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Biological implications of leukocyte responsiveness to tumour-derived relaxin Figueiredo, Kevin A.

Abstract

Leukocytes are critical effectors of inflammation and tumour biology. Chemokine-like factors produced by such inflammatory sites are key mediators of tumour growth that activate leukocyytc recruitment and tumour infiltration and suppress immune surveillance. The endocrine peptide hormone, relaxin has been implicated as a regulator of breast and prostate cancer progression. We have shown that relaxin is a regulator of leukocyte biology with properties important in recruitment to sites of inflammation. Our studies demonstrate upregulated relaxin gene expression during neuroendocrine differentiation of the human prostate cancer model, LNCaP. To examine the impact of relaxin on host cells associated with adenocarcinomas, we generated recombinant 6 His-tagged relaxin (RLXH) in a mammalian expression system. This immunoreactive and biologically active relaxin preparation was used to screen a variety of cell types for cAMP responsiveness. Of the cell types screened, none were more responsive to RLXH than the monocyte/macrophage cell line THP-1 and peripheral blood mononuclear cells (PBMC). Our studies indicate that relaxin promotes cell-cell clustering, substrate adhesion, and migratory capacity of mononuclear leukocytes in a relaxin dose-dependent manner proportional to cAMP accumulation. We demonstrate that these biological responses occur through a relaxin receptor LGR7-dependent mechanism likely involving cAMP-dependent regulation of the small GTPase Rap1. Relaxin-stimulated cAMP accumulation was observed to occur primarily in non-adherent cells, and relaxin-stimulated substrate adhesion also resulted in enhanced chemotaxis to monocyte chemoattractant protein-1. We demonstrate for the first time that the classic hormonal role for relaxin as a regulator of epithelial and stromal functions, can now be expanded to include a role in targeting blood cells as a cytokine with chemokine-like properties. In addition, we describe novel roles for relaxin in mediation of macrophage activation states with important implications in the context of tumour-induced inflammation and immunosuppression.

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