Recently, more than 10 studies [see References 1-11], published in the last 3-4 years indicate the presence of high intratumoral concentrations of catecholamines and that these neurohormonal mediators affect key components of tumor biology such as tumor growth, angiogenesis, and migration or invasion [for details see References 12-13]. These studies suggest that blocking beta-adrenoreceptor-mediated signaling pathways might have beneficial effect in preventing cancer development, progression or complications.
Catecholamines (CAs), such as norepinephrine (NE), also known as noradrenaline, and epinephrine(EPI), also known as adrenaline, are end products of the sympathetic nervous system (SNS), a major component of the autonomic nervous system. Peripheral organs, including lymphoid tissues, receive extensive sympathetic innervation, and all immune cells, with the possible exception of T helper (Th)2 cells (in humans), express mostly beta2>>beta1 adrenoreceptors (ADRs).
The SNS and the hypothalamic-pituitary-adrenal axis (HPA) axis constitute the peripheral arms of the stress system. Acute or chronic stress and conditions such as melancholic depression, social isolation, low socioeconomic status, major injury (serious traumatic injury and major burns) or major surgical procedures are associated with increased levels of stress hormones, even though different types of stress may have different neurochemical and neurohormonal ‘signatures’ or profiles, and proportions of NE vs. EPI, vs. cortisol involved [14-17].
Below is a short summary of the studies mentioned above:
Depression, low social support and elevated intratumoral norepinephrine in ovarian cancer
In 2009, and more recently in February of this year, two studies by Susan Lutgendorf and colleagues, published in Brain, Behavior, and Immunity showed that low subjective social support or depression are associated with elevated intratumoral NE in ovarian cancer; and that tumor NE provides distinct information from circulating plasma concentrations. Additionally, promoter-based bioinformatic analyses revealed increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-κB/ Rel, STAT, and Ets family transcription factors [1-2].
The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in breast cancer
In January 2011, Ming Shi et al. published a study demonstrating that Her2 over-expression and excessive phosphorylation of ERK induce an autocrine release of EPI from breast cancer cells, resulting in up-regulation of beta2-ADR expression. Her2 is a member of the epidermal growth factor receptor (EGFR) family. Given that previous studies have shown that CAs induce beta2-ADR-mediated up-regulation of Her2 expression by activating STAT3 transcription factor, the study put forward a new positive feedback mechanism for the cross-talk between Her2 and G protein-coupled receptors (GPCR) signaling.
The study also indicates that this mechanism may generate synergistic signaling, and promoting the expression of both receptors, which in turn may induce the proliferation of breast cancer cells, secretion of CAs, and other proangiogenic and prometastatic factors, including IL-8 and VEGF. Of note, this mechanism may explain the switch from normal autoregulation (desensitization, internalization and down-regulation) of beta2-ADRs to, in fact, an up-regulation of these receptors, and a process that may further promote the tumor growth .
Catecholamines up-regulate MMP-7 expression in gastric cancer
In October 2010, Ming Shi et al. published a study indicating that up-regulation of matrix metalloproteinase (MMP)-7 expression through beta2-ADR-mediated signaling pathway is involved in invasion and metastasis of gastric cancer .
The sympathetic nervous system as a regulator of breast cancer metastasis
In September 2010, Erica K. Sloan and associates from the UCLA published a study demonstrating that in an orthotopic mouse model of breast cancer, physical restraint, a standardized stressor or the beta-adrenoreceptor-agonist isoproterenol increased the metastasis of primary breast tumor cells to distant tissues by 38- and 22-fold, respectively.
The beta-adrenoreceptor antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited the tumor spread. The study suggests that a direct regulation of macrophage biology by catecholamines constitute a previously unrecognized pathway by which hyperactivity of the SNS can activate a metastatic switch within a growing primary tumor .
Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis
In May 2010, Anil Sood et al. reported that NE and EPI protect ovarian cancer cells from anoikis via a focal adhesion kinase (FAK)-mediated signaling pathway, initiated by beta2-ADRs and involving subsequent Src-associated phosphorylation of FAK. FAK is a non–receptor protein tyrosine kinase that localizes to focal adhesions and mediates physical attachment of cells to their extracellular matrix (ECM).
Normal cells enter apoptosis when separated from ECM and neighboring cells (a process known as anoikis). Tumor cells develop resistance to anoikis, which allows for their survival during the process of metastasis. The study identifies NE- and EPI-induced FAK activation as a novel mechanism by which stress might accelerate the pathogenesis of ovarian cancer .
A combination of beta-ADR antagonist and cyclooxygenase-2 inhibitor improves survival rates in murine models of postoperative metastasis
In March 2010, Ariella Glasner and colleagues showed that in mice, blocking beta-ADRs with propranolol, and simultaneously inhibiting prostaglandin synthesis with etodolac signiﬁcantly improves recurrence-free survival rates following 3LL or B16 primary tumor excision. The study suggests that the immediate postoperative period is critical for determining long-term tumor recurrence rates.
