title: The role of kinin receptors in cancer and therapeutic opportunities.
abstract: Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties. The multiple cross talks between kinin receptors and renin-angiotensin system (RAS) as well as its implications for targeting KKS or RAS for the treatment of malignancies are also discussed. It is expected that B1R antagonists would interfere less with housekeeping functions and therefore would be attractive compounds to treat selected types of cancer. Reliable clinical studies are needed to establish the translatability of these data to human settings and the usefulness of kinin receptor antagonists.
authors: Laboratório de Oncologia Experimental, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, Brazil.
authors: Patrícia L N
authors: PL
authors: da Costa
authors: CHUL Research Center, Laval University, Quebec City, Canada.
authors: Pierre
authors: P
authors: Sirois
authors: Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada.
authors: Ian F
authors: IF
authors: Tannock
authors: Laboratório de Oncologia Experimental, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, Brazil. Electronic address: rchammas@lim24.fm.usp.br.
authors: Roger
authors: R
authors: Chammas
mesh_terms: D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2
keywords: Angiogenesis; Bradykinin; Cancer; Kallikrein–kinin system; Kinin receptors; Renin–angiotensin system