Abstract
Simple SummaryBone represents the most common site of metastasis for breast cancer and the establishment and growth of metastatic cancer cells within the skeleton significantly reduces the quality of life of patients and their survival. The interplay between sympathetic nerves and bone cells, and its influence on the process of breast cancer bone metastasis is increasingly being recognized. Several mechanisms, all dependent on β-adrenergic receptor signaling in stromal bone cells, were shown to promote the establishment of disseminated cancer cells into the skeleton. This review provides a summary of these mechanisms in support of the therapeutic potential of β-blockers for the early management of breast cancer metastasis.The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases.
Highlights
Metastasis to distant organs represents a common and fatal complication in breast cancer patients [1,2]
A first mechanism of action whereby sympathetic nerves can promote skeletal breast cancer metastasis is through a vascular endothelial growth factor (VEGF)-dependent neo-angiogenic switch upon β2AR signaling in osteoblasts and stimulation of bone marrow vascular density, which increases the likelihood of circulating breast cancer cells colonizing the skeleton
An important implication of the findings summarized above is that β-adrenergic receptors (βARs) blockade should reduce the levels of VEGF, IL-1β, and receptor activator of nuclear factor kappa-B ligand (RANKL) produced by osteoblasts in response to sympathetic activation, and offer some level of protection against bone metastatic events
Summary
Metastasis to distant organs represents a common and fatal complication in breast cancer patients [1,2]. In line with the clinical findings associating stress and enhanced recurrence rate in cancer patients [42,43,44,45,46,47,48,49], in vitro studies demonstrated that NE decreases the efficacy of chemotherapeutics [104], and pharmacological βAR activation in breast cancer cells was shown to promote tumor cell growth and migration [114], as well as the expression of inflammatory and chemotactic cytokines required for metastasis and carcinogenesis [53,115,116,117,118] These effects were abolished when using the β-blocker propranolol [53,115,116,117]. A first mechanism of action whereby sympathetic nerves can promote skeletal breast cancer metastasis is through a VEGF-dependent neo-angiogenic switch upon β2AR signaling in osteoblasts and stimulation of bone marrow vascular density, which increases the likelihood of circulating breast cancer cells colonizing the skeleton. NE for its action or both, are targets of sympathetic-nerve-derived NE for its action on bone metastasis on bone metastasis remains unknown. remains unknown
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