Abstract
Metastatic melanoma is an aggressive type of skin cancer leading half of the patients to death within 8–10 months after diagnosis. Kinins are peptides that interact with B1 and B2 receptors playing diverse biological roles. We investigated whether treatment with B1 receptor agonist, des-Arg9-bradykinin (DABK), has effects in lung metastasis establishment after melanoma induction in mice. We found a lower number of metastatic colonies in lungs of DABK-treated mice, reduced expression of vascular cell adhesion molecule 1 (VCAM-1), and increased CD8+T-cell recruitment to the metastatic area compared to animals that did not receive treatment. To understand whether the effects of DABK observed were due to the activation of the B1 receptor in the tumor cells or in the host, we treated wild-type (WT) and kinin B1 receptor knockout (B1−/−) mice with DABK. No significant differences in the number of melanoma colonies established in lungs were seen between WT and B1−/−mice; however, B1−/−mice presented higher VCAM-1 expression and lower CD8+T-cell infiltration. In conclusion, we believe that activation of kinin B1 receptor by its agonist in the host stimulates the immune response more efficiently, promoting CD8+T-cell recruitment to the metastatic lungs and interfering in VCAM-1 expression. Moreover, treatment with DABK reduced establishment of metastatic colonies by mainly acting on tumor cells; hence, this study brings insights to explore novel approaches to treat metastatic melanoma targeting the B1 receptor.
Highlights
Metastatic melanomas are very resistant to standard chemotherapies with a survival time of 8–10 months after being diagnosed with stage IV melanoma (Eggermont et al, 2014)
As shown in our previous work (Dillenburg-Pilla et al, 2013), B1 receptor is constitutively expressed in B16F10 cells while messenger RNA expression of B2 receptor is not detected, providing a good model to study the effects of the B1 receptor activation
Our results show that the proinflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-6 and anti-inflammatory cytokines transforming growth factor (TGF)-β and IL-10 were downregulated upon DABK treatment (Figure 4C), suggesting that activation of the B1 receptor by DABK might be playing a dual role, anti- and proinflammatory, under the progress of metastasis in both groups
Summary
Metastatic melanomas are very resistant to standard chemotherapies with a survival time of 8–10 months after being diagnosed with stage IV melanoma (Eggermont et al, 2014). Despite the evidences that B1 receptor plays a protective role during melanoma growth, studies have demonstrated that kinin receptors are highly expressed in other types of tumors and their activation could contribute to cancer growth and migration (da Costa et al, 2014). It is still unknown whether the effects observed in these studies could be due to B1 receptor activation or due to a cross talk between B1 and B2 receptors (Barki-Harrington et al, 2003)
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