bims-netuvo 2025-11-02 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2025–11–02
nineteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

The nervous system in prostate cancer: A basic science and clinical perspective.
Reprogramming neural-tumor crosstalk: emerging therapeutic dimensions and targeting strategies.
The neuro-immune axis in cancer: from mechanisms to therapeutic opportunities.
Neurotransmitter Regulatory Networks: A New Perspective on Cancer Therapy.
Unveiling the Role of CCL3: A Driver of CIPN in Colon Cancer Patients?
Histopathological and Immunohistochemical Patterns of Malignant Peripheral Nerve Sheath Tumours in a Tertiary Institution of Northern Nigeria.
Heterogeneity of Tumor Glucose Metabolism in Schwannomas Between Trunk and Extremities: An Imaging Study.
Pan-cancer neural regulation pattern with implications for patient stratification and immunotherapy.
The role of the nervous system in the occurrence, development, and immune response of renal cell carcinoma.
An Orthotopic Sciatic Nerve Xenograft for Neurofibromatosis Type 1 Neurofibromas.
Unveiling the peripheral nerve hallmarks of chemotherapy-induced neuropathy: insights from paclitaxel treatment in a murine model.
Prognostic Impact of Concomitant Beta-Blocker Use on Survival in EGFR-Mutant Metastatic Non-Small Cell Lung Cancer Patients Treated with Erlotinib.
Perineural invasion as a prognostic factor and the efficacy of upfront surgery for low-risk cT2/T3N0M0 esophageal squamous cell carcinoma patients.
In Silico Multitarget Profiling of Non-Selective Beta-Blockers Highlights Their Potential as Key Agents in Breast Cancer Adjuvant Therapy via ADRB2, ERBB2, and NPYR Receptors.
Microencapsulated Quercetin and Bifidobacterium animalis Independently Preserve Jejunal Enteric Neurons During Colorectal Carcinogenesis.
Integration analysis of single-cell transcriptome reveals SPP1+ and TFF3+ macrophage subsets contributing to the brain metastasis from lung cancer.
Subtype- and Site-Specific Innervation of Melanocytic Nevi as Revealed by PGP 9.5 and CGRP Expression.
EXPRESS: Amino Acid Transporter SLC38A3 Mediates Bone Cancer Pain in Rats Via the PI3K/AKT/TRPV1 Signaling Pathway.
Optoacoustic imaging of the brain in a cachexia-inducing pancreatic cancer xenograft.

Semin Oncol. 2025 Oct 24. pii: S0093-7754(25)00117-4. [Epub ahead of print]53(1): 152425

The nervous system in prostate cancer: A basic science and clinical perspective.

Dawid Sigorski, Anna Kasprzyk-Pawelec, Maciej Michalak, Roman Sosnowski, Michał M Hryciuk, Aleksandra Sejda, Jacek Gulczyński, Joanna Kitlinska, Sergiusz Nawrocki, Ewa Iżycka-Świeszewska.

  Prostate cancer (PCa) constitutes an important health challenge worldwide. The nervous system, in a complex and multimodal manner, regulates prostate physiology and PCa development and affects the course of the disease. The phenomena of axonogenesis and neurogenesis, first described in PCa, were a breakthrough discovery that changed our understanding of cancer-nerve crosstalk. Different nerve types within the cancer stroma and tumor surroundings create complex interactions between the cancer microenvironment elements based on neurotransmission, affecting the hallmarks of cancer. The most common form of PCa and nerve interaction is the perineural invasion (PNI), which recently has been suggested as a driver of metastases. Additionally, many preclinical discoveries depict the molecular mechanisms of altered nerve activity, showing the pivotal role of sympathetic and parasympathetic signaling systems in localized and advanced PCa, axon-guidance molecules and neurotrophin. The neuroendocrine switch in advanced PCa is one of reasons of lethal, castration-resistant phase of the disease. Knowledge about the infiltration status of the periprostatic nerves present in radiological imaging is important for urologists in planning the treatment. Although some studies suggest that PNI and nerve density may be prognostic factors in PCa, it is necessary to evaluate these indicators better and apply them to practice. The neural-based therapeutic application in PCa is limited currently. Some studies showed that β blockers reduce PCa-specific mortality and neuroendocrine differentiation potential. This review provides a comprehensive, up-to date synthesis of PCa neurobiology, uniquely integrating both preclinial and clinical perspectives.

