Chronic Stress – Nervous Breakdown and Catatonia

The classic 1949 war movie, “Twelve Oclock High” starring Gregory Peck, reveals the effect of chronic stress on B-17 pilots during the war.  After many weeks of stressful daylight bombing raids,  Gregory Peck suffers a nervous breakdown, and is carried away in a catatonic state.   I was impressed with this brutally honest depiction of the effects of chronic stress in war time. (left image courtesy of Bantam Books)

Chronic Stress is a Bad Thing

Chronic stress is undoubtedly a bad thing because of release of massive adrenal hormones called catecholamines.  This is extremely deleterious to our immune system, increases susceptibility to viral infection and delays wound healing. (1-2)   Chronic stress has been implicated in cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, gastric ulcer, as well as cancer (2)

Can Chronic Stress Cause Cancer ?

This leads us to the main question of the article, can chronic stress cause cancer?  Let’s examine an animal model of chronic stress to answer this question.

Animal Model of Chronic Stress

The animal model of chronic stress involves restraining mice in narrow tubes for a few hours every day.   To make matters worse, the mice may be immersed in cold water.

Left image Schematic Showing Mouse retrained in narrow tube. This is restraint stress. Courtesy of  Zhang et al. “Restraint Stress Causes Acute Gastric Injury In Mice: ” Scientific reports 6 (2016).

Does Chronic Stress Causes Cancer ?

Dr Donald Lamkin used a lymphoblastic leukemia model in mice undergoing restraint stress to answer the question, does chronic stress cause cancer?(3)  Dr Lamkin’s  2012 study published in Brain Behavior showed that mice suffering from restraint stress (Red Ellipse in below image) had accelerated progression of cancer compared to controls (Green Ellipse).

Beta-Blockers Block Effect of Stress

The effect of stress was abrogated by giving the mice a Beta-Blocker drug called propranolol, which blocks the activation of the sympathetic nervous system. (see image below). The Propranolol treated mice actually showed regression of cancer compared to controls. Thus proving that beta-adrenergic stimulation drives cancer growth, and by blocking the effect of chronic stress with a beta blocker drug, we can slow the progression of cancer..Fig 3 B Beta-adrenergic signaling in stress-enhanced Acute Lymphoblastic Leukemia progression. Mice were injected with cancer cells tagged with fluorescent marker (blue spots)Green Ellipse shows control mice NO STRESS, injected with cancer cells.  Red Ellipse shows STRESSED mice with increased cancer growth compared to controls.  Propranolol treated mice (Beta Blocker) had actual regression of cancer compared to controls. Courtesy of  Lamkin, Donald M., et al. (3)

How does stress produces Beta-Adrenergic nervous system stimulation? 

Chronic stress stimulates the adrenal medulla to secrete massive amounts of  the catecholamines, epinephrine and norepinephrine. These stress hormones stimulate the Beta Adrenergic receptors in the nervous system, as well as in cancer cells.

Mobile cancer cells will frequently migrate to the adrenal glands, seeking the adrenal medulla which secretes high concentration of catecholamines thus causing large adrenal masses. See image below.

Adrenal Metastatic Disease is Quite Common

Above Image: Adrenal lymphoma on CAT scan. (left image a) Both Adrenals are replaced by large masses (white arrows) (Right image b) shows bulky retro-peritoneal nodal masses with renal invasion (black arrows)  Courtesy of Indian Journal of Endocrinology and Metabolism . 2015 Volume 19 Issue 1 P16-24  Adrenal imaging (Part 2): Medullary and secondary adrenal lesions by Ekta et al.

Modifying Diet to Down Regulate the Sympathetic Nervous System

In addition to the use of Beta Blocker Drugs, the sympathetic nervous system can be down regulated by dietary interventions as advocated by Nicholas Gonzalez MD as a part of his cancer treatment protocol.(19-22).

Conclusion: Chronic Stress is unhealthy because  it  releases catecholamines  which activate the Sympathetic Nervous system.  Cancer cells are sensitive to beta adrenergic stimulation caused by chronic stress.  This stimulates cancer cell growth.

