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 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.
Department of Biology, University of Pisa, Via San Zeno, 31, 56127, Pisa, Italy.
Federica
F
Sereni
Department of Biology, University of Pisa, Via San Zeno, 31, 56127, Pisa, Italy.
Massimo
M
Dal Monte
Neonatal Intensive Care Unit, Department of Critical Care Medicine, "A. Meyer" University Children's Hospital, Viale Gaetano Pieraccini, 24, Florence, Italy.
Luca
L
Filippi
Department of Biology, University of Pisa, Via San Zeno, 31, 56127, Pisa, Italy. paola.bagnoli@unipi.it.
Paola
P
Bagnoli
D018674:Adrenergic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000627:Aminophenols / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
D018674:Adrenergic Antagonists; D000627:Aminophenols; C120576:L 748,337; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides
Antibody validation; Catecholamines; Melanoma; β-adrenergic receptors