Keywords:  Axonogenesis; Cancer neuroscience; Nerve density; Nerve-sparing surgery; Neurogenesis; Perineural invasion; Prostate cancer

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152425
Mil Med Res. 2025 Oct 30. 12(1): 73

Reprogramming neural-tumor crosstalk: emerging therapeutic dimensions and targeting strategies.

Qian-Qian Liu, Zi-Kai Dong, Yong-Fei Wang, Wei-Lin Jin.

  Cancer neuroscience, an emerging convergent discipline, offers novel insights into the dynamic interplay between the nervous system and cancer progression. Bidirectional signaling between the nervous system and tumors, particularly within the innervated tumor microenvironment (TME), modulates key cancer hallmarks, including proliferation, immune evasion, angiogenesis, and metastasis. Neural ablation shows heterogeneous outcomes depending on nerve subtype and tumor context, underscoring the importance of nerve-type-specific and context-dependent therapeutic approaches. These mechanistic advances are catalyzing novel therapeutic strategies that target neural-TME interactions through the integration of neuroscience and oncology. Here, we highlight recent progress in cancer neuroscience and propose revised therapeutic frameworks aimed at the neuro-innervated TME. These strategies employ interdisciplinary approaches, such as drug repurposing [β-adrenergic receptor (β-AR) blockers, antipsychotics, antidepressants], and nanotechnology-enabled targeted delivery. Both preclinical and clinical data support the potential of neural-targeted therapies to improve precision, circumvent drug resistance, and enhance clinical outcomes. By bridging neuroscience and oncology, this framework delineates a translational pathway for harnessing neural-tumor crosstalk, presenting a promising avenue for advancing cancer therapeutics and improving patient care.

Keywords:  Bioelectricity; Cancer neuroscience; Drug repurposing; Neurotransmitters; Neurotrophic factors; Targeted therapy

DOI:  https://doi.org/10.1186/s40779-025-00661-9
J Hematol Oncol. 2025 Oct 28. 18(1): 93

The neuro-immune axis in cancer: from mechanisms to therapeutic opportunities.

Chunyu Zhang, Xiangdong Guo, Peikun Liu, Yanan Wang, Junbiao Zhang, Le Li, Kongming Wu, Jun Xiao, Qi Mei, Zhihua Wang.

  In recent years, neural mechanisms involved in tumor initiation, progression, and immune regulation have garnered growing attention, fueling the rapid advancement of the burgeoning interdisciplinary domain of neuro-oncology. As a central component of physiological homeostasis, the neurophysiological system also exerts significant influence on the development and dynamics of the tumor microenvironment via complex neuro-immune signaling. Studies have shown that neurotransmitters, neuropeptides, and their mediated signaling pathways can directly or indirectly affect the functional state of tumor-associated immune cells, notably B cells, T cells, macrophages, myeloid-derived suppressor cells, and dendritic cells, thereby contributing to tumor immune evasion. This review systematically summarizes recent advances in neuroimmune interactions within the tumor microenvironment, highlighting the therapeutic potential of neural targets such as β-adrenergic and acetylcholine receptors. It also evaluates the repurposing potential of existing neuroactive drugs in cancer immunotherapy and their future application prospects. Although research in this field is still in its early stages, a deeper understanding of neuro-immune interaction mechanisms is expected to provide new ideas and theoretical foundations for innovative cancer treatment strategies.

Keywords:  Cancer neuroscience; Immune evasion; Neuro-immune interaction; Tumor immune microenvironment; Tumor immunotherapy

DOI:  https://doi.org/10.1186/s13045-025-01748-5
Biomolecules. 2025 Oct 09. pii: 1429. [Epub ahead of print]15(10):

Neurotransmitter Regulatory Networks: A New Perspective on Cancer Therapy.

Xiaoyu Zhang, Jiaxin Cao, Yishu Zhang, Chuanxiong Li, Yuhong Jing.