It also promotes the clinical testing of a new approach for reducing long-term cancer recurrence: a combined blockade of excess release of catecholamines and prostaglandins in the perioperative period. Such an approach has not been tested clinically thus far .
Norepinephrine upregulates key angiogenic factors in human melanoma, multiple myeloma and nasopharyngeal carcinoma tumor cells
In 2006, 2008 and 2009, three studies by the group of Eric Yang and Ronald Glaser from the Ohio State University Medical Center demonstrated that NE stimulates the expression of VEGF in human melanoma tumor cell lines, multiple myeloma-derived cell lines and nasopharyngeal carcinoma tumor cells. The authors also showed that NE upregulated IL-8 and IL-6 expression in human melanoma tumor cell lines and MMP-2 and MMP-9 in nasopharyngeal carcinoma tumor cells. These data suggest that CAs may affect tumor progression, in part, through upregulation of factors responsible for invasion or angiogenic responses [8-10].
Norepinephrine and epinephrine increase the expression of IL-6 in human ovarian carcinoma cells
In October 2007, Monique Nilsson and colleagues reported that stress mediators, such as NE and EPI increase the expression of IL-6 mRNA and protein levels in ovarian carcinoma cells, and do so through a beta-ADR/Src tyrosine kinase signaling axis. This indicates that stress-induced activation of beta-adrenergic signal transduction pathways in ovarian tumor cells can enhance expression of highly angiogenic cytokines that supports progression of disease .
Previous studies and CAs-induced tumor-related immunosuppression
Apart from direct effects (most of the studies above), CAs may affect tumor growth, indirectly through effects on the immune system. These effects include an inhibition of natural killer (NK) cell activity, a key component of the anti-tumor immunity.
Noteworthy, NK cells appear to be the most “sensitive” cells to the suppressive effect of stress, most likely due to the fact that NK cells probably possess the highest number of beta2-ARs among lymphoid cells. In addition, CAs reduce T-cell responses to mitogens, block the capacity of IFN-gamma to activate macrophages to a tumoricidal state, and suppress the generation of anti-tumor cytotoxicity of splenic Tc lymphocytes [14,18].
Of note, the amount of IL-12 available at the tumor site appears to be crucial for tumor regression, and low levels of IL-12 have been associated with tumor growth, while local overproduction of IL-10 seems to play an inappropriate immunosuppressive role [cf. Ref. 17].
Although a matter of speculation, stress may contribute to these pathologic changes given that CAs (particularly EPI) are extremely potent inhibitors of IL-12 (and, thus, the development of Th1-type cells) and up-regulators of the Th2-related cytokine IL-10, which is a potent suppressor of the effector functions of macrophages, T cells, and NK cells [14,17,19-22]. An interesting recent finding, along these lines indicates that continuous stress may disrupt immunostimulatory effects of IL-12 .
On the other hand, CAs are able to upregulate IL-6 production by human endothelial cells, adipocytes, the liver and skeletal muscle, and IL-8 production by monocytes, lung epithelial cells and endothelial cells, indirectly, via an effect on platelets [cf. Ref. 14]. Thus, these effects of CAs in various normal cells may act in concert with the above-mentioned effects on IL-6 and IL-8 in tumor cells, and promote angiogenesis and disease progression.
The differences between inhibitory vs. certain ‘stimulatory’ effects of CAs can be explained by some differences of systemic vs. local effects or intracellular pathways involved (e.g. cAMP may enhance transcription through cAMP-responsive element in the regulatory region of the IL-10 and IL-6 genes), and in general, by the concept developed in the 1990s that stress hormones and CAs induce a selective suppression of Th1 responses and Th1-related cellular immunity, and a Th2 shift toward humoral immunity, rather than generalized immunosuppression, as previously believed [14,17,19-22].
Thus, this unique ‘signature’ of CAs – a selective and potent inhibition of Th1, NK and cellular immune responses that are key component of the anti-tumor immunity, and an upregulation of IL-10, a potent immunosuppressive agent, along with the highly angiogenic cytokines IL-6, IL-8 and VEGF, may, overall, provide systemic and/or local (micro)environment that may enhance or promote to a great extent the growth of certain tumors.
An increasing body of evidence indicates that CAs through stimulation of beta-ADRs are involved in tumor development and tumor-related immunosuppression. Thus, blocking beta-adrenoreceptor-mediated signaling pathways may open a new window of opportunities, and provide new conceptual advances in the therapy of malignancies.
This may also suggest that conceptual frameworks derived from the field of neuroendocrine-immunology and studies at the interface between neurosciences, endocrinology and immunology hold substantial potential for the development of promising therapeutical interventions in common human diseases.
Glasner A. et al., Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol, 2010, 184:2449.
Yang EV et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun, 2009, 23:267.
Yang EV, Donovan EL, Benson DM, Glaser R. VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine. Brain Behav Immun, 2008, 22:318.
Yang EV et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res, 2006, 66:10357.
Nilsson MB et al. Stress hormones regulate interleukin-6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. J Biol Chem, 2007, 282:29919.
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