title: GLI2 transcription factor mediates cytokine cross-talk in the tumor microenvironment.
abstract: Tumor cells interact with their surrounding microenvironment to survive and persist within the host. Cytokines play a key role in regulating this crosstalk between malignant cells and surrounding cells in the microenvironment. Although this phenomenon is clearly established, the molecular mechanisms mediating this cellular event remain elusive. Here, using as a model bone marrow stromal cells, we describe a novel signaling mechanism initiated by CCL5 in these cells leading to up-regulation of immunoglobulin secretion by malignant B cells. CCL5 increases IL-6 expression and secretion in bone marrow stromal cells. IL-6 in turn induces Ig secretion by malignant B cells. Analysis of the mechanism reveals that CCL5 signaling induces GLI2 through a PI3K-AKT-IκBα-p65 pathway and requires GLI2 transcriptional activity to modulate IL-6 expression and Ig secretion in vitro and in vivo. Together, these results identify a novel signaling pathway mediating the stromal-cancer cell interactions, leading to increased Ig production by malignant cells.
authors: Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Sherine F
authors: SF
authors: Elsawa
authors: Luciana L
authors: LL
authors: Almada
authors: Steven C
authors: SC
authors: Ziesmer
authors: Anne J
authors: AJ
authors: Novak
authors: Thomas E
authors: TE
authors: Witzig
authors: Stephen M
authors: SM
authors: Ansell
authors: Martin E
authors: ME
authors: Fernandez-Zapico
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007136:Immunoglobulins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D016207:Cytokines; C000618551:Gli2 protein, mouse; D020672:I-kappa B Proteins; D007136:Immunoglobulins; D015850:Interleukin-6; D051741:Kruppel-Like Transcription Factors; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D000075746:Zinc Finger Protein Gli2; D000072000:NF-KappaB Inhibitor alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt