• lipid signalling
• receptor pharmacology

• STAT3 Transcription Factor/metabolism
• STAT3 Transcription Factor/genetics
• Psoriasis/pathology
• Psoriasis/metabolism
• Psoriasis/genetics
• Animals
• Keratinocytes/metabolism
• Keratinocytes/pathology
• Humans
• Sphingosine-1-Phosphate Receptors/metabolism
• Mice
• Cell Proliferation
• Feedback, Physiological
• Signal Transduction
• Phosphorylation
• Mice, Inbred C57BL
• Mice, Knockout

• 82070912 National Natural Science Foundation of China (National Science Foundation of China)
• 82370899 National Natural Science Foundation of China (National Science Foundation of China)
• 81773326 National Natural Science Foundation of China (National Science Foundation of China)
• BE2019676 Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)

• Adrenergic receptor
• Beta-blocker
• Cancer neuroscience
• Chronic stress
• Drug repurposing
• Tumor macroenvironment
• Tumor microenvironment

• Humans
• Drug Repositioning
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Signal Transduction/drug effects
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Receptors, Adrenergic/metabolism
• Tumor Microenvironment/drug effects
• Sympathetic Nervous System/drug effects
• Adrenergic Antagonists/pharmacology
• Adrenergic Antagonists/therapeutic use

• cancer neuroscience
• cancer therapy
• neuroimmune crosstalk
• peripheral nervous system
• tumor microenvironment
• tumor‒nerve interactions

• National Natural Science Foundation of China

• CP: Cancer
• ERK pathway
• KRAS mutation
• RAF inhibitors
• cell-line-specific mechanistic model
• drug combinations
• pancreatic ductal adenocarcinoma
• synergy
• targeted therapy resistance

• Humans
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/metabolism
• Cell Line, Tumor
• MAP Kinase Signaling System/drug effects
• Protein Kinase Inhibitors/pharmacology
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/pathology
• Carcinoma, Pancreatic Ductal/metabolism
• Drug Synergism
• Proto-Oncogene Proteins p21(ras)/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• raf Kinases/metabolism
• raf Kinases/antagonists & inhibitors

• R01 CA244660 NCI NIH HHS
• R01 HL171773 NHLBI NIH HHS
• R33 HL088283 NHLBI NIH HHS

• cancer invasion
• neuroscience
• paracrine mode
• perineural invasion
• tumor microenvironment

• ovarian cancer
• fallopian tube
• norepinephrine
• metastasis
• metabolomics
• imaging mass spectrometry

• R01 CA240423 NCI NIH HHS
• National Institutes of Health
• Laura Crandall Brown Foundation

• Adrenergic
• Alpha-agonists
• Antitumor immunity
• Beta-blockers
• Chronic stress
• Immunotherapy

• Humans
• Neoplasms/pathology
• Neoplasms/metabolism
• Signal Transduction
• Receptors, Adrenergic/metabolism
• Animals
• Stress, Psychological/metabolism
• Tumor Microenvironment
• Chronic Disease

• biosensor
• focal adhesions
• phosphorylation
• protein kinase A (PKA)
• signal transduction

• Animals
• Humans
• Cell Adhesion
• Cell Movement
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Cytoskeleton/metabolism
• Focal Adhesions/enzymology
• Phosphorylation
• Tensins/metabolism
• Mice
• Rats
• Cell Line
• Signal Transduction/genetics

• R01 GM137611 NIGMS NIH HHS
• R35 GM131821 NIGMS NIH HHS
• R01 GM117490 NIGMS NIH HHS
• P30 ES020957 NIEHS NIH HHS
• P30 CA022453 NCI NIH HHS
• S10 OD030484 NIH HHS

• Ewing sarcoma
• cancer
• hypoxia
• neuroblastoma
• prematurity
• retinopathy
• β3-adrenoceptor

• Adult
• Child
• Humans
• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White/metabolism
• Lipolysis
• Receptors, Adrenergic, beta-3/metabolism
• Neoplasms/drug therapy

• Adrenergic receptors
• Adrenoceptors
• Compartmentalised signalling
• G proteins
• Intracellular receptors
• Signalling

