Cancer cells ability to evade apoptos-stress
A study published in the Journal of Clinical Investigation indicates that stress or the stress hormone adrenaline, through stimulation of beta-adrenoreceptors (ADRs), activate signaling pathways that lead to the inhibition of apoptosis. This enables prostate cancer cells to evade apoptosis, which is an important feature of tumor growth and metastasis.
An increasing body of evidence indicates that psychological stress, i.e., stress hormones and mediators, are involved in the development and progression of cancer – affecting directly or indirectly tumor growth, angiogenesis, and migration or invasion of tumor cells.
The idea that psychological factors may contribute to cancer development and progression is not new. It was probably Galen who first integrated the ‘immune system’ or ‘cancer’ with the person’s emotional and physiologic processes – circa 200 A.D. he wrote that melancholic women were more prone to develop ‘swellings’ of the breasts than were sanguine women.
In 1701, the English physician Gendron emphasized the effects of “disasters of life as occasion much trouble and grief” in the causation of cancer. In fact, throughout 18th and 19th century physicians had a firm belief that ‘stressful states’ predisposed to cancer.
Generally, research and clinical data, mostly from the last 10-15 years, strongly indicate that the sympathetic nervous system (SNS) innervation and a hyperactive SNS via activation of the β2-adrenergic receptors (β2-ARs) contributes to tumor-related immunosuppression and by extension to tumor proliferation, growth and metastasis.
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, which, when suppressed, induce apoptosis and blocks tumor growth.
In a 2013 study published in Science magazine, Claire Magnon et al. showed that autonomic nerves contribute to prostate cancer development, where the sympathetic nervous system (SNS) via the activation of β2 and β3-adrenergic receptor pathway participate in the early phase of tumor development. Moreover, a study with a cohort of 3561 prostate cancer patients indicated that the use of β-blockers was associated with reduced prostate cancer-specific mortality in patients with high-risk or metastatic disease.
The ability of tumor cells to evade apoptosis (the process of programmed cell death) is a characteristic hallmark of cancer. To date, there is no definitive experimental evidence on the mechanisms by which behavioral stress may influence prostate cancer development and therapy resistance.
In the Journal of Clinical Investigation study, Sazzad Hassan and colleagues from the Wake Forest University School of Medicine, Winston-Salem, North Carolina demonstrated that in 2 mouse models of prostate cancer – a prostate specific, androgen-dependent transgenic model, and an androgen-independent xenograft model – stress activated the ADRB2/PKA/BAD anti-apoptotic signaling pathway.
Thus, stress may represent a newly defined environmental factor contributing to prostate cancer pathogenesis through an anti-apoptotic signaling pathway that impinges on BCL2-associated death promoter (BAD) phosphorylation. These results are probably the first to establish the critical role of BAD phosphorylation in stress- or adrenaline-induced anti-apoptotic signaling in prostate tumors in vivo.
Importantly, the authors also demonstrate that stress may lead to resistance to anti-androgen (bicalutamide) therapy, an effect they were able to prevent by treatment with an ADRB2 antagonist (a ‘beta-blocker’).
According to the authors, as the prostate cancer diagnosis often increases stress and anxiety levels, the activation of a stress-induced anti-apoptotic pathway may lead to a vicious cycle of stress and cancer progression. The authors also expect that their results could help the identification of biomarkers to predict how a given tumor will respond to stress, and/or distinguish patients’ subgroups that could benefit from stress reduction and pharmacological blockade of stress-induced signaling.
In summary, in 2 distinct in vivo models of prostate cancer, the study indicates that behavioral stress activated the adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway, which in turn reduced therapeutic sensitivity and accelerated prostate cancer development. These data introduce behavioral stress as a new environmental component contributing to prostate cancer pathogenesis through a defined antiapoptotic signaling pathway that impinges on BAD phosphorylation.
Comments on this study, by a group of experts working on similar issues, are available in the same issue of the Journal of Clinical Investigation (Nagaraja et al., J Clin Invest. 2013; 123:558. doi:10.1172/JCI67887).
More general comments for this study are available on Forbes.com Pharma & Healthcare section.
Source: J Clin Invest, 2013 Jan 25. pii: 63324. doi: 10.1172/JCI63324. [Epub ahead of print]
