Activation of the Kinin B1 Receptor Attenuates Melanoma Tumor Growth and Metastasis

Abstract

Melanoma is a very aggressive tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. Furthermore, acquiring the ability to metastasize in melanoma and many other tumor types is directly related to incurable disease. The B1 kinin receptor participates in a variety of cancer-related pathophysiological events, such as inflammation and angiogenesis. Therefore, we investigated whether this G protein-coupled receptor plays a role in tumor progression. We used a murine melanoma cell line that expresses the kinin B1 receptor and does not express the kinin B2 receptor to investigate the precise contribution of activation of the B1 receptor in tumor progression and correlated events using various in vitro and in vivo approaches. Activation of the kinin B1 receptor in the absence of B2 receptor inhibits cell migration in vitro and decreases tumor formation in vivo. Moreover, tumors formed from cells stimulated with B1-specific agonist showed several features of decreased aggressiveness, such as smaller size and infiltration of inflammatory cells within the tumor area, higher levels of pro-inflammatory cytokines implicated in the host anti-tumor immune response, lower number of cells undergoing mitosis, a poorer vascular network, no signs of invasion of surrounding tissues or metastasis and increased animal survival. Our findings reveal that activation of the kinin B1 receptor has a host protective role during murine melanoma tumor progression, suggesting that the B1 receptor could be a new anti-tumor GPCR and provide new opportunities for therapeutic targeting.

Host kinin B1 receptor plays a protective role against melanoma progression

“…In fact, a cross-talk between those receptors has been described 47 , suggesting that a pro-tumor role of the B1 receptor might depend on B2 receptor expression. A recent report from our group using a B2-free cellular system showed that activation of kinin B1 receptor in the tumor cells resulted in less aggressive tumors, as evidenced by decreased proliferation, vascularization and metastasis, which ultimately improved animal survival 17 . Here, using a syngeneic model in a B1 receptor free microenvironment, we show that targeting the kinin B1 receptor from the host resulted in tumors with unfavorable prognostic factors.…”

“…As high immune response has been correlated with good prognosis in melanomas 27 and activation of B1 receptor in tumor cells has been shown to decrease melanoma development 17 , we hypothesized that absence of host kinin B1 receptor could potentially impact cytokine production in the tumor area, which ultimately would lead to altered host immune response. Therefore, we evaluated cytokine expression profiles in tumors from WT and B1 −/− mice.…”

“…For the kinin B1 receptor, a much less clear scenario appears. Although its activation has been related to induction of cell proliferation and primary tumor growth in lung and prostate cancer xenografts 16 , a recent report from our group showed that activation of kinin B1 receptor in tumor cells reduces melanoma progression, significantly decreasing metastasis and therefore improving animal survival 17 . Regarding the contribution of the B1 receptor present in the host, there is no data in the literature describing its role during melanoma development and metastasis.…”

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…At the same time, recent studies demonstrate the influence of kinin B1 (B1R) and B2 receptors (B2R) on proliferation, chemotaxis, and tumor invasion (11), such as in melanoma (12), bladder cancer (13,14), and glioblastoma (15,16 (17) recently reported that the human GBM cell line U373 produced and bound kininogens, synthesized kallikreins, as well as carboxypeptidases M and E, resulting in the production of B1R and B2-activating kinins, affecting cell invasion. Therefore, considering the effects of GBM-MSC interaction and of kinin receptor activation on proliferation, chemotaxis, and tumor invasion of glioma cells, here we investigate whether direct and indirect co-cultures of bone marrow derived MSC with malignant GBM cells U87-MG would affect B1R and B2R expression, as well as consider possible inductions of protease mediated increase in GBM progression and invasion.…”

Non-canonical signalling and roles of the vasoactive peptides angiotensins and kinins

“…Taub et al [202] showed that desArg 9 -BK enhances cell migration in prostate cancer cells, increasing ERK1/2 and Akt phosphorylation. Interestingly, it was recently reported by our group that the activation of the B 1 receptor by desArg 9 -BK in murine melanoma exerts a tumour-growth-suppressor effect [203], a process that is dependent on whether the B 2 receptor is co-expressed. Such controversial data regarding the effects of B 1 and B 2 receptor agonists have also been observed in other pathologies, such as the hypertrophy of renal arteries [204], suggesting that particular signalling pathways may be activated depending on the cell type and/or the pathophysiological conditions and depending on the balance of B 1 and B 2 receptor expression levels and the cross-talk between these two receptors.…”