• Humans
• Animals
• Receptors, Adrenergic/metabolism
• Receptors, Adrenergic/physiology
• Signal Transduction
• Cyclic AMP/metabolism

• cancer
• hormones
• pathogenesis
• pathophysiology
• stress

• Animals
• Humans
• Neoplasms/etiology
• Cell Death
• Cell Proliferation
• Homeostasis
• Immunosuppression Therapy
• Tumor Microenvironment

• NADH
• aldehyde dehydrogenase
• carvedilol
• lung cancer
• repurposing
• β-agonists
• β-blockers

• MPH/1/55/2019 Scientific Research Support Fund of the Ministry of Higher Education & Scientific Research, Jordan

• biomarkers
• cancer outcomes
• diet
• mental health
• physical exercise
• prostate cancer
• stress reduction

• adverse events
• disease modeling
• drug discovery
• functional genomics
• innovation
• network analysis
• polypharmacology
• systems pharmacology

• adrenergic beta-antagonists
• cardiovascular diseases
• drug repositioning
• pancreatic neoplasms
• pharmacoepidemiogy

• Cancer treatment
• Chronic stress
• Tumor development
• Tumor microenvironment

• COVID-19
• SARS-CoV-2
• disease modelling
• evidence-based medicine
• hypothesis generation
• molecular mechanisms

• Atherosclerosis
• Cancer patient risk stratification
• Cardiac assessments in cancer patients
• Cardio-oncology
• Shared risk factors

• SARS-CoV-2
• disease modeling
• evidence-based medicine
• molecular mechanisms
• translational research

• autocrine/paracrine interactions
• hallmarks of cancer
• signal transduction
• tumor–nervous system molecular crosstalk

• SPARC
• fallopian tube
• imaging mass spectrometry (IMS)
• ovarian cancer
• proteomics
• tumor micro environment

• Cancer
• Neuroimmune axis
• Parasympathetic nervous system
• Sympathetic nervous system
• Tumor microenvironment

Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body’s immune response, causing tumor cells to escape the “surveillance” of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.

• HPA axis
• adrenergic receptor
• cancer
• central nervous system
• glucocorticoid receptor
• neuropeptide Y receptor
• stress
• sympathetic nervous system

Chronic stress has been reported to stimulate the release of catecholamines, including norepinephrine (NE) and epinephrine (E), which promote cancer progression by activating the adrenergic receptor (AR). Although previous studies showed that β2-AR mediated chronic stress-induced tumor growth and metastasis, the underlying mechanism has not been fully explored. In this study, we aimed to investigate the molecular mechanism by which β2-AR exerts a pro-metastatic function in hepatocarcinoma (HCC) cells and breast cancer (BC) cells. Our results showed that Hep3B human HCC cells and MDA-MB-231 human BC cells exhibited the highest ADRB2 expression among diverse HCC and BC cell lines. NE, E, and isoprenaline (ISO), adrenergic agonists commonly increased the migration and invasion of Hep3B cells and MDA-MB-231 cells. The phosphorylation level of Src was significantly increased by E/NE. Dasatinib, a Src kinase inhibitor, blocked E/NE-induced migration and invasion, indicating that AR agonists enhanced the mobility of cancer cells by activating Src. ADRB2 knockdown attenuated E/NE-induced Src phosphorylation, as well as the metastatic ability of cancer cells, suggesting the essential role of β2-AR. Taken together, our results demonstrate that chronic stress-released catecholamines promoted the migration and invasion of HCC cells and BC cells via β2-AR-mediated Src activation.

• Adrenergic Agonists
• Catecholamines
• Cell Line, Tumor
• Dasatinib
• Epinephrine/pharmacology
• Humans
• Isoproterenol/pharmacology
• Neoplastic Processes
• Norepinephrine/metabolism
• Norepinephrine/pharmacology
• Receptors, Adrenergic, beta-2/genetics
• Signal Transduction
• src-Family Kinases/genetics
• src-Family Kinases/metabolism

• Antiviral Agents
• Humans
• Inflammation
• Neoplasms/therapy
• Ribonucleoproteins
• Ubiquitin-Protein Ligases/metabolism

• National Natural Science Foundation of China

The nervous system communicates with the whole organism, regulating several physiological pathways. The modification of nerve activity could deregulate the state of cellular and tissue homeostasis which could drive cancer development. This paper provides the current state of knowledge, in an evidence-oriented manner, that the nervous system is able to participate in the carcinogenesis process by inducing biochemical, physiological, and cellular modifications involved in the hallmarks of cancer.

The involvement of the nervous system in the development of cancer is controversial. Several authors have shown opinions and conflicting evidence that support the early effect of the nervous system on the carcinogenic process. For about a century, research has not been enough, questions remain open, ideas are not discarded, and although more research is still needed to answer all the questions, there is now enough evidence to support the theories and give hope of finding one more possible form of treatment. It is clear that malignant neoplasms have endogenous characteristics that allow them to establish and progress. Some of these characteristics known as hallmarks of cancer, are damage mechanisms in the pathology but necessary during other physiological processes which show some nerve dependence. The nervous system communicates with the whole organism, regulating physiological processes necessary to respond to external stimuli and for the maintenance of homeostasis. The modification of nerve activity could generate an overload and deregulate the state of cellular and tissue homeostasis; this could drive cancer development. In this review, we will address the issue in an evidence-oriented manner that supports that the nervous system is able to participate in the initial and progressive process of carcinogenesis by inducing biochemical, physiological, and cellular modifications involved in the hallmarks of cancer.

• Epinephrine
• Glucocorticoids
• Norepinephrine
• Tumor formation
• Tumor inhibition
• Tumor progression

• Carcinogenesis
• Humans
• Hypothalamo-Hypophyseal System
• Pituitary-Adrenal System
• Stress, Psychological/complications
• Sympathetic Nervous System

• 82073280 National Natural Science Foundation of China
• LG-QS-202205-09 Seeking Outstanding Youth Program
• 2018ZX09201017-006 National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology

• Rho GTPases
• cell migration
• compartmentalization
• ion channels
• leading edge
• protein kinase A
• subcellular signaling
• tyrosine kinases

• R01 GM117490 NIGMS NIH HHS
• R01 GM137611 NIGMS NIH HHS
• National Institutes of Health

• Intravascular survival
• Lifestyle
• Metastasis
• Pre-metastatic niche
• Targeted therapy

• ADRB2
• Beta-2 adrenergic receptor
• Breast cancer
• HER2
• Trastuzumab

Promising drug development efforts may frequently fail due to unintended adverse reactions. Several methods have been developed to analyze such data, aiming to improve pharmacovigilance and drug safety. In this work, we provide a brief review of key directions to quantitatively analyzing adverse events and explore the potential of augmenting these methods using additional molecular data descriptors. We argue that molecular expansion of adverse event data may provide a path to improving the insights gained through more traditional pharmacovigilance approaches. Examples include the ability to assess statistical relevance with respect to underlying biomolecular mechanisms, the ability to generate plausible causative hypotheses and/or confirmation where possible, the ability to computationally study potential clinical trial designs and/or results, as well as the further provision of advanced features incorporated in innovative methods, such as machine learning. In summary, molecular data expansion provides an elegant way to extend mechanistic modeling, systems pharmacology, and patient‐centered approaches for the assessment of drug safety. We anticipate that such advances in real‐world data informatics and outcome analytics will help to better inform public health, via the improved ability to prospectively understand and predict various types of drug‐induced molecular perturbations and adverse events.

• Adverse Drug Reaction Reporting Systems
• Drug-Related Side Effects and Adverse Reactions
• Humans
• Machine Learning
• Marketing
• Pharmacovigilance

A high intratumoral nerve density is correlated with poor survival, high metastasis, and high recurrence across multiple solid tumor types. Recent research has revealed that cancer cells release diverse neurotrophic factors and exosomes to promote tumor innervation, in addition, infiltrating nerves can also mediate multiple tumor biological processes via exosomes and neurotransmitters. In this review, through seminal studies establishing tumor innervation, we discuss the communication between peripheral nerves and tumor cells in the tumor microenvironment (TME), and revealed the nerve-tumor regulation mechanisms on oncogenic process, angiogenesis, lymphangiogenesis, and immunity. Finally, we discussed the promising directions of ‘old drugs newly used’ to target TME communication and clarified a new line to prevent tumor malignant capacity.

