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

Abstract

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 β-adrenergic receptors (β-ARs), stimulates melanoma cell proliferation and tumor angiogenesis. Among β-ARs, β3-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 β1- and β2-ARs in melanoma growth and we determined whether the role of β3-ARs can be influenced by the absence of stromal β1- and β2-ARs. As compared to wild-type mice, β1/2-AR knockout mice displayed (i) increased intratumoral levels of both NE and β3-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 β3-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 β-AR signaling in melanoma microenvironment suggesting that non-neoplastic stromal cells may be targeted by β-AR-related drugs. The additional fact that β3-ARs play an important role in melanoma growth suggests selective β3-AR antagonists as important proapoptotic agents.

• Authors: Federica Sereni, Massimo Dal Monte, Luca Filippi, Paola Bagnoli
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 388 Issue 12 Pg. 1317-31 (Dec 2015) ISSN: 1432-1912 [Electronic] Germany
• PMID: 26285646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic Antagonists
• Aminophenols
• L 748,337
• Receptors, Adrenergic, beta-1
• Receptors, Adrenergic, beta-2
• Receptors, Adrenergic, beta-3
• Sulfonamides

Topics

• Adrenergic Antagonists (pharmacology, therapeutic use)
• Aminophenols (pharmacology, therapeutic use)
• Animals
• Male
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Receptors, Adrenergic, beta-1 (physiology)
• Receptors, Adrenergic, beta-2 (physiology)
• Receptors, Adrenergic, beta-3 (physiology)
• Sulfonamides (pharmacology, therapeutic use)