Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The overexpression of macrophage migration inhibitory factor (MIF) has been observed in many tumors and is implicated in oncogenic transformation and tumor progression. MIF activates CXCR2 and CD74 receptors and, as recently reported, may also bind to the stromal-derived factor-1 (SDF-1)-binding receptor CXCR4. Here, we report that human rhabdomyosarcoma (RMS) cell lines secrete MIF and that this chemokine (a) induces phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 and AKT, (b) stimulates RMS cell adhesion, (c) enhances tumor vascularization, but surprisingly (d) decreases recruitment of cancer-associated fibroblasts (CAF). Because RMS cells used in our studies do not express CXCR2 and CD74 receptors, the biological effects of MIF on RMS cells depend on its interaction with CXCR4, and as we report here for the first time, MIF may also engage another SDF-1-binding receptor (CXCR7) as well. Interestingly, downregulation of MIF in RMS cells inoculated into immunodeficient mice led 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 when locally secreted by a growing tumor, MIF prevents responsiveness of RMS to chemoattractants secreted outside the growing tumor (e.g., SDF-1) and thereby prevents release of cells into the circulation. On the other hand, despite its obvious proangiopoietic effects, MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. Our data indicate that therapeutic inhibition of MIF in RMS may accelerate metastasis and tumor growth.
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PMID:Macrophage migration inhibitory factor is secreted by rhabdomyosarcoma cells, modulates tumor metastasis by binding to CXCR4 and CXCR7 receptors and inhibits recruitment of cancer-associated fibroblasts. 2086 Nov 57

Suppression of the host's immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.
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PMID:Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. 2496 59