Norepinephrine promotes tumor microenvironment reactivity through ?3-adrenoreceptors during melanoma progression.

ABSTRACT: Stress has an emerging role in cancer and targeting stress-related ?-adrenergic receptors (AR) has been proposed as a potential therapeutic approach in melanoma. Here we report that ?3-AR expression correlates with melanoma aggressiveness. In addition, we highlight that ?3-AR expression is not only restricted to cancer cells, but it is also expressed in vivo in stromal, inflammatory and vascular cells of the melanoma microenvironment. Particularly, we demonstrated that ?3-AR can (i) instruct melanoma cells to respond to environmental stimuli, (ii) enhance melanoma cells response to stromal fibroblasts and macrophages, (iii) increase melanoma cell motility and (iv) induce stem-like traits. Noteworthy, ?3-AR activation in melanoma accessory cells drives stromal reactivity by inducing pro-inflammatory cytokines secretion and de novo angiogenesis, sustaining tumor growth and melanoma aggressiveness. ?3-ARs also play a mandatory role in the recruitment to tumor sites of circulating stromal cells precursors, in the differentiation of these cells towards different lineages, further favoring tumor inflammation, angiogenesis and ultimately melanoma malignancy. Our findings validate selective ?3-AR antagonists as potential promising anti-metastatic agents. These could be used to complement current therapeutic approaches for melanoma patients (e.g. propranolol) by targeting non-neoplastic stromal cells, hence reducing therapy resistance of melanoma.

SUBMITTER: Calvani M 

PROVIDER: S-EPMC4467103 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature