Nerves are integral to the adenoid cystic carcinoma (ACC) microenvironment. The strong association of ACC with perineural invasion (PNI) is considered a hallmark of this disease. In human salivary ACC, we identify intratumoral, small-caliber, disorganized sympathetic nerves not observed in other salivary neoplasms. Norepinephrine or sympathetic ganglia explants enhance ACC proliferation in vitro. Two novel orthotopic ACC patient-derived xenograft (PDX) models recapitulate ACC morphology and demonstrate sympathetic innervation. Pharmacologic or surgical blockade of sympathetic nerves decreases ACC PDX growth. Bulk RNA sequencing of salivary ACC reveals correlations between noradrenergic nerve development signatures and worse patient survival. Metastatic ACC foci exhibit lower nerve signature gene expression levels than primary ACC. Sympathetic innervation in ACC is distinct from PNI and reflects tumor axonogenesis driven by noradrenergic neural development programs. These programs support ACC progression, are associated with poor prognosis, and may be inhibited as a therapeutic strategy.

Receptor-mediated targeted drug delivery has emerged as a pivotal strategy in cancer therapy, offering precision and specificity in combating malignant diseases while minimizing systemic toxicity. This review explores the multifaceted role of receptors in cancer biology, emphasizing their contributions to cancer progression, metastasis, and their potential as therapeutic targets. Ligand-based targeting approaches highlight the utility of small molecules, peptides, and antibodies, as well as the development of novel targeting ligands. A critical focus is placed on engineering receptor-targeted nanoparticles and advanced drug delivery systems. Innovations in dual-targeting strategies and the targeted delivery to the tumour microenvironment (TME) and metastatic niches are discussed, underscoring their potential to enhance therapeutic efficacy. Additionally, receptor-targeted imaging is reviewed for its dual role in diagnosis and real-time treatment monitoring. To address the challenges of side effects and off-target toxicity, strategies that minimize these risks while targeting overexpressed receptors in solid tumours are explored. Finally, the review outlines future directions in receptor-targeted cancer therapy, emphasizing the need for interdisciplinary research to refine these strategies further. This comprehensive analysis aims to provide a roadmap for advancing receptor-based therapeutic approaches, ultimately improving outcomes for cancer patients.

The pathological role and mechanism of psychological stress in cancer progression are little known. Here we show in a mouse model that psychological stress drives pancreatic ductal adenocarcinoma (PDAC) progression by stimulating tumour nerve innervation. We demonstrate that nociception and other stressors activate sympathetic nerves to release noradrenaline, downregulating RNA demethylase alkB homologue 5 (Alkbh5) in tumour cells. Alkbh5 deficiency in these cancer cells causes aberrant N6-methyladenosine (m6A) modification of RNAs, which are packed into extracellular vesicles and delivered to nerves in the tumour microenvironment, enhancing hyperinnervation and PDAC progression. ALKBH5 levels are inversely correlated with tumour innervation and survival time in patients with PDAC. Animal experiments identify a natural flavonoid, fisetin, that prevents neurons from taking in extracellular vesicles containing m6A-modified RNAs, thus suppressing the excessive innervation and progression of PDAC tumours. Our study sheds light on a molecular mechanism by which crosstalk between the neuroendocrine system and cancer cells links psychological stress and cancer progression and raises a potential strategy for PDAC therapy.

Heart failure (HF) often coexists with cancer. Beyond the known cardiotoxicity of some cancer treatments, HF itself has been associated with increased cancer incidence. The 2 conditions share common risk factors, mechanisms, and interactions that can worsen patient outcomes. The bidirectional relationship between HF and cancer presents a complex interplay of factors that are not fully understood. Recent preclinical evidence suggests that HF may promote tumor growth via the release of protumorigenic factors from the injured heart, revealing HF as a potentially protumorigenic condition. Our review discusses the biological crosstalk between HF and cancer, emphasizing the impact of HF on tumor growth, with inflammation, and modulating the immune system as central mechanisms. We further explore the clinical implications of this connection and propose future research directions. Understanding the mechanistic overlap and interactions between HF and cancer could lead to new biomarkers and therapies, addressing the growing prevalence of both conditions and enhancing approaches to diagnosis, prevention, and treatment.

A tumor's ability to attract innervation is a critical factor in tumor progression and immune escape, with the sympathetic nervous system playing a major role. Catecholamines released by sympathetic nerves activate adrenergic receptors on tumor cells, enhancing growth and resistance to therapies, while activation of adrenergic receptors on immune cells triggers immunosuppressive activity in the tumor microenvironment. Nerve growth factor (NGF) produced by tumor cells is a key driver of tumor innervation, making it a promising target for novel therapeutic strategies. In this commentary, we highlight a recent study by Yang et al, which examines NGF single-chain variable fragment (scFv)-secreting chimeric antigen receptor(CAR) T cells and the impact of NGF neutralization by CAR T cells on CAR T-cell function and the remodeling of the tumor microenvironment. This work shows that we may be able to exploit a tumor-derived survival factor as a vulnerability and a means to enhance antitumor immune activity.

Though a correlation exists between carcinogenesis and epinephrine signaling, the ability of epinephrine in regulating epidermal growth factor (EGF) actions remains largely unknown and necessitates investigation in cervical cancer (CC) cells. The present study aims to understand the role of epinephrine, a stress-induced cytokine on EGF actions in human papilloma virus (HPV)-positive SiHa, ME180 and HPV-negative C33A cells. De-identified database and molecular docking were used to identify the relationship between beta-adrenergic receptor 2 (ADRB2) and EGF receptor (EGFR). Cell viability, mitochondrial labeling, reactive oxygen species (ROS) production, evaluation of ADRB2 and superoxide dismutase-2 (SOD-2) mRNA abundance, SOD-1/2 enzymatic activities, migration assay, gelatin zymography and protein expression analysis of epithelial-mesenchymal transition (EMT) markers were performed to validate the regulatory role of epinephrine and EGF. A significant up-regulation of ADRB2 in HPV-16-positive individuals and binding between epinephrine and EGFR is noted computationally. A reduced survival in high ADRB2 along with the significant reduction in CC survival in Asian population is also observed. Epinephrine augmented the phosphorylation of EGFR and EGF-induced cell viability, ROS production and DNA synthesis. A positive correlation between SOD-2 and ADRB2 was corroborated with the increased ADRB2 and SOD-2 mRNA transcripts. An increase in MMP-2 activity and EMT markers by EGF and epinephrine potentiated the CC cells toward enhanced migration. This study also opens up several new avenues and warrants substantial in vivo studies to support this contention for the inclusion of beta-blockers as adjuvant for EGFR-driven cancers.

Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP).

Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses.

The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells.

These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.

Efforts to deconvolve the complex interactions of cancer cells with other components of the tumor micro- and macro-environment have exposed a common tendency for cancers to subvert systems physiology and exploit endogenous programs involved in homeostatic control of metabolism, immunity, regeneration, and repair. Many such programs are engaged in the healing response to surgery which, together with other abrupt biochemical changes in the perioperative period, provide an opportunity for the macroevolution of residual disease. This review relates contemporary perspectives of cancer as a systemic disease with the overlapping biology of host responses to surgery and events within the perioperative period. With a particular focus on examples of cancer cell plasticity and changes within the host, we explore how perioperative inflammation and acute metabolic, neuroendocrine, and immune dyshomeostasis might contribute to cancer evolution within this contextually short, yet crucially influential timeframe, and highlight potential therapeutic opportunities within to further optimize surgical cancer care and its long-term oncological outcomes.

β2-adrenergic receptor (β2-AR) and cyclooxygenase-2 (COX-2) are overexpressed in various malignant tumours including oral squamous cell carcinoma (OSCC), suggesting that they may contribute to the development of OSCC. This study aims to investigate the potential synergistic effect of β2-AR blockade and COX-2 inhibition on suppressing the development of OSCC.

Effects of blocking β2-AR and inhibiting COX-2 on migration and invasion of OSCC cells were detected by wound-healing assay and transwell invasion assay. Western blot and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of genes related to the progression of OSCC. In vivo, OSCC xenograft models were established to evaluate the effect of combined treatment on survival time, tumour size, and submandibular lymph node metastasis. Immunohistochemistry, Western blot, and ELISA were used to detect the expression of invasion and metastasis relative genes.

In vitro, blocking β2-AR or inhibiting COX-2 alone could suppress invasion and metastasis of OSCC cells, and suppression with combined treatment was more significant. Expression of genes related to invasion and metastasis, including EGFR, TGF-β1, IL-1β, MMP2, and VEGFA, were downregulated significantly, especially in the combined treatment group. In vivo, the combined treatment could significantly prolong survival time in tumour-bearing mice and inhibit the growth of tumours. Furthermore, submandibular lymph node metastasis was less in the combined treatment group, and expression of the abovementioned genes was also downregulated.

The combination of β2-AR blockade and COX-2 inhibition can significantly suppress the development of OSCC via downregulating EGFR, TGF-β1, IL-1β, MMP2, and VEGFA. Findings suggest that the combined use of a β2-AR blocker and a COX-2 inhibitor could be a promising adjuvant therapy in OSCC. Both drugs are commonly prescribed, and their safety and efficacy are well established. Their use in adjuvants in OSCC should therefore be promoted in clinical practice.

This study examined whether sick leave due to severe stress (stress leave) and duration of leave are associated with future cancer risk.

We conducted a matched case-control study using complete-population data from Swedish national registers (2005 to 2018), including 516,678 primary cancer cases and 2,357,433 matched controls. Odds ratios (OR) were calculated by conditional logistic regression and adjusted for pre-specified confounders.

Stress leave of any duration, reported to the Swedish Social Insurance Register, was associated with a slightly increased cancer risk, with the highest risk estimate for 1-30 versus 0 days (adjusted OR 1.05, 95% CI 1.02-1.09). In men, a clear exposure-response trend was present. We observed increased risks of prostate cancer (adjusted OR for > 90 days: 1.10, 95% CI 1.01-1.20) and cervical cancer (adjusted OR for > 90 days: 1.11, 95% CI 1.05-1.17, including cancer in situ). In etiology-based analyses, a positive association was found for smoking-related cancers, and the risk relationship for non-cervical HPV-related cancers was similar to that for cervical cancer. Risk estimates were above one for several types of stress in relation to overall cancer risk, including an exposure-response trend for acute stress reactions (p-trend 4.0 × 10-4) but a null association for post-traumatic stress disorder.

Stress leave was associated with a modestly higher risk of cancer overall and prostate and cervical cancers specifically. Regardless of whether the link is biological or reflective of lifestyle mediators or for cervical cancer, lower participation in screening, these findings suggest a potential relevance of severe stress for cancer prevention.

The association of mortality with resting heart rate (RHR) and predicted risk of incident cardiovascular disease (CVD) has not been comprehensively elucidated.

The purpose of this study was to evaluate the individual and combined impacts of RHR and predicted CVD risk on mortality among Chinese adults.

A total of 108,257 Chinese adults underwent follow-up during 1992 to 2015. The Cox proportional hazards model was used to assess the hazard ratio (HR) and 95% confidence interval (CI) of mortality associated with RHR and the predicted risk of incident CVD.

During an average of 8.53 years of follow-up, we identified 6267 nonaccidental deaths, including 2324 CVD deaths. High-RHR participants had higher HRs of nonaccidental (HR 1.58; 95% CI 1.47-1.70), CVD (HR 1.71; 95% CI 1.53-1.92), and non-CVD mortality (HR 1.50; 95% CI 1.37-1.64) than low-RHR participants. Compared to individuals with low CVD risk, those with high CVD risk demonstrated HRs of 1.67 (95% CI 1.51-1.83) and 3.90 (95% CI 3.29-4.61) for nonaccidental and CVD mortality, respectively. Mortality risk gradually increased with elevation of CVD risk and RHR, showing the greatest HRs of nonaccidental (HR 2.57; 95% CI 2.24-2.94) and CVD mortality (HR 7.16; 95% CI 5.52-9.29) among participants with both high CVD risk and high RHR.

Our findings demonstrated that RHR and CVD risk are independently associated with mortality, and integrating them potentially could refine risk stratification of mortality. The study highlighted their important role in personalized strategies for primordial and primary prevention.

Hypertension (HTN) is prevalent in non-small cell lung cancer (NSCLC) patients, yet the cardioprotective and survival benefits of β-adrenergic blockers during radiotherapy (RT) remain underexplored. We analyzed data from a Chinese clinical cohort of 750 patients with stage IIIA to IIIB NSCLC and HTN receiving RT between 2014 and 2018. The findings were further validated using data from the NHANES database. In Chinese clinical cohort, β-adrenergic blockers were associated with improved OS (β-adrenergic blockers: median overall survival (mOS) 17.64 months, 95% CI, 15.95-19.33; no β-adrenergic blockers: mOS 13.16 months, 95% CI, 12.62-13.70; p < 0.0001) and PFS (β-adrenergic blockers: median progression-free survival (mPFS) 7.50 months, 95% CI, 6.50-8.50; without β-adrenergic blockers: mPFS 4.91 months, 95% CI, 4.53-5.31; p < 0.0001). Simultaneously, in the NHANES database, the utilization of β-adrenergic blockers exhibited no discernible impact on OS within the entire tumor population, as evidenced by the Kaplan-Meier curve, which revealed no statistically significant difference between the two groups (p = 0.254). β-adrenergic blockers may improve OS and PFS in patients with HTN and NSCLC undergoing RT. β-adrenergic blockers show potential and warrant further investigation in the context of RT.

immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC), significantly improving survival outcomes. However, a subset of patients do not respond to ICIs, prompting research into potential predictive factors. Commonly prescribed medications such as corticosteroids, proton-pump inhibitors (PPIs), antibiotics (Abs), antihypertensives, and analgesics may influence ICI effectiveness.

we conducted a literature search on PubMed to investigate the impact of concomitant medications on the outcomes of patients with mUC, treated with ICIs. We selected the most relevant studies and performed a narrative review.

corticosteroids, PPIs and Abs have been associated with reduced survival in ICI-treated patients, including those with mUC. In contrast, antihypertensive agents like renin-angiotensin system inhibitors and beta-blockers may enhance ICI efficacy, though evidence remains inconclusive. The impact of other medications, such as statins, metformin, and analgesics, on ICI outcomes is less clear, with some data suggesting a detrimental impact on immune response.

this narrative review synthesizes current evidence on how concomitant medications affect outcomes in mUC patients treated with ICIs.

Ewing sarcoma (ES) is a highly aggressive soft tissue tumor that primarily affects the long bones of children and young adults. It is distinguished by a characteristic chromosomal translocation between the Ewing sarcoma breakpoint region 1 (EWS) gene and the erythroblast transformation-specific (ETS) family of genes, most commonly resulting in the EWS-friend leukemia integration 1 (EWS-FLI1) fusion gene. This translocation is observed in approximately 80%-85% of ES cases. This fusion gene encodes a non-physiological chimeric fusion protein that plays a central role in tumorigenesis by interacting with numerous partner proteins. Several studies have demonstrated the tumorigenic potential of the EWS-FLI1 protein when transfected into non-cancer cell lines. However, targeting EWS-FLI1 directly remains a significant challenge, as no drug to date has been reported to bind to and inhibit its activity effectively. An alternative therapeutic strategy involves targeting key overexpressed protein complexes implicated in ES tumorigenesis, many of which may be downstream interacting partners of EWS-FLI1. This review explores emerging protein targets as potential therapeutic avenues in ES treatment.

Sympathetic nerves innervate bone marrow and various immune organs, where norepinephrine-the primary sympathetic neurotransmitter-directly interacts with immune cells that express adrenergic receptors. This article reviewed the key molecular pathways triggered by sympathetic activation and explored how sympathetic activity influences immune cell migration. Norepinephrine serves as a chemoattractant for monocytes, macrophages, and stem cells, promoting the migration of myeloid cells while inhibiting the migration of lymphocytes at physiological concentrations. We also examined the role of immune cell infiltration in cardiovascular diseases and cancer. Evidence suggests that sympathetic activation increases myeloid cell infiltration into target tissues across various cardiovascular diseases, including atherosclerosis, hypertension, cardiac fibrosis, cardiac hypertrophy, arrhythmia, myocardial infarction, heart failure, and stroke. Conversely, inhibiting sympathetic activity may serve as a potential therapeutic strategy to treat these conditions by reducing macrophage infiltration. Furthermore, sympathetic activation promotes macrophage accumulation in cancer tissues, mirroring its effects in cardiovascular diseases, while suppressing T lymphocyte infiltration into cancerous sites. These changes contribute to increased cancer growth and metastasis. Thus, inhibiting sympathetic activation could help to protect against cancer by enhancing T cell infiltration and reducing macrophage presence in tumors.

The β2-adrenergic receptor (β2-AR) is a therapeutic target for circulatory agonists and exhibits oncogenic activity in several cancers. However, its role in advanced colorectal cancer (CRC) treated using chemotherapy remains unclear. We investigated the potential of β2-AR as a novel chemosensitivity marker and therapeutic target in inoperable CRC.

β2-AR expression was evaluated immunohistochemically in 80 advanced or recurrent CRC cases for which untreated resected specimens were available before systemic chemotherapy implementation. We assessed the relationship among β2-AR protein expression, clinicopathological factors, therapeutic response, and prognosis. Furthermore, we evaluated the significance of β2-AR as an in vitro and in vivo therapeutic target using CRC cell lines and a CRC xenograft model treated with the β-blocker, propranolol, and other anticancer agents.

High tumoral β2-AR expression was associated with shorter progression-free survival and chemotherapeutic resistance in patients treated with oxaliplatin-based regimens and bevacizumab-based regimens. We found no synergistic effect between propranolol and oxaliplatin. However, combined administration of propranolol and bevacizumab induced significant tumor shrinkage in the CRC xenograft model.

β2-AR is a possible biomarker for chemosensitivity and prognosis in advanced CRC. Repositioning existing β-blockers could be beneficial for treating CRC resistant to existing treatment regimens.

Prostate cancer is a leading cause of cancer death in men, and the development of effective treatments is of great importance. This study explored to identify the candidate drugs for prostate cancer by transcriptomic data and CMap database analysis. After integrating the results of omics analysis, bisoprolol is confirmed as a promising drug. Moreover, cell experiment reveals its potential inhibitory effect on the proliferation of prostate cancer cells. Importantly, machine learning methods are employed to predict the targets of bisoprolol, and the dual-target ADRB3 and hERG are explored by dynamic simulation. The findings of this study demonstrate the potential of bisoprolol as a multi-target drug for prostate cancer treatment and the feasibility of using beta-adrenergic receptor inhibitors in prostate cancer treatment. In addition, the proposed research approach is promising for discovering potential drugs for cancer treatment by leveraging the concept of drug side effects leading to anticancer effects. Further research is necessary to investigate the pharmacological action, potential toxicity, and underlying mechanisms of bisoprolol in treating prostate cancer with ADRB3.Communicated by Ramaswamy H. Sarma.

Background/Objectives: The experience of prenatal stress results in various physiological disorders due to an alteration of an offspring's methylome and transcriptome. The objective of this study was to determine whether PNS affects DNA methylation (DNAm) and gene expression in the stress axis tissues of mature Brahman cows. Methods: Samples were collected from the paraventricular nucleus (PVN), anterior pituitary (PIT), and adrenal cortex (AC) of 5-year-old Brahman cows that were prenatally exposed to either transportation stress (PNS, n = 6) or were not transported (Control, n = 8). The isolated DNA and RNA samples were, respectively, used for methylation and RNA-Seq analyses. A gene ontology and KEGG pathway enrichment analysis of each data set within each sample tissue was conducted with the DAVID Functional Annotation Tool. Results: The DNAm analysis revealed 3, 64, and 99 hypomethylated and 2, 93, and 90 hypermethylated CpG sites (FDR < 0.15) within the PVN, PIT, and AC, respectively. The RNA-Seq analysis revealed 6, 25, and 5 differentially expressed genes (FDR < 0.15) in the PVN, PIT, and AC, respectively, that were up-regulated in the PNS group relative to the Control group, as well as 24 genes in the PIT that were down-regulated. Based on the enrichment analysis, several developmental and cellular processes, such as maintenance of the actin cytoskeleton, cell motility, signal transduction, neurodevelopment, and synaptic function, were potentially modulated. Conclusions: The methylome and transcriptome were altered in the stress axis tissues of mature cows that had been exposed to prenatal transportation stress. These findings are relevant to understanding how prenatal experiences may affect postnatal neurological functions.

The mechanisms through which chronic stressors may be associated with tumor biologic characteristics, immune response, and health disparities remain insufficiently understood.

To investigate the proteomic, transcriptomic, and genomic effects associated with multilevel chronic stressors (perceived stress, perceived inadequate social support, perceived racial and ethnic discrimination, and neighborhood deprivation) in Black and White women with breast cancer.

This cross-sectional study was conducted from February 28, 2012, to September 5, 2023, in which blood samples, breast tumors, and adjacent noncancerous tissues were collected from women with breast cancer. Participants, recruited at 2 Baltimore, Maryland, hospitals, completed demographic and psychosocial questionnaires. Data analysis was conducted from September 2023 to April 2024.

Perceived stress, perceived social support, perceived racial and ethnic discrimination, and the 2010 census tract-level neighborhood deprivation index, in which scores range from -2.51 to 6.77, with higher scores indicating greater deprivation.

The main outcomes included levels of 92 circulating immune-oncologic markers and associated biologic pathways, tumor immune cell profiles, breast tissue gene expression, and tumor mutational burden. Data were analyzed using covariate-adjusted linear regression modeling for continuous outcomes with effect estimates presented as β values with 95% CIs.

The study included 121 women with breast cancer (mean [SD] age, 56.27 [12.62] years), of whom 56 (46.3%) were Black, and 65 (53.7%) were White. The analytic subsample sizes included 117 blood samples, 48 breast tumors, and 41 adjacent noncancerous tissues. Levels of perceived stress and social support were comparable by race, while Black women resided in more socioeconomically deprived neighborhoods (mean [SD] neighborhood deprivation index, 2.28 [2.30] for Black women compared with -0.22 [2.01] for White women). Greater perceived social support was associated with more favorable immune-stimulatory changes (eg, increased serum IL-5 [β, 0.06 (95% CI, 0.02-0.10); P = .003] and activated natural killer cells in noncancerous breast tissue of Black women [β, 0.11 (95% CI, 0.04-0.17); P = .002). Higher levels of perceived stress, exposure to discrimination, and neighborhood deprivation were associated with systemic inflammation (eg, serum IL-6 with both perceived stress [β, 0.04 (95% CI, 0.01-0.07); P = .006] and discrimination [β, 0.69 (95% CI, 0.15-1.23); P = .01]); deleterious immune cell profiles (eg, tumor-associated M2 macrophages with discrimination [β, 0.82 (95% CI, 0.14-1.51); P = .02]); and aggressive tumor biologic characteristics. Race-stratified analyses uncovered distinct immunologic features in Black women associated with stressors, including chemotaxis with stress (β, 0.28 [95% CI, 0.001-0.56]; P = .049) and immune suppression with stress (β, 0.37 [95% CI, -0.002 to 0.75]; P = .05) at the systemic level and increased tumor-associated myeloid cells (monocytes and M1 and M2 macrophages) at the tissue level. Perceived stress was associated with elevated tumor mutational burden (β, 0.02 [95% CI, 0.01-0.04]; P = .04).

The findings of this cross-sectional study of Black and White women with breast cancer suggest that perceived stress, perceived inadequate social support, perceived racial and ethnic discrimination, and neighborhood deprivation were associated with deleterious alterations to the systemic and tumor immune environment, particularly for Black women. Understanding biology as a possible mediator of cancer health disparities may inform prevention and public health interventions.

Adolescents and young adults (AYAs) receiving hematopoietic cell transplantation (HCT) are at high risk for poor psychosocial outcomes. Heart rate variability (HRV), a surrogate for autonomic nervous system activity, is a promising digital biomarker that has been linked to important outcomes. The objectives of this study were to prospectively describe the trajectory of HRV among AYAs receiving HCT and explore the association between HRV and patient-reported outcomes (PROs).

This was a multi-site study embedded in a randomized trial among AYAs receiving HCT (NCT03640325). We collected sequential 24-h HRV metrics, including the standard deviation of normal-to-normal beats (SDNN), root-mean-square of successive differences (RMSSD), as well as frequency domain measures. PRO surveys queried anxiety, depression, quality of life, hope, and resilience at baseline and 3 months. We summarized outcomes using descriptive statistics, and Pearson correlation coefficients were used to examine the relationship between HRV and PROs.

Thirty-nine HRV recordings were collected from n = 16 participants aged 12-21 years. There was a moderately strong correlation between inferior baseline HRV and higher anxiety and depression (anxiety: r = -0.35 (p = 0.18) for SDNN, r = -0.47 (p = 0.07) for RMSSD; depression: r = -0.26 (p = 0.34) for SDNN, r = -0.39 (p = 0.14) for RMSSD). Among participants with elevated baseline anxiety, higher HRV suggested greater improvement in anxiety over time (r = -0.66 (p = 0.08) for SDNN, r = -0.31 (p = 0.45) for RMSSD).

There was a correlation between HRV and PROs in this study, and among those with elevated anxiety, HRV predicted improvement over time. Digital biomarkers may augment behavioral intervention design and implementation.

Background/Objectives: Tamoxifen (TAM) is an anti-breast cancer drug suffering from acquired resistance development, prompting cancer relapse. Propranolol (PRO)'s repurposing for cancer therapy has gained interest. This work aimed to investigate combined TAM/PRO therapy for potentiating the anti-breast cancer activity of TAM. The work probed bilosomes versus standard noisome for simultaneous oral and intratumor delivery of TAM and PRO. Methods: Bilosomes comprising Span60, cholesterol, and increasing concentrations of bile salts were prepared together with bile salts containing free standard niosomes. The vesicular size and morphology were characterized. The entrapment and release efficiencies of TAM and PRO from the tailored vesicles were determined. The in vivo investigations of anti-tumor activity of TAM with or without PRO employed the solid Ehrlich carcinoma model. Results: The vesicles of all fabricated dispersions were spherical and negatively charged, with a size ranging from 104 to 182 nm. The entrapment efficiency depended on the nature of the drug, recording values ranging from 87.5% to 97.8% for TAM and from 31.0% to 46.8% for PRO. Incorporation of bile salts into vesicles increased TAM and PRO release compared to standard niosomes. Oral administration of combined TAM/PRO bilosomes showed a significant reduction in tumor growth volume compared to that recorded following naked drug administration. Histopathological investigations reflected a significant decline in tumor giant cells and mitotic figures, implying the in vivo capability of the TAM/PRO combination to interfere with cancer cell proliferation and persistence. Conclusions: The overall results demonstrated the impact of repurposed PRO to enhance the anti-breast cancer activity of TAM when both were co-encapsulated into bilosomes.

Previous studies have demonstrated that norepinephrine (NE) released during chronic stress promotes breast cancer (BC) metastasis via adrenergic receptors (ARs). However, the effect of NE on tumor-associated macrophage polarization and the underlying mechanisms remain largely unknown. In this study, we aimed to investigate the influence of NE on M2 macrophage polarization, with a particular focus on the crosstalk between macrophages and BC cells. Our results demonstrated that, although NE alone did not directly induce the expression of M2 macrophage markers, conditioned medium from NE-treated MDA-MB-231 human BC cells (NE CM) significantly promoted M2 macrophage polarization in THP-1 macrophages. We found that NE stimulated IL-6 production in MDA-MB-231 cells via β2-AR/NF-κB pathway, which activated STAT3 in THP-1 cells to induce M2 macrophage polarization. NE failed to induce IL-6 production and NF-κB activation when ADRB2 was knocked down in MDA-MB-231 cells. Furthermore, ADRB2 knockdown in cancer cells suppressed NE CM-induced M2 macrophage polarization, as well as M2 macrophage-induced cancer cell migration. Taken together, our results suggest that NE stimulates M2 macrophage polarization by inducing IL-6 secretion from BC cells through a β2-AR-dependent mechanism, which subsequently promotes cancer cell migration. Targeting β2-AR may represent a promising strategy to prevent chronic stress-induced BC metastasis.

Cardiovascular diseases and cancer represent the largest disease burden worldwide. Previously, these two conditions were considered independent, except in terms of cardiotoxicity, which links cancer treatment to subsequent cardiovascular issues. However, recent studies suggest that there are further connections between cancer and heart disease beyond cardiotoxicity. It has been revealed that myocardial dysfunction may promote carcinogenesis, indicating that additional common pathophysiological mechanisms might be involved in the relationship between cardiology and oncology, rather than simply a connection through cardiotoxic effects. These mechanisms may include shared risk factors and common molecular pathways, such as persistent inflammation and neurohormonal activation. This review explores the connection between myocardial dysfunction and cancer, emphasizing their shared risk factors, similar biological mechanisms, and causative factors like cardiotoxicity, along with their clinical implications.

Cancer neuroscience, as an emerging converging discipline, provides us with new perspectives on the interactions between the nervous system and cancer progression. As the sympathetic nervous system, in particular adrenergic signaling, plays an important role in the regulation of tumor activity at every hierarchical level of life, from the tumor cell to the tumor microenvironment, and to the tumor macroenvironment, it is highly desirable to dissect its effects. Considering the far-reaching implications of drug repurposing for antitumor drug development, such a large number of adrenergic receptor antagonists on the market has great potential as one of the means of antitumor therapy, either as primary or adjuvant therapy. Therefore, this review aims to summarize the impact of adrenergic signaling on cancer development and to assess the status and prospects of intervening in adrenergic signaling as a therapeutic tool against tumors.

Overactivation of the stress response can influence cancer outcomes through immune-related pathways. Adolescents and young adults (AYAs) undergoing hematopoietic cell transplantation (HCT) are at risk for poor outcomes, yet there are limited behavioral interventions and no psychosocial biomarker data for this population. The Conserved Transcriptional Response to Adversity (CTRA) is an inflammation-related pattern observed in conditions of heightened stress and is associated with HCT outcomes. The objective of the current study was to explore the CTRA gene regulatory impact of Promoting Resilience in Stress Management (PRISM) intervention among AYAs receiving HCT. We hypothesized that patients who received the intervention would have favorable gene expression signatures compared to those in the control arm. This was an ancillary study within a randomized trial testing the PRISM intervention on psychosocial outcomes among AYAs aged 12 to 24 years receiving HCT (NCT03640325). CTRA was quantified through genome-wide transcriptional profiles obtained from whole blood collected at baseline, 1-, and 3-month post-HCT. Group differences in CTRA gene expression were estimated using mixed-effect linear models. There were no baseline group differences in CTRA expression, but PRISM participants showed a greater decline in CTRA at 1 month compared to controls (β -0.301 ± SE 0.114, P = .016), even when controlling for demographic (Group × Time interaction: F(2, 18) = 7.41, P = .004; β -0.386 ± 0.127, P = .007) and clinical covariates (Group × Time interaction: F(2, 20) = 7.03, P = .005; β -0.480 ± 0.144, P = .003). These differences were not detectable at 3 months (β -0.147 ± SE 0.120, P = .235). There was a change in stress-related gene expression among AYAs randomized to a psychosocial intervention. The stress-inflammation axis may be a targetable pathway in the AYA HCT population.

The discovery and characterization of the signal cascades of the β-adrenergic receptors have made it possible to effectively target the receptors for drug development. β-Adrenergic receptors are a class A rhodopsin type of G protein-coupled receptors (GPCRs) that are stimulated mainly by catecholamines and therefore mediate diverse effects of the parasympathetic nervous system in eliciting "fight or flight" type responses. They are detectable in several human tissues where they control a plethora of physiological processes and therefore contribute to the pathogenesis of several disease conditions. Given the relevance of the β-adrenergic receptor as a molecular target for many pathological conditions, this comprehensive review aims at providing an in-depth exploration of the recent advancements in β3-adrenergic receptor research. More importantly, we delve into the prospects of the β3-adrenergic receptor as a therapeutic target across a variety of clinical domains.

