Host kinin B1 receptor plays a protective role against melanoma progression

Abstract

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.

Activation of the Kinin B1 Receptor by Its Agonist Reduces Melanoma Metastasis by Playing a Dual Effect on Tumor Cells and Host Immune Response

“…At the end of the protocol, lung metastases were screened. Animals treated with DABK presented a lower number of metastatic colonies as compared with animals treated with vehicle ( Figure 2A ), corroborating the previous findings that kinin B1 receptor has a positive role protecting the host from metastatic melanoma colony establishment (Dillenburg-Pilla et al, 2013; Maria et al, 2016). Differences in gain or loss of weight observed during the period studied were not statistically significant ( Figure 2B ).…”

“…Corroborating these data, immunohistochemistry analysis showed increased expression of VEGF in lungs of B1 −/− DABK-treated mice ( Figure 6C ). Moreover, in our previous study (Maria et al, 2016), we did not observe differences in the number of melanoma colonies established in the lungs of non-treated B1 −/− mice compared to non-treated WT animals and found an increased number of vessels in the lungs of B1 −/− mice.…”

“…Although the B1 receptor is known for its role in the regulation of inflammatory processes (Costa-Neto et al, 2008), the precise function of kinin B1 receptor in tumor development and metastasis is still controversial. Previous work from our group showed that either the presence of the B1 receptor in the host microenvironment or pretreatment of melanoma cells with the B1 receptor agonist can protect against tumor progression (Dillenburg-Pilla et al, 2013; Maria et al, 2016).…”

“…Mice with tumors derived from TM5 melanoma cells previously activated with B1 receptor agonist, des-Arg 9 -bradykinin (DABK), presented smaller tumors and increased animal survival (Dillenburg-Pilla et al, 2013). Moreover, primary melanomas developed in B1 receptor knockout (B1 −/− ) mice showed a higher number of mitotic cells and increased activation of proliferative pathways (Maria et al, 2016). 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).…”

Renin-angiotensin inhibitors reprogram tumor immune microenvironment: A comprehensive view of the influences on anti-tumor immunity

“…The overall effect of BK through either B1R, B2R, or both is to promote vascular cell proliferation [ 103 ], influence barrier permeability [ 104 ] and possibly stimulate the release of pro-inflammatory cytokines [ 105 ]. The role of kinin receptors has been investigated in various types of cancer, including melanoma, renal, prostate, lung and breast and mesothelioma [ 106 – 110 ], among others. Recently our laboratory found that both human and mouse CRC cell lines showed a strong positive expression of B1R and B2R, and while the inhibition of both receptors delayed tumor growth, only B1R blockade reduced tumor load and increased tumor apoptosis [ 105 ].…”