Role of host β1-and β2-adrenergic receptors in a murine model of B16 melanoma: functional involvement of β3-adrenergic receptors

Complex interactions between tumor cells and their surrounding compartment are strongly influenced by the host in which the tumor grows. In melanoma, for instance, stress-associated norephinephrine (NE), acting at beta-adrenergic receptors (beta-ARs), stimulates melanoma cell proliferation and tumor angiogenesis. Among beta-ARs, beta 3-ARs play a role acting not only at tumor cells but also at non-neoplastic stromal cells within the melanoma. In the present study, we used a murine model of B16 melanoma to evaluate the role of the host beta 1- and beta 2-ARs in melanoma growth and we determined whether the role of beta 3-ARs can be influenced by the absence of stromal beta 1- and beta 2-ARs. As compared to wild-type mice, beta 1/2-AR knockout mice displayed (i) increased intratumoral levels of both NE and beta 3-ARs, as evidentiated at both messenger and protein levels; (ii) increased tumor vascularization; (iii) decreased tumor cell proliferation but increased tumor cell apoptosis; and (iv) increased responsiveness to intratumoral injection of the beta 3-AR blocker L-748,337 in terms of decrease in tumor growth, tumor vascular response, tumor cell proliferation, and increase in tumor cell death. These findings together validate the role of beta-AR signaling in melanoma microenvironment suggesting that non-neoplastic stromal cells may be targeted by beta-AR-related drugs. The additional fact that beta 3-ARs play an important role in melanoma growth suggests selective beta 3-AR antagonists as important proapoptotic agents.