Articles with Related Interest:  Adrenal Fatigue

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
954-792-4663

Links and References

free pdf
1) Glaser, Ronald, and Janice K. Kiecolt-Glaser. “Stress-induced immune dysfunction: implications for health.” Nature Reviews Immunology 5.3 (2005): 243-251. stress-induced-immune-dysfunction-implications-for-health-nature-reviews-immunology-2005-glaser-ronald
free pdf
Reiche, Edna Maria Vissoci, Sandra Odebrecht Vargas Nunes, and Helena Kaminami Morimoto. “Stress, depression, the immune system, and cancer.” The lancet oncology 5.10 (2004): 617-625.stress-depression-the-immune-system-cancer-lancet-oncology-reiche-edna-maria-2004

stress promotes cancer – Nice flourescent mouse images

3) Lamkin, Donald M., et al. “Chronic stress enhances progression of acute lymphoblastic leukemia via ß-adrenergic signaling.” Brain, behavior, and immunity 26.4 (2012): 635-641.
Clinical studies suggest that stress-related biobehavioral factors can accelerate the progression of hematopoietic cancers such as acute lymphoblastic leukemia (ALL), but it is unclear whether such effects are causal or what biological pathways mediate such effects. Given the network of sympathetic nervous system (SNS) fibers that innervates the bone marrow to regulate normal (non-leukemic) hematopoietic progenitor cells, we tested the possibility that stress-induced SNS signaling might also affect ALL progression. In an orthotopic mouse model, Nalm-6 human pre-B ALL cells were transduced with the luciferase gene for longitudinal bioluminescent imaging and injected i.v. into male SCID mice for bone marrow engraftment. Two weeks of daily restraint stress significantly enhanced ALL tumor burden and dissemination in comparison to controls, and this effect was blocked by the ß-adrenergic antagonist, propranolol. Although Nalm-6 ALL cells expressed mRNA for ß1- and ß3-adrenergic receptors, they showed no evidence of cAMP signaling in response to norepinephrine, and norepinephrine failed to enhance Nalm-6 proliferation in vitro. These results show that chronic stress can accelerate the progression of human pre-B ALL tumor load via a ß-adrenergic signaling pathway that likely involves indirect regulation of ALL biology via alterations in the function of other host cell types such as immune cells or the bone marrow microenvironment.

Chronic restraint stress significantly enhanced pre-B ALL tumor burden and dissemination in a well-established mouse xenograft model of the most prevalent form of human pediatric leukemia. Pharmacologic inhibition studies showed that stress effects were mediated by ß-adrenergic signaling in vivo
Mechanistic investigations have documented a key role of ß-adrenergic signaling in mediating stress effects on progression of several types of solid tumor (Sloan et al., 2010; Stefanski & Ben-Eliyahu, 1996; Thaker et al., 2006).

the present results raise the possibility that cancer-related anxiety might contribute to disease recurrence and that pharmacologic inhibition of such effects at the level of the ß-adrenergic receptor may represent an effective strategy for managing those effects in patients with pre-B ALL who are in remission or still have active disease.

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Beta Blockers and Cancer

nice review

4) http://www.tandfonline.com/doi/full/10.1517/13543784.2013.825250
Nagaraja, Archana S., et al. “ß-blockers: a new role in cancer chemotherapy?.” Expert opinion on investigational drugs 22.11 (2013): 1359-1363.
ß-blockers are a class of drugs that are widely used in treating cardiac, respiratory and other ailments. They act by blocking ß-adrenergic receptor-mediated signaling. Studies in various cancers have shown that patients taking a ß-blocker have higher survival and lower recurrence and metastasis rates. This is supported by several preclinical and in vitro studies showing that adrenergic activation modulates apoptosis, promotes angiogenesis and other cancer hallmarks, and these effects can be abrogated by ß-blockers. These studies provide a rationale for the use of ß-blockers as adjuvants with cancer chemotherapy. However, all published studies so far are retrospective and most do not take into account the specific ß-blocker used or address which is most likely to benefit cancer patients. The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors. Knowledge of the ß-adrenergic receptor status of tumor cells is essential in choosing the best ß-blocker for adjuvant therapy. A comprehensive, prospective study is necessary to definitively prove the utility of using ß-blockers with chemotherapy and to identify the specific ß-blocker most likely to benefit patients with cancer.

There are three subtypes of ß-adrenergic receptors, designated ADRB1, ADRB2 and ADRB3, which are encoded by genes located on chromosomes 10, 5 and 8, respectively. ADRBs are activated by catecholamines (such as noradrenaline and adrenaline) that are secreted largely in response to sympathetic nervous system stimulation, resulting in the ‘fight-or-flight’ response. Although acute activation of adrenergic receptors has been shown to be beneficial for human health, prolonged activation is associated with decreased immune function, heart failure, arrhythmia and hypertension. Sustained activation can be a result of altered behavioral states such as those seen in depression, anxiety and chronic stress.