Stress responses can impact bladder cancer (BC) outcomes via immune-inflammatory pathway modulation. This study explores heart rate variability (HRV) associations with serum immune-inflammatory biomarkers, blood count inflammatory markers, and psychosocial self-report measures in patients versus healthy controls. The TREM-1 and TREM-2 expressions on peripheral blood monocytes were analysed via flow cytometry; serum inflammatory biomarkers by ELISA; HRV (5-min ECG) pre-tumour resection; blood counts by haematology analyser; and psychosocial factors by validated questionnaires. Patients exhibited altered immune-inflammatory profiles with increased TREM-1/TREM-2, sTREM-1, sTREM-1/sTREM-2 ratio, BDNF, MCP-1, and NLR, and reduced IFN-γ, IL-10, LMR, and PMR. HRV analysis indicated sympathetic dominance (SNS, Stress indices, ACmod) and reduced parasympathetic modulation (PNS index, SDNN, RMSSD, 2UV%, DCmod, SD1). Sympathetic HRV indices correlated positively with sTREM-1, sTREM-1/sTREM-2 ratio, fractalkine, and inflammatory markers (SII, NLR, PLR) and negatively with parasympathetic HRV indices-correlations absent in controls. Only in patients, reduced physical function and social support, and higher anxiety, depression, and fatigue, associated positively with sympathetic HRV indices and inflammatory markers. This study links immune-inflammatory markers, HRV parameters, and psychosocial factors in BC, suggesting that immune and autonomic variations may relate to unfavourable outcomes. Incorporating these assessments could help tailor more personalised treatment strategies for BC patients.

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune-mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)-KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL-KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)-dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep-deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women, with psychosocial stress commonly cited by patients as one of its causes. While there is conflicting epidemiological evidence investigating the association between psychosocial stress and breast cancer incidence and progression, there is reason to believe that interventions aimed at reducing stress pharmacologically or psychologically may improve breast cancer outcomes. The aim of this review is to discuss the molecular and biological mechanisms of stress-attributed breast cancer incidence and progression, including the induction of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as well as decreased immune function and stress hormone-induced resistance to chemotherapy. Moreover, these mechanisms have been cited as potential therapeutic targets of pharmacologic and psychological interventions that may improve the care, well-being and survival of breast cancer patients. Further research is recommended to investigate whether interventions in the primary care setting for women with risk factors for breast cancer development may lead to a decreased incidence of invasive breast tumors.

Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines.

A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay.

The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells).

The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.

PRKACA alterations have clear diagnostic and biological roles in the fibrolamellar variant of hepatocellular carcinoma and a potential predictive role in that cancer type. However, the roles of PRKACA have not been comprehensively examined in gastric and colorectal cancers (GC and CRC). This study, therefore, sought to investigate the roles of PRKACA expression in GC and CRC.

The clinico-genomic data of 441 GC and 629 CRC cases were analyzed for therapeutic, clinicopathological, and biological correlates using appropriate bioinformatics and statistical tools. Furthermore, the deregulation of PRKACA expression in GC and CRC was investigated using correlative and regression analyses.

The results showed that PRKACA expression subsets were enriched for gene targets of chemotherapeutics, tyrosine kinase, and β-adrenergic inhibitors. Moreover, high PRKACA expression was associated with adverse clinicopathological and genomic features of GC and CRC. Gene Ontology Enrichment Analysis also showed that PRKACA-high subsets of the GI cancers were enriched for the biological and molecular functions that are associated with cell motility, invasion, and metastasis but not cell proliferation. Finally, multiple regression analyses identified multiple methylation loci, transcription factors, miRNA species, and PRKACA copy number changes that deregulated PRKACA expression in GC and CRC.

This study has identified potential predictive and clinicopathological roles for PRKACA expression in GI cancers and has added to the growing body of knowledge on the deregulation of PRKACA in cancer.

Recently, cancer neuroscience has become the focus for scientists. Interactions between the nervous system and cancer (both systemic and local) can regulate tumorigenesis, progression, treatment resistance, compromise of anti-cancer immunity, and provocation of tumor-promoting inflammation. We assessed the related research on cancer neuroscience through bibliometric analysis and explored the research status and hotspots from 2020 to 2024.

Publications on cancer neuroscience retrieved from the Web of Science Core Collection. CiteSpace, VOSviewer, and Scimago Graphica were used to analyze and visualize the result.

A total of 744 publications were retrieved, with an upward trend in the overall number of articles published over the last 5 years. As it has the highest number of publications (n = 242) and citations (average 13.63 citations per article), the United States holds an absolute voice in the field of cancer neuroscience. The most productive organizations and journals were Shanghai Jiaotong University (n = 24) and Cancers (n = 45), respectively. Monje M (H-index = 53), Hondermarck H (H-index = 42), and Amit M (H-index = 39) were the three researchers who have contributed most to the field. From a global perspective, research hotspots in cancer neuroscience comprise nerve/neuron-tumor cell interactions, crosstalk between the nervous system and other components of the tumor microenvironment (such as immune cells), as well as the impact of tumors and tumor therapies on nervous system function.

The United States and European countries are dominating the field of cancer neuroscience, while developing countries such as China are growing rapidly but with limited impact. The next focal point in this field is likely to be neurotrophic factors. Cancer neuroscience is still in its infancy, which means that many of the interactions and mechanisms between the nervous system and cancer are not yet fully understood. Further investigation is necessary to probe the interactions of the nervous system with cancer cell subpopulations and other components of the tumor microenvironment.

Chronic stress-induced epinephrine (EPI) accelerates breast cancer progression and metastasis, but the molecular mechanisms remain unclear. Herein, we found a strong positive correlation between circulating EPI levels and the tumoral expression of ubiquitin-specific peptidase 22 (USP22) in patients with breast cancer. USP22 facilitated EPI-induced breast cancer progression and metastasis by enhancing adipose triglyceride lipase (ATGL)-mediated lipolysis. Targeted USP22 deletion decreased ATGL expression and lipolysis, subsequently inhibiting EPI-mediated breast cancer lung metastasis. USP22 acts as a bona fide deubiquitinase for the Atgl gene transcription factor FOXO1, and EPI architects a lipolysis signaling pathway to stabilize USP22 through AKT-mediated phosphorylation. Notably, USP22 phosphorylation levels are positively associated with EPI and with downstream pathways involving both FOXO1 and ATGL in breast cancers. Pharmacological USP22 inhibition synergized with β-blockers in treating preclinical xenograft breast cancer models. This study reveals a molecular pathway behind EPI's tumor-promoting effects and provides a strong rationale for combining USP22 inhibition with β-blockers to treat aggressive breast cancer.

