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.
Highlights
Melanoma is a very aggressive and metastatic tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies
The kinin B1 receptor is functionally expressed in Tm5 melanoma cells
To investigate the contribution of the kinin B1 receptor in tumor progression, we first evaluated the expression of key components of kallikrein-kinin in normal and tumor (Tm5) cells
Summary
Melanoma is a very aggressive and metastatic tumor that does not respond well to standard therapeutic approaches, such as radio- and chemotherapies. The mechanisms behind each of these multi-step processes are not completely elucidated, it is known that many tumor cells can hijack the physiological function of G-protein-coupled receptors (GPCR) and take advantage of their multiple functions to proliferate, promote angiogensis, evade immune response and invade host tissues to colonize secondary organs [3]. A small number of metastatic suppressor genes have been described that significantly reduce metastasis in vitro and in vivo [4,5] One of these metastasis suppressor genes is KiSS1, the precursor of the ligand for the Gaq – protein coupled receptor GPR54 [6], which was originally shown to inhibit melanoma metastasis [4] and more recently to inhibit CXCR4-mediated chemotactic response in breast cancer cells [7] and endometrial cancer metastasis [8]
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