Topical application of local anesthetics to melanoma increases the efficacy of anti-PD-1 therapy.

Experimental and clinical data have shown that the nervous system can significantly stimulate the initiation and progression of melanoma. In support of this, approaches that reduce the transmission of signals from peripheral nerves to effector tissues reduce the recurrence of melanoma. Therefore, we investigated the effect of topical application of the local anesthetic Pliaglis (7% lidocaine and 7% tetracaine) on the growth of melanoma induced by intradermal application of B16F0 cells in mice without treatment and in mice treated with the anti-PD-1 antibody. We found that application of Pliaglis to melanoma significantly reduced its growth and this effect was even pronounced in mice treated with the anti-PD-1 antibody. To determine the mechanisms and pathways responsible for the observed effect, the in vitro effect of incubating melanoma cells with lidocaine and/or tetracaine and the in vivo gene expression of cancer and immune-related factors, percentage of immune cells, gene expression of selected neurotransmitter receptors and nerve growth factors in melanoma tissue were studied. We found that lidocaine and tetracaine significantly reduced the viability of B16F0 cells in vitro. In mice with melanoma, Pliaglis potentiated the effect of anti-PD-1 antibody on gene expression of COX-2, IL-1ß, IL-6, CCL11, F4/80, CD206, and NCR1. In addition, Pliaglis increased the gene expression of α9nACHR and 5-HT2a receptors and decreased the gene expression of nerve growth factor receptor (p75NTR) and p53. We also observed Pliaglis-mediated changes in myeloid populations. Topical application of this local anesthetic cream decreased the CD11b+Gr1- population and increased the CD11b+Gr1high population. Our data suggest that Pliaglis reduces melanoma growth through a direct effect on melanoma cells as well as through modulation of the immune response. The involvement of nervous system-related signaling in the inhibitory effect of Pliaglis on melanoma is inconclusive from our data.

Gene-Directed Enzyme/Prodrug Therapy of Rat Brain Tumor Mediated by Human Mesenchymal Stem Cell Suicide Gene Extracellular Vesicles In Vitro and In Vivo.

MSC-driven, gene-directed enzyme prodrug therapy (GDEPT) mediated by extracellular vesicles (EV) represents a new paradigm-cell-free GDEPT tumor therapy. In this study, we tested the efficacy of yeast cytosine deaminase::uracilphosphoribosyl transferase (yCD::UPRT-MSC)-exosomes, in the form of conditioned medium (CM) to inhibit the growth of C6 glioblastoma cells both in vitro and in vivo. MSCs isolated from human adipose tissue, umbilical cord, or dental pulp engineered to express the yCD::UPRT gene secreted yCD::UPRT-MSC-exosomes that in the presence of the prodrug 5-fluorocytosine (5-FC), inhibited the growth of rat C6 glioblastoma cells and human primary glioblastoma cells in vitro in a dose-dependent manner. CM from these cells injected repeatedly either intraperitoneally (i.p.) or subcutaneously (s.c.), applied intranasally (i.n.), or infused continuously by an ALZET osmotic pump, inhibited the growth of cerebral C6 glioblastomas in rats. A significant number of rats were cured when CM containing yCD::UPRT-MSC-exosomes conjugated with 5-FC was repeatedly injected i.p. or applied i.n. Cured rats were subsequently resistant to challenges with higher doses of C6 cells. Our data have shown that cell-free GDEPT tumor therapy mediated by the yCD::UPRT-MSC suicide gene EVs for high-grade glioblastomas represents a safer and more practical approach that is worthy of further investigation.

Chronic propranolol treatment moderately attenuated development of N-methyl-N-nitrosourea-induced mammary carcinoma in female rats.

The sympathetic nervous system participates in the development and progression of several cancer types and this effect is mediated mainly via ß-adrenergic signaling. However, the potential of ß-adrenergic signaling blockade to prevent cancer development after exposure to carcinogens has not been investigated, yet. Therefore, in our study, we determined the effect of the ß-blocker propranolol on the development and progression of mammary cancer induced in female rats by administration of the chemical carcinogen N-methyl-N-nitrosourea (MNU). The propranolol treatment (20 mg/kg body weight) started 12 days after MNU administration and lasted 10 weeks. We found that both saline and propranolol treatment significantly increased gene expression of the catecholamine-synthesizing enzyme tyrosine hydroxylase, indicating that repeated injection of saline or propranolol-induced stress in these two groups. However, compared to the vehicle-treated group, propranolol slightly delayed the development and moderately reduced the incidence of mammary carcinoma in animals. To evaluate the mechanisms mediating the effect of propranolol on the development of MNU-induced cancer, we investigated several parameters of the tumor microenvironment and found that propranolol increased gene expression of Casp3. Our data indicate that propranolol treatment that starts after exposure to carcinogens might represent a new, useful approach for preventing the development of cancer, especially in stressed individuals. However, the potential efficiency of propranolol treatment for preventing cancer development and progression in individuals exposed to carcinogens needs further investigation.

Stress and cancer. Part II: Therapeutic implications for oncology.

Accumulated evidence has confirmed the ability of stress to promote the induction and progression of cancer (for review see Stress and cancer. Part I: Mechanisms mediating the effect of stressors on cancer). In support of this, data from clinical trials utilizing approaches that reduce stress-related signaling have shown prolonged survival of cancer patients. Therefore, the question has arisen as to how we can utilize this knowledge in the daily treatment of cancer patients. The main aim of this review is to critically analyze data from studies utilizing psychotherapy or treatment by ß-blockers on the survival of cancer patients. Because these approaches, especially treatment by ß-blockers, have been routinely used in clinical practice for decades in the treatment of non-cancer patients, their wider introduction into oncology might be realized in the near future.

Stress and cancer. Part I: Mechanisms mediating the effect of stressors on cancer.

