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.

Biphasic effects of propranolol on tumour growth in B16F10 melanoma‐bearing mice

“…Here, we show that propranolol administration in immunocompetent mice has no effect on B16F10 tumour angiogenesis but increases tumour arteriolar remodelling at the highest dose. This result is in accordance with the observation that genetic deletion of β 1/2 ‐adrenoceptors increases tumour vascularization in the B16F10 melanoma model (Sereni et al , ). Conversely, a recent study performed in immunodeficient mice showed that propranolol administered in drinking water decreases intratumour vessel density in a preclinical model of human melanoma (Wrobel and Le Gal, ).…”

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial

“…Additionally, considering the serious adverse effects observed in newborns receiving oral propranolol with plasma concentrations around 20 ng/mL, this value is currently considered a sort of safe cut-off value [55]. For this reason, if the mean propranolol plasma concentration will be less than 20 ng/ml, as expected, the treatment with propranolol eye drops should be considered safe, being unable to cause high plasma levels of propranolol.…”

“…The hypothesis that the insensitivity to propranolol of 129S6 mice was due to the preponderance in this strain of β3-ARs, that are minimally blocked by propranolol [51], was confirmed by the discovery that this receptor is involved in VEGF production in hypoxic retinas, through the nitric oxide pathway [52]. The discovery of a proangiogenic action of β3-ARs suggested to investigate a possible role for this receptor also in cancer growth [53–55], a new frontier of research currently for neonatologists.…”

β‐Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3‐adrenoceptors

“…The possible pro‐tumourigenic role of β 3 ‐adrenoceptors has been confirmed by some findings obtained in a mouse model of melanoma in which syngeneic B16F10 cells have been inoculated in mice with β 1 ‐ and β 2 ‐adrenoceptor gene deletion (β 1 /β 2 ‐adrenoceptor knockout; Sereni et al ., ). This model has contributed to reveal an important role for host β 1 ‐ and/or β 2 ‐adrenoceptors in regulating the levels of catecholamines and β 3 ‐adrenoceptors in the tumour mass.…”

“…So far, the role of β 3 ‐adrenoceptors in melanoma has been poorly studied, although some preclinical data demonstrate that these receptors may participate in melanoma progression suggesting that blocking β 3 ‐adrenoceptors may be a relevant treatment for melanoma (Dal Monte et al ., ; Dal Monte et al ., ; Calvani et al ., ; Sereni et al ., ). However, the limited understanding of β 3 ‐adrenoceptor function and the poor pharmacological profile of the β 3 ‐adrenoceptor blockers currently available have hampered the development of clinical studies, thus making it difficult to extrapolate results from preclinical studies to humans.…”