Leukemia Inhibitory Factor: A Newly Identified Metastatic Factor in Rhabdomyosarcomas

Abstract

Rhabdomyosarcoma frequently infiltrates bone marrow and this process involves the stromal-derived factor-1 (SDF-1)-CXCR4 axis. Because leukemia inhibitory factor (LIF), like SDF-1, is secreted by bone marrow stroma and directs the regeneration of skeletal muscles, we examined whether the LIF-LIF receptor (LIF-R) axis affects the biology of rhabdomyosarcoma cells. We found that in rhabdomyosarcoma cells, LIF stimulates the following: (a) phosphorylation of mitogenactivated protein kinase p42/44, AKT, and signal transducers and activators of transcription 3, (b) adhesion and chemotaxis, and (c) increased resistance to cytostatics. To compare the biological effects of LIF versus SDF-1, we examined the RH30 cell line, which is highly responsive to both ligands, and found that the chemotaxis of these cells is significantly reduced when the inhibitors of both receptors (T140 for CXCR4 and gp190 blocking antibody for LIF-R) are added simultaneously. Subsequently, by using repetitive chemotaxis to LIF or SDF-1, we selected from the RH30 line subpopulations of cells that respond to LIF but not SDF-1 (RH30-L) or to SDF-1 but not LIF (RH30-S). We found that (a) RH30-L cells seed better to the bone marrow, liver, and lymph nodes of immunodeficient mice than RH30-S cells and (b) mice inoculated i.m. with the RH30-L cells had more rhabdomyosarcoma cells in the bone marrow and lung after 6 weeks. Thus, we present the first evidence that the LIF-LIF-R axis may direct rhabdomyosarcoma metastasis. Further, because we showed that the in vivo metastasis of RH30 cells is inhibited by small interfering RNA against LIF-R, molecular targeting of this axis could become a new strategy to control the metastasis of rhabdomyosarcoma. [Cancer Res 2007;67(5):2131-40]

DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

“…Their early selection seems crucial for subsequent formation of metastases. When recapitulated in vitro, such a selection enables identification of basic cellular properties crucial for early cancer progression [21]. In the present study, we describe an experimental approach enabling the assessment of heterogeneity of prostate carcinoma cells with regard to Cx43 expression and their invasive potential.…”

Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

“…The growth and metastatic behavior of primary tumors are largely mediated by autocrine and paracrine pathways in a cytokinedependent manner (Kellokumpu-Lehtinen et al, 1996;Wysoczynski et al, 2007). Recent studies indicate that members of the interleukin 6 family of cytokines, including oncostatin M (OSM) and leukemia inhibitory factor (LIF), contribute to the proliferation and metastasis of several cancers (Estrov et al, 1995;Jorcyk et al, 2006;Kellokumpu-Lehtinen et al, 1996;Liu et al, 1998;Queen et al, 2005).…”

“…Recent studies indicate that members of the interleukin 6 family of cytokines, including oncostatin M (OSM) and leukemia inhibitory factor (LIF), contribute to the proliferation and metastasis of several cancers (Estrov et al, 1995;Jorcyk et al, 2006;Kellokumpu-Lehtinen et al, 1996;Liu et al, 1998;Queen et al, 2005). A common receptor is shared between OSM and LIF, but these proteins have distinct effects on the biological activities of cancer cells (Wysoczynski et al, 2007). Exogenous LIF promotes the proliferation of several types of cancers, whereas OSM inhibits cancer cell growth (Garcia-Tunon et al, 2008;Grant et al, 2001).…”

Optimization of a synthetic siRNA delivery for the treatment of rhabdomyosarcoma

“…MET receptor was already a target of RNA interference, however, a lentiviral system was used [19]. After choosing optimal conditions, we also tested siRNA against CXCR4 receptor, LIF receptor (LIFR) and PAX3-FKHR, all of them shown previously to be very important factors contributing to metastatic behavior of RMS cells [17,20,21]. CXCR4 has not been targeted previously in a RMS setting.…”

“…CXCR4 has not been targeted previously in a RMS setting. LIFR and PAX3-FKHR fusion protein were already targeted in RMS cells using siRNA [21,22].…”