Olive oil consumption has been reportedly associated with lower mortality rates, mostly from cardiovascular diseases, but its potential impact on cancer death remains controversial. Moreover, biological mechanisms possibly linking olive oil consumption to mortality outcomes remain unexplored.

We longitudinally analysed data on 22,892 men and women from the Moli-sani Study in Italy (follow-up 13.1 y), to examine the association of olive oil consumption with mortality. Dietary data were collected at baseline (2005-2010) through a 188-item FFQ, and olive oil consumption was standardised to a 10 g tablespoon (tbsp) size. Diet quality was assessed through a Mediterranean diet score. Multivariable-adjusted Cox proportional hazard models, also including diet quality, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The potential mediating role of inflammatory, metabolic, cardiovascular and renal biomarkers on the association between olive oil intake and mortality was evaluated on the basis of change-in-estimate and associated p values.

Multivariable HRs for all-cause, cancer, cardiovascular and other cause mortality associated with high (>3 tbsp/d) versus low (≤1.5 tbsp/d) olive oil consumption were 0.80 (0.69-0.94), 0.77 (0.59-0.99), 0.75 (0.58-0.97) and 0.97 (0.73-1.29), respectively. Taken together, the investigated biomarkers attenuated the association of olive oil consumption with all-cause and cancer mortality by 21.2% and 13.7%, respectively.

Higher olive oil consumption was associated with lower cancer, cardiovascular and all-cause mortality rates, independent of overall diet quality. Known risk factors for chronic diseases only in part mediated such associations suggesting that other biological pathways are potentially involved in this relationship.

Beta blockers (BBs) are commonly used cardiovascular medications, and their association with breast cancer outcomes has been examined in several previous observational studies and meta-analyses. In this study, an updated meta-analysis was undertaken to ascertain the association between BBs and both breast cancer death (BCD) and breast cancer recurrence (BCR).

Articles were sourced from various databases up until the 14th of August 2023. Effect estimates were pooled using the random effects model, and the Higgins I2 statistic was computed to ascertain heterogeneity. Subgroup analyses were conducted by the potential for immortal time bias (ITB), the exposure period (prediagnosis vs postdiagnosis), and type of BB (selective vs non-selective). Publication bias was assessed using funnel plots and Egger's regression tests.

Twenty-four studies were included. Pooled results showed that there was no statistically significant association between BB use and both BCD (19 studies, hazard ratio = 0.90, 95% CI 0.78-1.04) and BCR (16 studies, HR = 0.87, 95% CI 0.71-1.08). After removing studies with ITB, the associations were attenuated towards the null. There was no effect modification for either outcome when stratifying by the exposure period or type of BB. There was clear evidence of publication bias for both outcomes.

In this meta-analysis, we found no evidence of an association between BB use and both BCD and BCR. Removing studies with ITB attenuated the associations towards the null, but there was no effect modification by the exposure period or type of BB.

Olanzapine (OLZ) reverses chronic stress-induced anxiety. Chronic stress promotes cancer development via abnormal neuro-endocrine activation. However, how intervention of brain-body interaction reverses chronic stress-induced tumorigenesis remains elusive.

KrasLSL-G12D/WT lung cancer model and LLC1 syngeneic tumor model were used to study the effect of OLZ on cancer stemness and anxiety-like behaviors. Cancer stemness was evaluated by qPCR, western-blotting, immunohistology staining and flow-cytometry analysis of stemness markers, and cancer stem-like function was assessed by serial dilution tumorigenesis in mice and extreme limiting dilution analysis in primary tumor cells. Anxiety-like behaviors in mice were detected by elevated plus maze and open field test. Depression-like behaviors in mice were detected by tail suspension test. Anxiety and depression states in human were assessed by Hospital Anxiety and Depression Scale (HADS). Chemo-sensitivity of lung cancer was assessed by in vivo syngeneic tumor model and in vitro CCK-8 assay in lung cancer cell lines.

In this study, we found that OLZ reversed chronic stress-enhanced lung tumorigenesis in both KrasLSL-G12D/WT lung cancer model and LLC1 syngeneic tumor model. OLZ relieved anxiety and depression-like behaviors by suppressing neuro-activity in the mPFC and reducing norepinephrine (NE) releasing under chronic stress. NE activated ADRB2-cAMP-PKA-CREB pathway to promote CLOCK transcription, leading to cancer stem-like traits. As such, CLOCK-deficiency or OLZ reverses NE/chronic stress-induced gemcitabine (GEM) resistance in lung cancer. Of note, tumoral CLOCK expression is positively associated with stress status, serum NE level and poor prognosis in lung cancer patients.

We identify a new mechanism by which OLZ ameliorates chronic stress-enhanced tumorigenesis and chemoresistance. OLZ suppresses mPFC-NE-CLOCK axis to reverse chronic stress-induced anxiety-like behaviors and lung cancer stemness. Decreased NE-releasing prevents activation of ADRB2-cAMP-PKA-CREB pathway to inhibit CLOCK transcription, thus reversing lung cancer stem-like traits and chemoresistance under chronic stress.