Chronic Stress and Ovarian Cancer Progression

Guillermo A-P, Allen JK, Cruz A, et al. Src activation by b-adrenoreceptors is a key switch for tumour metastasis. Nat Commun. 2013;4:1403.

This papers summarizes a multiphase study that examined stress and ovarian cancer progression via activation of the Src pathway. The first component of this publication utilized in vitro analysis to determine which intracellular pathways and associated end-product proteins were most enhanced in norepinephrine-treated ovarian cancer cells. The authors confirmed the biological significance of this activation using tumor-implanted mice in an in vivo analysis. The authors then used an ex vivo analysis to determine the correlation between Src activation, stress, and ovarian cancer survival in humans. Finally, the authors used tumor tissue from 91 patients with invasive epithelial ovarian cancer and correlated depression scores by those patients with Src activation. As final proof of principle, the authors analyzed patient data from the FDA’s Adverse Event Reporting System to examine whether the use of beta-blockers (adrenergic receptor blocking agents) was correlated with reduced death rates among people with cancer.

Ovarian cancer cells do not produce norepinephrine (NE) but do express adrenergic receptors that bind NE. Experimentally exposing these cells to various NE concentrations that correlate with the physiologic levels found in ovarian tissues and tumors under physiological and stress conditions provide a reliable indication of the external influence of NE on ovarian cancer cell behavior. The authors determined that NE activated the intracellular Src pathway in ovarian cancer cells. This activation, as demonstrated by increased phosphorylation affected the entire Src cascade of kinase pathways, which includes KIT, EGFR, ABL1, and IGF-1. The net result of this activation is increased cell invasiveness, migration, and proliferation. The in vivo testing of tumor-implanted mice exposed to stress (by restraint) demonstrated increased activation of Src, in response to the elevated stress-induced NE. Furthermore, there was a concomitant increase in tumor growth and metastasis in these stressed mice. The authors further demonstrated that treating the mice with beta-blockers, known to block adrenergic receptors, abrogated the activation effect of stress.

 

Finally, in the human portion of this study, the authors found that increased Src expression was noted in 88% of the obtained ovarian tumor samples, and that elevated Src expression was associated with poor mean patient survival by univariate analysis (1.67 years versus not yet reached; P<0.001). Furthermore, patients with depression, as measured by high CES-D scores (>16) had significantly higher levels of tumoral phosphorylated (therefore activated) Src (P<0.008) compared with those with low scores. Finally, using data from the FDA Adverse Event Reporting System, the authors found that among people with all major cancer types, the use of beta blockers reduced death as a reported outcome by an average of 17%, with a 14.6% decrease in mortality among patients with ovarian and cervical cancer.

Previous work by these same authors and others has established that activation of beta-adrenergic receptors expressed on ovarian cancer cells results in activation of pro-survival pathways.^1–3 This study confirmed that this activity was translated through Src-induced kinase activation. Src activation causes angiogenesis, cell proliferation, and increased invasiveness. By elucidating the mechanism of action, this study confirms the key role that Src activation plays in tumorigenesis and metastasis. The confirmation of the role of beta-adrenergic receptor activation by norepinephrine, cortisol, and epinephrine in Src activation provides a mechanistic understanding of a link between stress and cancer progression. The stress-associated catecholamines are a manifestation of sympathetic stimulation associated with the hypothalmic-pituitary-adrenal (HPA) axis–mediated stress response. Thus, chronic activation of the HPA axis, as is seen in chronically and significantly stressed individuals, provides a pervasive growth signal to tumors and malignant progression. It is unclear if these mechanisms are additionally in play for the initial development of cancer.

The clinical implications of this work are significant. The central role of chronic stress in cancer progression cannot be safely ignored. Adrenergic receptor stimulation has been demonstrated to be involved in the accelerated progression of many cancer types, including, but not limited to, cancers of the head and neck, breast, prostate, rectum, cervix, ovary, and pancreas, as well as melanoma and leukemia.⁴ Given the preponderance of beta adrenergic receptors expressed by malignant cells, it is imperative to reduce their stimulation by minimizing tissue catecholamine levels and/or by blocking activation of the adrenergic receptors. One way to accomplish this is to reduce stress and HPA axis activation. Myriad integrative strategies can help. Many of these strategies have been evaluated in cancer patients and have been shown to have stress-reducing benefits. Some of the more well-proven strategies include regular physical exercise,⁵ mindfulness-based stress reduction,⁶ and adaptogenic herbs such as Withania somnifera.⁷ Furthermore, the use of beta blockers as an antineoplastic agent should be considered,⁸ as the use of beta-blockers has been linked with reduced disease progression in a variety of cancers in early phase I and pre-clinical studies.⁹ This work also highlights the criticality of Src activation to cancer progression. While clinical evaluation of Src activation is not currently feasible, the biological significance of Src in tumor progression has already stimulated the development of numerous SRC inhibitors now in clinical trials (dasatinib, bosutinib, saracatinib).¹⁰ This declares the Src kinase pathway as a key oncologic target, and a focus of continued development of future cancer treatments.

 

Overall, prolonged and extensive activation of sympathetic catecholamines in association with HPA activation does not bode well for people with established cancer. The importance of this mechanism in accelerating cancer progression will undoubtedly spark the development of randomized controlled trials that will further elucidate the involved mechanisms and the role of B-blockage alone and in comparison with other known stress-modifying interventions. Finally, further research on the role of stress as an instigating factor in the initial development of cancer will be a welcome addition to this growing body of inquiry and research.

 

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