Abstract 3849

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of adolescents and children and frequently infiltrates the bone marrow (BM) to the degree that it mimics acute lymphoblastic leukemia. Here we show that human RMS cells highly express and secrete the small chemokine, macrophage migration inhibitory factor (MIF). MIF overexpression has been observed in several tumors and is implicated in oncogenic transformation and tumor progression. MIF activates CXCR2 and CD74 receptors, and surprisingly, as recently reported, may also bind to the stromal-derived factor-1 (SDF-1)–binding receptor CXCR4 (Nat Med 2007;13:587). Here we report that RMS-secreted MIF i) induces phosphorylation of MAPKp42/44 and AKT, ii) stimulates RMS cell adhesion, and iii) enhances tumor vascularization. Furthermore, since RMS cells employed in our studies do not express CXCR2 and CD74 receptors, the biological effects of MIF on RMS cells depend on its interaction with CXCR4. Moreover, as we report here for the first time, receptor internalization/binding studies reveal that MIF may also engage another SDF-1–binding receptor (CXCR7) as well. Since bone marrow fibroblasts highly express the MIF-binding receptor CXCR2, we became interested in the potential role of the MIF-mediated interaction between RMS and stromal cells and, to our surprise, observed that RMS-secreted MIF decreases recruitment of stromal fibroblasts to expanding sarcomas. In support of this finding, downregulation of MIF in RMS cells inoculated into immunodeficient mice lead to formation of larger tumors that displayed higher stromal-cell support. Based on these observations, we postulate that MIF is an important autocrine/paracrine factor that stimulates both CXCR4 and CXCR7 receptors to enhance the adhesiveness of RMS cells. We also envision that MIF in those situations when it is locally secreted by a growing tumor, may desensitize CXCR4 and CXCR7 receptors expressed on the tumor cells and thus prevents their responsiveness to SDF-1 secreted at potential future sites of metastasis and thereby prevents egress of cancer cells into the circulation. On the other hand, despite its obvious pro-angiopoietic effects, MIF inhibits recruitment of stromal cells to the growing tumor. This MIF-mediated impaired recruitment of stromal elements significantly slows down as evidenced by our in vivo xenograft studies tumor growth/expansion. Based on this, we suggest that therapeutic inhibition of MIF in expanding solid tumors may accelerate both metastasis and tumor growth. Thus, the potential application of MIF inhibitors for treatment of MIF-secreting tumors should be reconsidered.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.