期刊
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
卷 388, 期 12, 页码 1317-1331出版社
SPRINGER
DOI: 10.1007/s00210-015-1165-7
关键词
beta-adrenergic receptors; Catecholamines; Melanoma; Antibody validation
资金
- Ministero della Salute [RF-2011-02351158]
- Regione Toscana
- Ente Cassa di Risparmio di Firenze
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.
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