Sympathetic nervous system – breast cancer
A study published in the journal Cancer Research identifies sympathetic nervous system (SNS) activation as a novel physiologic regulator of breast cancer metastasis to distant tissue sites.
The effects of the neuroendocrine system and microenvironment on breast cancer metastasis remain largely unexplored.
Recently, however, tumor tissue innervation is becoming accepted as a new hallmark of cancer. Experimental and clinical studies confirmed presence of sympathetic nerves in majority of human cancers, including breast cancer. Also, tumor cells originating from various tissues express adrenergic receptors, especially the β2-subtype. In vitro studies have shown that administration of β-adrenergic agonist stimulates tumor cell growth, whereas administration of β-blockers binding on β2-subtype significantly reduce cell growth. This subtype of adrenergic receptors is expressed also on breast cancer cells.
Sympathetic nervous system nerve fibers are present in organs that serve as key targets for breast cancer metastasis, including the lymph nodes, lung and bone but little is known about the effects of the SNS function or chronic stress on the dissemination of metastatic cancer cells from a primary tumor to distant target organs.
It appears that in cancer, the hyperactive SNS, via activation of β2-adrenergic receptors mediates substantial:
- Suppression of cellular immunity, and particularly NK and Th1 cells.
- Upregulation of immunosuppressive Treg cells.
- Upregulation of TGF-β, IL-6, IL-8 and IL-10 immunosuppressive cytokines.
- Upregulation of immunosuppressive MDSCs cells.
- Direct effect of β-adrenergic receptors on tumor proliferation and metastasis.
To investigate the role of neuroendocrine activation in cancer progression, in the Cancer Research study, Erica K. Sloan and colleagues used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer.
The authors demonstrate that physical restraint, applied as a standardized stressor increased the metastasis of primary breast tumor cells to distant tissues by 38-fold, and stress increased metastasis in clinically relevant tissues, with a 37-fold increase in the lung and a 67% increase in the lymph nodes.
The beta-adrenoreceptor-agonist isoproterenol increased metastasis to distant tissues by 22-fold, whereas treatment of stressed animals with the beta-adrenoreceptor antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues.
SNS effects were mediated through beta-adrenergic signaling, which acted to recruit alternatively activated macrophages into the primary tumor parenchyma and thereby induce a prometastatic gene expression signature.
Sloan et al. argue that a direct regulation of macrophage biology by the SNS seems to constitute a previously unrecognized pathway by which external conditions affecting the autonomic nervous system can activate a metastatic switch within a growing primary tumor.
They suggest that pharmacologic inhibition of SNS activity could potentially constitute a novel adjunctive strategy for minimizing breast cancer metastasis. Furthermore, they also stress the importance of considering the patient’s overall physiology in the development of new therapeutic approaches to limit cancer progression and minimize metastatic rates in breast cancer.
The findings of this study are also substantiated by a recent report showing that the stress mediator epinephrine (adrenaline) promotes the transformation of M1-type to M2-type macrophages and, thus, accelerating tumor growth in a mouse model of breast cancer.
Furthermore, myeloid-derived suppressor cells (MDSC), a class of immune suppressor cells (≤1% of circulating cells), are characterized by the ability to suppress immune responses and expand during cancer. Of note, chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating β-adrenergic signalling. It appears that stress upregulates MDSCs in breast cancer in mice. Furthermore, chronic psychosocial stress not only increases the number of MDSC and Treg cells, but in the case of MDSC also enhances their suppressive capacity.
In conclusion, recent evidence indicates that the hyperactive SNS in breast cancer patients may drive and promote tumor proliferation, growth and metastasis. These features appear to be extremely amplified in triple-negative breast cancer (TNBC), the most aggressive type of breast cancer. In TNBC, the SNS overdrive is most likely coupled with an overexpression of β-adrenergic receptors in tumor cells, providing the micro and macro-environment for the growth of this very invasive and metastatic BC subtype.
Clearly beta-blockers hold therapeutic potential, and at least for propranolol the potential for repurposing is being actively pursued in multiple clinical trials.
SOURCE: Cancer Res 2010, 70: 7042
An Update
A 2021 review by Francisco Conceição, et al. summarizes the current knowledge about the complex interactions that take place in the tumor microenvironment, with a special emphasis on the sympathetic nervous system (SNS) modulation of breast cancer cells and stromal cells.
To date, adrenergic signaling has been implicated in several steps of disease progression, promoting tumor growth, angiogenesis, immunosuppression and invasion.
Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted.
In particular, the authors discuss the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche.
Future developments in novel targeted therapeutic strategies such as tumor-specific denervation via viral vectors are exciting fields of research that will require input from various areas of expertise before becoming applicable in a clinical setting. It is still unclear whether this technique can be applied to locally and specifically denervate bone in preclinical studies.
Finally, clinical observations on the usage of beta-blockers for the treatment of breast cancer suggest that interfering with SNS signaling could have beneficial effects on patients, particularly in the control of metastatic spread.
Taken together, the data summarized in this review highlight the importance of SNS activation in breast cancer. In the next few years, exciting new developments are expected that would allow us to complement our understanding of the molecular cues that drive breast cancer progression.
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