Observations indicating a link between psychosocial stress and cancer can be traced back almost 2 millennia. However, the pathways and mechanisms interconnecting them has only been elucidated in more detail since the end of the 20th century. Importantly, recently accumulated evidences have confirmed the ability of stress to promote the induction and progression of cancer. The main aim of this review is to describe the pathways and mechanisms mediating the stimulatory effects of the neuroendocrine stress response on the induction of cancer, potentiation of cancer growth, and the development of metastases.

Increased cancer incidence in "cold" countries: An (un)sympathetic connection?

Published data has shown that there is an unexpected, significantly increased cancer mortality and incidence in countries with low or subnormal environmental temperatures. There have been several hypotheses developed to elucidate the mechanisms behind these findings. It is well documented that cold represents a very efficient stressor that activates sympathetic nerves and increases tissue and plasma norepinephrine levels. Importantly, recently accumulated data indicate that norepinephrine can stimulate carcinogenesis and the progression of cancer. Therefore, we suggest that the effect of a cold environment on cancer incidence and mortality might be mediated, at least partially, by norepinephrine released from sympathetic nerves in response to cold. Data supporting this hypothesis are discussed here and potential preventive approaches are described.

Increased cancer risk in polycystic ovary syndrome: An (un)sympathetic connection?

Women with polycystic ovary syndrome (PCOS) have been shown to have a higher incidence of cancer. It is suggested that several factors, including hyperinsulinemia, dyslipidemia, raised estrogen levels, chronic inflammation, and reduced apoptosis are responsible for this association. However, in this paper we propose the hypothesis that increased sympathetic activity may represent an important factor that interconnects PCOS and cancer. This hypothesis is based on two facts: a) in women with PCOS is found sympathetic hyperactivity and b) recent data showing a stimulatory effect of the sympathetic system on cancer initiation, progression, and development of metastases. If our hypothesis is correct, then new preventive approaches might be used to reduce cancer risk in women with PCOS.

E-Cigarettes and Cancer Risk.

From the time of their introduction, the popularity of e-cigarettes (electronic nicotine-delivery systems) has been rising. This trend may reflect the general belief that e-cigarettes are a less hazardous alternative to combustible cigarettes. However, the potential cancer-related effects of increased activation of the sympathoadrenal system induced by the inhalation of nicotine, the primary component of the e-cigarettes, are completely overlooked. Therefore, the aim of this review is to describe mechanisms that may connect the use of e-cigarettes and an increased risk for cancer development, as well as their stimulatory effect on cancer progression. Available preclinical data indicate that activation of the sympathetic nervous system by nicotine inhaled from e-cigarettes may stimulate cancer development and growth by several mechanisms. This issue might be especially important for oncological patients as they may have the misconception that compared with combustible cigarettes, e-cigarettes represent a risk-free alternative.

Ivabradine reduces baseline and stress-induced increase of heart rate and blood pressure and modulates neuroendocrine stress response in rats depending on stressor intensity.

Ivabradine, a selective inhibitor of the sinoatrial pacemaker, is used in clinical practice to reduce heart rate. However, its potential effect on the neuroendocrine stress response has not been investigated. Therefore, we determined the effect of administering ivabradine to rats on cardiovascular parameters and plasma levels of epinephrine, norepinephrine, and corticosterone. Ivabradine was administered intraperitoneally 30 min before exposing animals to either handling, restraint, or immobilization stress. Heart rate and blood pressure were monitored telemetrically. Blood samples were collected before, during, and after stressor exposure to determine the extent of the neuroendocrine stress response as reflected by plasma epinephrine, norepinephrine, and corticosterone levels. In animals pretreated with ivabradine, significantly lower values of heart rate and blood pressure were found during both the baseline period and during exposure to stressors, as well as during the rest period following stressor exposure. Ivabradine also significantly reduced handling-induced epinephrine and norepinephrine release into the bloodstream. However, ivabradine significantly potentiated restraint- and immobilization-induced increases of plasma epinephrine levels, whereas stress-induced changes in plasma norepinephrine and corticosterone levels were ambiguous. Our data shows that ivabradine significantly reduces blood pressure in rats during both baseline and stressful conditions, and also affects the neuroendocrine stress response. These findings show that viscerosensory signaling from the cardiovascular system may significantly modulate the neuroendocrine stress response.

Psychoneuroimmunology of Cancer - Recent Findings and Perspectives.

BACKGROUND: Gallen observed that psychosocial factors influence tumor incidence. Findings of the last decades have enabled us to understand the mechanisms and pathways responsible for this influence. Ader, Solomon, Besedovsky, and other pioneers of psychoneuroimmunology demonstrated that the nervous system can regulate the activity of immune cells. Based on their findings, the mechanisms via which psychosocial stressors potentiate tumor growth indirectly through inhibition of anti-tumor immune cells have been reported. Human tumor innervation, the presence of ß-adrenergic receptors on tumor cells, and the stimulating effect of noradrenaline on tumor growth and metastasis development have revealed that psychosocial stressors have a direct stimulatory effect on tumor growth, mainly via sympathetic nerves. In recent years, the possibility of modulating signal transduction between the nervous system, immune system, and tumor cells, with the intention of inhibiting tumor growth and metastasis, has been intensively investigated. PURPOSE: The aim of this review paper is to provide an overview of recent experimental and clinical findings from psychoneuroimmunological research, which reveal an increasingly complex link between stress and the onset and progression of tumor diseases and provide a basis for the introduction of new therapeutic approaches for the treatment of cancer patients. CONCLUSION: Some approaches tested in psychoneuroimmunological studies reported that they had inhibitory eff ects on cancer growth and used already clinically-approved drugs and psychological procedures, which may facilitate their application in oncology in the near future.