5) https://www.ncbi.nlm.nih.gov/pubmed/23912960
Breast Cancer Res Treat. 2013 Aug;140(3):567-75. doi: 10.1007/s10549-013-2654-3. Epub 2013 Aug 3.  Therapeutic effect of ß-blockers in triple-negative breast cancer postmenopausal women.  Botteri E1, Munzone E, Rotmensz N, Cipolla C, De Giorgi V, Santillo B, Zanelotti A, Adamoli L, Colleoni M, Viale G, Goldhirsch A, Gandini S.

Beta-blockers (BB) drugs have been used for decades worldwide, mainly to treat hypertension. However, in recent epidemiological studies, BBs were suggested to improve cancer prognosis. In the wake of this evidence, we evaluated the possible therapeutic effect of BBs in triple-negative breast cancer (TNBC) patients. We identified 800 postmenopausal women operated between 1997 and 2008 for early primary TNBC. The effect of BB intake on the risk of breast cancer (BC) recurrence and death was evaluated through competing risk and Cox regression survival models. At cancer diagnosis, 74 (9.3 %) women out of 800 were BBs users. Median age was 62 years in BB users and 59 years in non-users (P = 0.02). BB users and non-users were similarly distributed by all tumor characteristics. The 5-year cumulative incidence of BC-related events was 13.6 % in BB users and 27.9 % in non-users (P = 0.02). The beneficial impact of BBs remained statistically significant at multivariable analysis (HR, 0.52; 95 % CI 0.28-0.97), after the adjustment for age, tumor stage, and treatment, peritumoral vascular invasion and use of other antihypertensive drugs, antithrombotics, and statins. Adjusted HRs for metastases and for BC deaths were 0.32 (95 % CI 0.12-0.90) and 0.42 (95 % CI 0.18-0.97), respectively, in favor of BBs. Hypertension, other antihypertensive drugs, antithrombotics, and statins did not impact prognosis. In this series of postmenopausal TNBC patients, BB intake was associated with a significantly decreased risk of BC-related recurrence, metastasis, and BC death. Innovative therapeutic strategies including BBs should be urgently explored in cancer patients.

6) https://www.ncbi.nlm.nih.gov/pubmed/21632501
J Clin Oncol. 2011 Jul 1;29(19):2645-52. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer.
Melhem-Bertrandt A1, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM.
1The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

To examine the association between beta-blocker (BB) intake, pathologic complete response (pCR) rates, and survival outcomes in patients with breast cancer treated with neoadjuvant chemotherapy.
PATIENTS AND METHODS:We retrospectively reviewed 1,413 patients with breast cancer who received neoadjuvant chemotherapy between 1995 and 2007. Patients taking BBs at the start of neoadjuvant therapy were compared with patients with no BB intake. Rates of pCR between the groups were compared using a ?² test. Cox proportional hazards models were fitted to determine the association between BB intake, relapse-free survival (RFS), and overall survival (OS).
RESULTS:Patients who used BBs (n = 102) were compared with patients (n = 1,311) who did not. Patients receiving BBs tended to be older and obese (P < .001). The proportion of pCR was not significantly different between the groups (P = .48). After adjustment for age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use, BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P = .09). Among patients with triple-negative breast cancer (TNBC; n = 377), BB intake was associated with improved RFS (HR, 0.30; 95% CI, 0.10 to 0.87;P = .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00;P = .05).
CONCLUSION:In this study, BB intake was associated with improved RFS in all patients with breast cancer and in patients with TNBC. Additional studies evaluating the potential benefits of beta-adrenergic blockade on breast cancer recurrence with a focus on TNBC are warranted.

7) https://www.ncbi.nlm.nih.gov/pubmed/26516037
Clin Breast Cancer. 2015 Dec;15(6):426-31. doi: 10.1016/j.clbc.2015.07.001. Epub 2015 Jul 10.
ß-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis.
Childers WK1, Hollenbeak CS2, Cheriyath P3.
The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the ß-adrenergic receptor (ß-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the ß-AR. Retrospective cohort studies on the clinical outcomes of ß-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of ß-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving ß-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of ß-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of ß-blockers significantly reduced risk of breast cancer death among women with breast cancer.

