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Abstract
Enhanced sympathetic signaling, often associated with obesity and chronic stress, is increasingly acknowledged as a contributor to cancer aggressiveness. In prostate cancer, intact sympathetic nerves are critical for tumor formation, and sympathectomy induces apoptosis and blocks tumor growth. Perineural invasion, involving enrichment of intra-prostatic nerves, is frequently observed in prostate cancer and is associated with poor prognosis. β2-adrenergic receptor (ADRB2), the most abundant receptor for sympathetic signals in prostate luminal cells, has been shown to regulate trans-differentiation of cancer cells to neuroendocrine-like cells and to affect apoptosis, angiogenesis, epithelial–mesenchymal transition, migration, and metastasis. Epidemiologic studies have shown that use of β-blockers, inhibiting β-adrenergic receptor activity, is associated with reduced prostate cancer-specific mortality. In this review, we aim to present an overview on how β-adrenergic receptor and its downstream signaling cascade influence the development of aggressive prostate cancer, primarily through regulating neuroendocrine differentiation.
Highlights
Most men die with and not from prostate cancer
Prostate cancer was the primary cause of death in more than 300,000 men worldwide in 2012, with an estimated 630,000 deaths to be expected in 2035 [1]
The collective evidence fails to point in any obvious direction in terms of whether adrenergic signaling is beneficial or disadvantageous for prostate cancer patients
Summary
Most men die with and not from prostate cancer. Despite this, prostate cancer was the primary cause of death in more than 300,000 men worldwide in 2012, with an estimated 630,000 deaths to be expected in 2035 [1]. Drugs targeting androgen receptor activity promote development of a neuroendocrine prostate cancer phenotype [5] and increases the prevalence of neuroendocrine cells [6], and as more drugs in this category reach the clinic the occurrence is expected to rise. Neuroendocrine-like cancer cells are differentiated to a varying extent and may express luminal, mesenchymal, and/or stem cell markers in addition to neuroendocrine markers [7,8,9,10,11]. This reflects the high plasticity of these cells. The molecular mechanisms underlying neuroendocrine differentiation in vivo are poorly understood, inflammation [12], androgen deprivation [13], ionizing radiation therapy [14], and activation of the β-adrenergic receptor (ADRB) have been shown to induce trans-differentiation of prostate cancer cell lines to neuroendocrine-like cells in vitro
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