Host kinin B1 receptor plays a protective role against melanoma progression

Melanoma is a very aggressive tumor that arises from melanocytes. Late stage and widely spread diseases do not respond to standard therapeutic approaches. The kallikrein-kinin system (KKS) participates in biological processes such as vasodilatation, pain and inflammatory response. However, the role of KKS in tumor formation and progression is not completely understood. The role of the host kinin B1 receptor in melanoma development was evaluated using a syngeneic melanoma model. Primary tumors and metastasis were respectively induced by injecting B16F10 melanoma cells, which are derived from C57BL/6 mice, subcutaneously or in the tail vein in wild type C57BL/6 and B1 receptor knockout mice (B1(-/-)). Tumors developed in B1(-/-) mice presented unfavorable prognostic factors such as increased incidence of ulceration, higher levels of IL-10, higher activation of proliferative pathways such as ERK1/2 and Akt, and increased mitotic index. Furthermore, in the metastasis model, B1(-/-) mice developed larger metastatic colonies in the lung and lower CD8(+) immune effector cells when compared with WT animals. Altogether, our results provide evidences that B1(-/-) animals developed primary tumors with multiple features associated with poor prognosis and unfavorable metastatic onset, indicating that the B1 receptor may contribute to improve the host response against melanoma progression.Sao Paulo State Research Foundation (FAPESP)FAPESPUniv Sao Paulo, Dep Biochem & Immunol, BR-14049900 Ribeirao Preto, BrazilUniv Sao Paulo, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, BrazilUniv Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, BR-14049900 Ribeirao Preto, BrazilUniv Fed Sao Paulo, Dept Biophys, BR-04039032 Sao Paulo, BrazilInst Gustave Roussy, INSERM, U981, F-94800 Villejuif, FranceUniv Fed Sao Paulo, Dept Biophys, BR-04039032 Sao Paulo, BrazilFAPESP: 2010/13346-4FAPESP: 2012/20148-0FAPESP: 2011/02144-4Web of Scienc