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8) http://www.mdpi.com/2073-4409/5/1/2/htm
Entschladen, Frank, Dane A. Thyssen, and David W. Drell. “Re-Use of Established Drugs for Anti-Metastatic Indications.” Cells 5.1 (2016): 2.
To date, the by far most striking discovery in the context of drug repurposing in oncology is the anti-metastatic function of beta-blockers

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beta blocker and ovarian cancer 2015

9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575637/

Cancer. 2015 Oct 1; 121(19): 3444–3451.
Published online 2015 Aug 24. doi:  10.1002/cncr.29392
PMCID: PMC4575637
NIHMSID: NIHMS717272
Clinical Impact of Selective and Non-selective Beta Blockers on Survival in Ovarian Cancer Patients
Jack L. Watkins,1,* Premal H. Thaker,2,* Alpa M. Nick,3 Lois M. Ramondetta,3 Sanjeev Kumar,4 Diana L. Urbauer,5 Koji Matsuo,6 Kathryn Squires,2 Susan K. Lutgendorf,7 Pedro T. Ramirez,3 and Anil K. Sood3,8,

Preclinical evidence suggests that sustained adrenergic activation can promote ovarian cancer growth and metastasis. We examined the impact of beta-adrenergic blockade on clinical outcome of women with epithelial ovarian, primary peritoneal or fallopian tube cancers (collectively, EOC).
METHODS A multicenter review of 1,425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta blocker use during chemotherapy and those without beta blocker use.
RESULTS  The median age of patients in this study was 63 years (range, 21–93 years). The sample included 269 patients who received beta blockers. Of those, 193 (71.7%) were receiving beta-1 adrenergic receptor (ADRB1) selective agents, and the remaining patients were receiving non-selective beta antagonists. The primary indication for beta blocker use was hypertension but also included arrhythmia and post-myocardial infarction management. For patients receiving any beta blocker, the median overall survival (OS) was 47.8 months versus42 months (P = 0.04) for non-users. The median OS based on beta blocker receptor selectivity was 94.9 months for those receiving non-selective beta blockers versus 38 months for those receiving ADRB1 selective agents (P < 0.001). Hypertension was associated with decreased OS compared to no hypertension across all groups. However, even in patients with hypertension, users of a non-selective beta blocker had a longer median OS than non-users observed (38.2 vs 90 months, P < 0.001).
CONCLUSION  Use of non-selective beta blockers in epithelial ovarian cancer patients was associated with longer OS. These findings may have implications for new therapeutic approaches.

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10) Yuan, Aihua, et al. “Psychological aspect of cancer: From stressor to cancer progression (Review).” Experimental and therapeutic medicine 1.1 (2010): 13-18.
Substantial evidence indicates that psychological stress can influence the incidence and progression of cancers, and adequate psychotherapies are beneficial to cancer patients. Recently, the mechanisms responsible for the effects of psychological stress on cancer cells have been extensively investigated at the systemic, biochemical and molecular levels. Accumulating data indicate that the effects of psychological stress on cancer cells are mainly mediated by key stress-related mediators and their corresponding receptors in multi-fold pathways: chronic stressors act on the paraventricular nucleus and the suprachiasmatic nuclei. The effects are then transmitted through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, amplified by the unchecked release of stress-related mediators and altered behaviors. These mediators act as immunosuppressors or mitogens in the tumor micro-environment. The converging effects of psychological stress on cancer cells finally signal through receptors of the stress mediators and cytokines to activate the intracellular pro-proliferative and pro-migratory signaling pathways, and reset the molecular clock in tumor cells. Understanding these action mechanisms of psychological stress in promoting the growth and invasion of cancer cells is crucial for devising effective interventions.

Not until the recent past few years, by using in vitro animal models and human clinical perspective study approaches, have researchers begun to uncover the complex relationship between psychosocial stress and cancer progression at the systemic, biochemical and molecular levels. Accumulating data indicate that the psychological stress caused by chronic stressors is a major risk factor for cancer occurrence, growth and metastasis (5–8).

11)   Jin Shin, Kyeong, et al. “Molecular mechanisms underlying psychological stress and cancer.” Current pharmaceutical design 22.16 (2016): 2389-2402.
Curr Pharm Des. 2016;22(16):2389-402.

Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.

12)  Cole, Steven W., et al. “Sympathetic nervous system regulation of the tumour microenvironment.” Nature Reviews Cancer 15.9 (2015): 563-572.
Experimental analyses in in vivo animal models have now shown that behavioral stress can accelerate the progression of breast, prostate, and ovarian carcinomas 35,49–52, neuroblastomas 53,54, malignant melanomas 55,56, pancreatic carcinoma 24,57, and some haematopoietic cancers such as leukaemia 58,59. In many of these experimental models, the biological effects of stress could be efficiently blocked by β-adrenergic antagonists and mimicked by pharmacologic β-agonists 14

13)   Magnon, Claire. “Role of the autonomic nervous system in tumorigenesis and metastasis.” Molecular & Cellular Oncology 2.2 (+15): e975643.