• autonomic nervous system
• endometrial cancer
• nerve plasticity
• nerve-cancer
• neuroreceptor
• neurotherapy
• neurotransmitter
• sex hormones signaling

Studies published in the last two decades have clearly demonstrated that the nervous system plays a significant role in carcinogenesis, the progression of cancer, and the development of metastases. These studies, combining oncological and neuroscientific approaches, created the basis for the emergence of a new field in oncology research, the so‐called “neurobiology of cancer.” The concept of the neurobiology of cancer is based on several facts: (a) psychosocial factors influence the incidence and progression of cancer diseases; (b) the nervous system affects DNA mutations and oncogene‐related signaling; (c) the nervous system modulates tumor‐related immune responses; (d) tumor tissues are innervated; (e) neurotransmitters released from nerves innervating tumor tissues affect tumor growth and metastasis; (f) alterations or modulation of nervous system activity affects the incidence and progression of cancers; (g) tumor tissue affects the nervous system. The aim of this review is to characterize the pillars that create the basis of cancer neurobiology, to describe recent research advances of the nervous system's role in cancer diseases, and to depict potential clinical implications for oncology.

• adrenergic signaling
• epinephrine
• hypothalamic-pituitary-adrenocortical axis
• innervation
• neurobiology of cancer
• norepinephrine
• propranolol
• psychoneuroimmunology
• stress
• sympathoadrenal system
• β-blockers

• adrenergic receptors
• catecholamines
• exercise
• stress

• Adrenergic nerve circuitry
• Adrenergic nerve signaling
• Adrenergic neuron
• Autonomic nervous system
• Cancer neuroscience
• Central nervous system
• Hypothalamo-pituitary-adrenal axis
• Sympathetic nervous system
• Sympathoadrenal system
• Tumor axonogenesis
• Tumor microenvironment
• Tumor neurogenesis

• GABAAR
• lung metastasis
• propofol
• tumor

• Anesthetics, Intravenous/pharmacology
• Animals
• Disease Models, Animal
• Female
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/secondary
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Propofol/pharmacology
• Receptors, GABA-A/drug effects
• Receptors, GABA-A/genetics
• Receptors, GABA-A/metabolism
• Ribonucleoproteins/drug effects
• Ribonucleoproteins/genetics
• Ribonucleoproteins/metabolism

• 81720108012 National Natural Science Foundation of China
• 81571034 (Yuan Shen) National Natural Science Foundation of China
• 81801067 (Qidong Liu) National Natural Science Foundation of China
• 2018M630472 China Postdoctoral Science Foundation
• 2019T120356 (Qidong Liu) China Postdoctoral Science Foundation
• National Natural Science Foundation of China
• China Postdoctoral Science Foundation

