Abstract
Author SummaryImproved detection programs and better drugs to eradicate breast tumors have increased survival in women with breast cancer. However, pain and metastasis to distant organs, including bone, remain significant clinical problems. Understanding why and how metastatic cancer cells colonize specific organs is therefore critical if we are to further improve morbidity and mortality for these patients. Using a mouse model of breast cancer bone metastasis, we present evidence that activation of sympathetic nerves, which is typical in chronic stress or depression, promotes the colonization and establishment of metastatic cancer cells within the bone marrow, leading to an increase in bone osteolytic lesions. We show that this effect is mediated via a β-adrenergic receptor-dependent response of the host bone marrow stroma to catecholamines, that are released upon sympathetic activation, and via the pro-migratory activity of RANKL, a cytokine that is well known to promote bone resorption. Of importance clinically, blocking sympathetic activation with a β-blocker, or blocking RANKL signaling in cancer cells, inhibited the stimulatory effect of sympathetic activation on bone metastasis in this mouse model. Stress-induced sympathetic activation may thus explain, at least in part, the reduced survival rate of breast cancer patients experiencing severe depression. The data also support the use of β-blockers or RANKL blockade as possible adjuvant therapy for women with breast cancer.
Highlights
Breast cancer metastasizes to bone, lung, liver, brain, and lymph nodes
Using a mouse model of breast cancer bone metastasis, we present evidence that activation of sympathetic nerves, which is typical in chronic stress or depression, promotes the colonization and establishment of metastatic cancer cells within the bone marrow, leading to an increase in bone osteolytic lesions
We show that this effect is mediated via a b-adrenergic receptor-dependent response of the host bone marrow stroma to catecholamines, that are released upon sympathetic activation, and via the pro-migratory activity of Receptor Activator of Nuclear Factor k B (RANKL), a cytokine that is well known to promote bone resorption
Summary
Breast cancer metastasizes to bone, lung, liver, brain, and lymph nodes. Among these metastases, those targeted to bone are preponderant and observed in approximately 70% of breast cancer fatalities [1]. The process of cancer metastasis is multifactorial, influenced by a combination of genes [4], and dependent upon intrinsic cancer cell characteristics that dictate how cells migrate, survive, and proliferate, as well as on the cellular and cytokine profile of the tissue from which the cells initially egress. This process is driven by the microenvironment to which metastatic cancer cells home [5].
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