14)   Gao, Guolan, et al. “Chronic stress promoted the growth of ovarian carcinoma via increasing serum levels of norepinephrine and interleukin-10 and altering nm23 and NDRG1 expression in tumor tissues in nude mice.” Bioscience trends 7.1 (2013): 56-63.
.
The current study aimed to examine the effects and underlying mechanisms of chronic psychological stress on the growth of ovarian carcinoma. Human ovarian carcinoma cells SKOV-3 were subcutaneously inoculated into nude mice to establish an ectopic mouse model. The animals were experimentally stressed 6 h daily for a total of 42 days with a physical restraint system. We examined the effects of stress on the growth of tumor cells that were inoculated 7 days after the initiation of stress. The growth of SKOV-3 xenografts in the stress group showed a more rapid trend than that in the control. The mean weight of tumors that were removed at the end of the experiment increased by 71.7% in the stress group as compared to the control. In order to explore the underlying mechanisms, we first determined the serum levels of norepinephrine (NE) and interleukin 10 (IL-10) in the mice using an enzyme-linked immunoabsorbent assay (ELISA) and then analyzed protein expression profiles of SKOV-3 xenografts using a proteomics-based approach combining two-dimensional electrophoresis with ultra performance liquid chromatography-electrospray tandem mass spectrometry (nanoUPLC-ESI-MS/MS). Results demonstrated that serum levels of NE and IL-10 were obviously increased in the mice receiving 6 h of immobilization daily for 42 days. In xenografts exposed to stress, a tumor promoting protein nm23 was significantly upregulated while a tumor suppressing protein NDRG1 was obviously downregulated, which were confirmed by subsequent Western blot analysis. Results obtained in the current study suggested that chronic stress promoted the growth of ovarian carcinoma in nude mice through increasing serum levels of NE and IL-10 and altering nm23 and NDRG1 expression in tumor tissues.

15)   Krizanova, O., Petr Babula, and K. Pacak. “Stress, catecholaminergic system and cancer.” Stress 19.4 (2016): 419-428.
Stress as a modern civilization factor significantly affects our lives. While acute stress might have a positive effect on the organism, chronic stress is usually detrimental and might lead to serious health complications. It is known that stress induced by the physical environment (temperature-induced cold stress) can significantly impair the efficacy of cytotoxic chemotherapies and the anti-tumor immune response. On the other hand, epidemiological evidence has shown that patients taking drugs known as β-adrenergic antagonists (“β-blockers”), which are commonly prescribed to treat arrhythmia, hypertension, and anxiety, have significantly lower rates of several cancers. In this review, we summarize the current knowledge about catecholamines as important stress hormones in tumorigenesis and discuss the use of β-blockers as the potential therapeutic agents.

16) Exp Oncol. 2011 Dec;33(4):222-5.  Depressive-like psychoemotional state versus acute stresses enhances Lewis lung carcinoma metastasis in C57BL/6J mice.
Amikishieva AV1, Ilnitskaya SI, Nikolin VP, Popova NA, Kaledin VI.
The effect of a depression-like status formed by chronic stress on the development of Lewis lung carcinoma metastases in C57Bl/6J mice was investigated. Two types of acute stress (restraint and social stress) were used for comparison.
METHODS:The depression-like status was induced by eight-week exposure to repeated but unpredictable stressors (chronic mild stress model) and was assessed in the forced swim test. Tumor cells were inoculated an hour after the onset of social stressor or immediately after physical or chronic stressor impacts. The number of metastases was counted 17 days after the inoculation.
RESULTS:Chronic mild stress provokes the development of a depression-like state in mice and causes a twofold increase in the number of metastases in the lungs, while both types of acute stress have no such effects.
CONCLUSION:Depressive-like psychoemotional state of animals enhances the metastasis of Lewis lung carcinoma.

17)  Lamkin, Donald M., et al. “α 2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression.“ Psychoneuroendocrinology 51 (2015): 262-270.

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Propranolol reduces Cancer risk

18) Chang, Ping-Ying, et al. “Propranolol reduces Cancer risk: a population-based cohort study.” Medicine 94.27 (2015).
β-Blockers have been reported to exhibit potential anticancer effects in cancer cell lines and animal models. However, clinical studies have yielded inconsistent results regarding cancer outcomes and cancer risk when β-blockers were used. This study investigated the association between propranolol and cancer risk.

