIF increases adhesion of RMS and NBS cells to stroma and endothelium and upregulated expression of angiopoietic factors such as VEGF and IL-8. Finally we found that LIF-mediated responses were specifically inhibited by anti-LIF-R blocking antibodies. In conclusion, we present evidence for first time that LIF-LIF-R (cytokine-gp130 signaling receptor axis) may direct metastasis and enhance the invasive potential of human solid tumor cells. Hence molecular targeting of LIF or LIF-R may become a new antimetastatic strategy to improve therapeutic outcome from pediatric sarcomas. Molecular strategies aimed at inhibiting the LIF-LIF-R axis, and the SDF-1-CXCR4 axis, for example, by the use of small-molecule inhibitors, could lead to the development of new anti-metastatic therapies that could complement the conventional radio- or chemotherapy in preventing the dissemination of RMS and NBS cells into bone marrow and lymph nodes. This is currently being tested in animal models in our laboratory.
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