Lung cancer ranks as a leading cause of death. Although targeted therapies usually trigger profound initial patient responses, these effects are transient due to drug resistance and severe side effects. Xihuang Pill (XHW) is a popular Chinese medicine formula that might benefit cancer patients when used as a complementary therapy. However, its underlying mechanism when combined with anticancer drugs is not clearly understood. Here, we used an integrated strategy to reveal the regulatory properties of XHW in increasing the antitumor activity of anlotinib in lung cancer. We evaluated the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung carcinoma (LLC). We applied untargeted metabolomics to identify the differences metabolism and found that XHW improved the effects of anlotinib on lung cancer. The components and targets related to the effects of XHW treatment on lung cancer were obtained through network pharmacology. Then, by integrating the biologically active components of XHW and anlotinib as well as the treatment-responsive metabolites and their related targets, an interaction network was constructed to evaluate the combination therapy. Finally, important protein candidates for this response were verified by immunohistochemistry of tumor tissues. The results showed that XHW significantly improved the inhibitory effect of anlotinib on tumor growth in LLC-bearing mice. Additionally, 12 differentially-abundant metabolites were identified by untargeted metabolomics in the XHW/anlotinib group compared with the XHW or anlotinib groups, and they were mainly enriched in fatty acid metabolism, lipid metabolism and amino acid metabolism pathways. Anlotinib, 23 components in Shexiang, 2 components in Niuhuang, 30 components in Ruxiang and 60 components in Moyao work together to act on 30 targets to regulate hexadecanoic acid (also named palmitic acid), linoleic acid, lactosylceramide, adrenaline, arachidonic acid and lysoPC(18:1(9Z)). The results of immunohistochemistry showed that XHW combined with anlotinib reduced the expression of PDGFRA in tumors. Overall, the key metabolites of XHW that enhances the efficacy of anlotinib were regulated by a multicomponent and multitarget interaction network. Our results suggested that anlotinib combined with XHW may be a promising strategy for the treatment of lung cancer.

• Xihuang pill
• anlotinib
• integrated strategy
• lung cancer
• network pharmacology
• untargeted metabolomics

In the past decade, several discoveries have documented the existence of innervation in ovarian cancer and cervical cancer. Notably, various neurotransmitters released by the activation of the sympathetic nervous system can promote the proliferation and metastasis of tumor cells and regulate immune cells in the tumor microenvironment. Therefore, a better understanding of the mechanisms involving neurotransmitters in the occurrence and development of gynecological cancers will be beneficial for exploring the feasibility of using inexpensive β-blockers and dopamine agonists in the clinical treatment of gynecological cancers. Additionally, this article provides some new insights into targeting tumor innervation and neurotransmitters in the tumor microenvironment.

• dopamine
• epinephrine
• glucocorticoids
• neurotrophic factors
• noradrenaline
• perineural invasion
• tumor immune microenvironment

• IL-6
• adverse childhood experiences
• cancer progression
• mTOR
• melanoma
• stress-related disorders

Previous experimental studies have indicated that exposure to beta blocker provides protective effects against ovarian cancer (OC). However, findings from epidemiologic studies have still been controversial. Therefore, we carried out a meta-analysis to update and quantify the correlation between post-diagnostic beta blocker usage and OC prognosis.

The meta-analysis had been registered at PROSPEPO. The number of registration is CRD42020188806. A comprehensive search of available literatures in English prior to April 16, 2020, was conducted in PubMed, EMBASE, and the Web of Science databases. Random-effects models were used to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Publication bias assessments, and subgroup, sensitivity, and meta-regression analyses were also performed.

Of the 637 initially identified articles, 11 retrospective cohort studies with 20,274 OC patients were included. The summary HRs did not reveal any statistically significant associations between post-diagnostic beta blocker use and OC prognosis characteristics, such as total mortality (HR = 1.08, 95% CI = 0.92–1.27, I² = 76.5%, n = 9), cancer-specific mortality (HR = 1.22, 95% CI = 0.89–1.67, I² = 88.1%, n=3), and progression-free survival (HR = 0.88, 95% CI = 0.75–1.05, I² = 0, n = 4). No evidence of publication bias was observed in current analysis. In our subgroup analyses, the majority of results were consistent with the main findings. However, several positive correlations were detected in studies with ≥800 cases (HR = 1.20, 95% CI = 1.05–1.37), no immortal time bias (HR = 1.28, 95% CI = 1.10–1.49), and adjustment for comorbidity (HR = 1.20, 95% CI = 1.05–1.37). In the meta-regression analysis, no evidence of heterogeneity was detected in the subgroups according to study characteristics and confounding factors.

Post-diagnostic beta blocker use has no statistical correlation with OC prognosis. More prospective cohort studies are necessary to further verify our results.

Identifier (CRD42020188806).

• beta blocker
• meta-analysis
• ovarian cancer
• post-diagnostic
• survival
• systematic review

• dopamine
• gastrointestinal inflammation
• liver fibrosis
• neurotransmitters
• serotonin