Between January 1, 2000 and December 31, 2011, a patient cohort was extracted from the Longitudinal Health Insurance Database 2000, a subset of the Taiwan National Health Insurance Research Database. A propranolol cohort (propranolol usage >6 months) and nonpropranolol cohort were matched using a propensity score. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of cancer associated with propranolol treatment.

The study sample comprised 24,238 patients. After a 12-year follow-up period, the cumulative incidence for developing cancer was low in the propranolol cohort (HR: 0.75; 95% CI: 0.67–0.85; P < 0.001). Patients with propranolol treatment exhibited significantly lower risks of cancers in head and neck (HR: 0.58; 95% CI: 0.35–0.95), esophagus (HR: 0.35; 95% CI: 0.13–0.96), stomach (HR: 0.54; 95% CI: 0.30–0.98), colon (HR: 0.68; 95% CI: 0.49–0.93), and prostate cancers (HR: 0.52; 95% CI: 0.33–0.83). The protective effect of propranolol for head and neck, stomach, colon, and prostate cancers was most substantial when exposure duration exceeded 1000 days.

This study supports the proposition that propranolol can reduce the risk of head and neck, esophagus, stomach, colon, and prostate cancers. Further prospective study is necessary to confirm these

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Diet – Nicholas Gonzalez / Kelly

19) Pancreatic Cancer, Proteolytic Enzyme Therapy and Detoxification
Excerpted with permission from the November 1999 Clinical Pearls News
Gonzalez NJ: Pancreatic cancer, proteolytic enzyme therapy and detoxification [excerpts].

20) Cancer and Enzyme Therapy, Dr. Kelley’s Enzyme Therapy
Dr. Nicholas Gonzalez’s Enzyme Therapy
So, whatever other effect a vegetarian diet has, in terms of autonomic nervous system function, such a diet will reduce sympathetic activity and stimulate the parasympathetic system.
A meat diet is loaded with minerals such as phosphorous and zinc, which tend to have the opposite effect. A high-meat diet stimulates the sympathetic system and tones down parasympathetic activity. Furthermore, such a diet is loaded with sulfates and phosphates that in the body are quickly converted into free acid that in turn stimulates the sympathetic nervous system while suppressing parasympathetic activity.

21) The Sympathetic and Parasympathetic Nervous Systems
Chapter 15 / Lesson 6 Transcript
Gonzalez NJ, Isaacs LL: Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 33 (2): 117-24, 1999. [PUBMED Abstract]

22) Gonzalez N: Dr. Nicholas Gonzalez on nutritional cancer therapy: a Moneychanger interview. The Moneychanger July 1995.

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PATENT

23) http://www.google.ch/patents/WO2009151569A2?cl=en
Beta adrenergic receptor agonists for the treatment of b-cell proliferative disorders
WO 2009151569 A2
Zusammenfassung

24) https://www.ncbi.nlm.nih.gov/pubmed/21141740
Oncol Res. 2010;19(1):45-54.
Beta-adrenergic receptors in cancer: therapeutic implications.
Pérez-Sayáns M1, Somoza-Martín JM, Barros-Angueira F, Diz PG, Gándara Rey JM, García-García A.
The beta-adrenergic receptors transduce catecholamine signals to the G protein, which through a cascade of chemical reactions in cells generates highly specific parallel signals. The beta2-adrenergic receptor (ADRB2) is the most involved in the carcinogenic processes. Previous studies have determined the relationship of ADRB2 with various aspects related to cancer. Basically, it seems to be related with cell proliferation and apoptosis, chemotaxis, development of metastasis and tumor growth, and angiogenesis. The purpose of this review is to update the implications of these receptors in the pathogenesis of cancer and study the possible application of agonist drugs and/or antagonists in antitumor therapy.

25) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294063/
Cole, Steven W., and Anil K. Sood. “Molecular pathways: beta-adrenergic signaling in cancer.” Clinical cancer research 18.5 (2012): 1201-1206.
β-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor-mediated activation of PKA and EPAC signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression and now suggest a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and pre-clinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology.

Weddle, D. L., et al. “β-Adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas.” Carcinogenesis 22.3 (2001): 473-479.

pdf
Eng, Jason W-L., et al. “A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response.” Cancer Immunology, Immunotherapy 63.11 (2014): 1115-1128.

pdf
Powe, D. G., et al. “Alpha-and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study.” Breast cancer research and treatment 130.2 (2011): 457-463.

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