title: Exploiting agonist biased signaling of chemokines to target cancer.
abstract: As knowledge of growth-independent functions of cancer cells is expanding, exploration into the role of chemokines in modulating cancer pathogenesis, particularly metastasis, continues to develop. However, more study into the mechanisms whereby chemokines direct the migration of cancer cells is needed before specific therapies can be generated to target metastasis. Herein, we draw attention to the longstanding conundrum in the field of chemokine biology that chemokines stimulate migration in a biphasic manner; and explore this phenomenon's impact on chemokine function in the context of cancer. Typically, low concentrations of chemokines lead to chemotactic migration and higher concentrations halt migration. The signaling mechanisms that govern this phenomenon remain unclear. Over the last decade, we have defined a novel signaling mechanism for regulation of chemokine migration through ligand oligomerization and biased agonist signaling. We provide insight into this new paradigm for chemokine signaling and discuss how it will impact future exploration into chemokine function and biology. In the pursuit of producing more novel cancer therapies, we suggest a framework for pharmaceutical application of the principles of chemokine oligomerization and biased agonist signaling in cancer. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ishan
authors.initials: I
authors.lastname: Roy
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Getschman
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.|MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000819:agonists* / Q000737:chemistry; D018450:Disease Progression; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D055503:Protein Multimerization; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D043562:Receptors, G-Protein-Coupled
keywords: G protein coupled receptor; biased agonist; functional selectivity