  In recent years, the scientific community has increasingly delved into the study of the interaction between the nervous system and tumors, revealing that the nervous system not only regulates bodily functions under physiological conditions, but also assumes a vital part in the emergence and progression of tumors. Research has demonstrated that the extensive neural network directly regulates tumor progression and can influence tumors by modulating the tumor microenvironment and immune system. Moreover, tumors induce neural networks to provide favorable conditions for their proliferation and metastasis. In the above process, neurotransmitters play a vital role. They directly act or bind to their receptor, activating various classical signaling pathways, among which are PI3K/AKT, MEK/ERK, and WNT/β-catenin, to facilitate tumor advancement. Therefore, this study systematically reviews the regulatory mechanisms of neurotransmitters and their receptors in the advancement of cancer, along with the utilization of targeted drugs. At the same time, we also analyzed that targeting specific receptor subtypes may produce more significant therapeutic effects in different types of cancer. Additionally, this research further explores the limitations of neurotransmitter-based drugs currently used in clinical cancer treatment. In summary, the field of cancer neuroscience is rapidly advancing, constantly revealing the regulatory effects of neurotransmitters on tumor progression and their specific molecular mechanisms, providing broad application prospects for future clinical therapy.

Keywords:  PI3K/AKT pathway; cancer neuroscience; neural signaling; neurotransmitters; receptor; targeted therapy

DOI:  https://doi.org/10.3390/biom15101429
Biomedicines. 2025 Oct 15. pii: 2512. [Epub ahead of print]13(10):

Unveiling the Role of CCL3: A Driver of CIPN in Colon Cancer Patients?

Irene Luzac, Cynthia Rosa Regalado, Mihály Balogh.

  Cancer neuroscience is an emerging field revealing how malignancies interact with the nervous system to shape disease progression and symptom burden. In colorectal cancer (CRC), increasing evidence suggests a direct interplay between tumor cells and peripheral sensory neurons, contributing not only to cancer progression but also to chemotherapy-induced side effects such as peripheral neuropathy. Chemokines, particularly CCL3, appear to be key players in this bidirectional communication. This literature review aims to critically examine the role of CCL3 in CRC and chemotherapy-induced peripheral neuropathy (CIPN), with a focus on identifying potential mechanistic overlaps. Specifically, we evaluate whether CCL3 may serve as a molecular link between cancer progression and the development of neuropathic pain. In CRC, CCL3 is frequently upregulated, promoting tumor proliferation, invasion, and immune remodeling through CCR5- and MAPK-dependent pathways. Elevated CCL3 expression correlates with advanced stage, nerve infiltration, and worse prognosis, while select studies suggest it may also enhance antitumor immunity via dendritic cell recruitment. In parallel, CCL3 is also upregulated in the nervous system during CIPN, where it contributes to chronic pain through activation of glial cells, sensitization of nociceptive pathways (e.g., TRPV1, P2X7), and desensitization of opioid receptors. Notably, MAPK signaling is a shared downstream pathway in both contexts, suggesting a potential mechanistic bridge between tumor biology and neurotoxicity. In conclusion, CCL3 emerges as a central molecule at the intersection of CRC and CIPN. Understanding its context-dependent roles may offer new opportunities for risk prediction, biomarker development, and therapeutic intervention-contributing to the broader goals of cancer neuroscience in improving both oncologic and neurologic outcomes.

Keywords:  CCL3; CIPN; cancer neuroscience; chemotherapy-induced neuropathic pain; colon cancer

DOI:  https://doi.org/10.3390/biomedicines13102512
Niger Med J. 2025 May-Jun;66(3):66(3): 1135-1158

Histopathological and Immunohistochemical Patterns of Malignant Peripheral Nerve Sheath Tumours in a Tertiary Institution of Northern Nigeria.

Zainab Ali Adamu, Mikhail Olayinka Buhari, Abdullahi Mohammed.

   Background: Malignant peripheral nerve sheath tumours (MPNSTs)are uncommon, aggressive sarcomas arising from a peripheral nerve or extra neural soft tissue and show evidence of nerve sheath differentiation. These tumours exhibit variability in grade and can either occur as familial or sporadic tumours. Immunohistochemistry is a paramount tool in the evaluation of these tumours. This study aimed at analyzing the histopathological and immunohistochemical patterns of these tumours and determining the frequency, demographic and anatomical site distribution.
Methodology: This was a 10-year retrospective hospital-based study. Formalin fixed paraffin embedded tissue blocks were sectioned and the slides werereviewed and interpreted. Morphological features were noted and immunohistochemical analysis was performed using four primary antibodies. Descriptive statistical analysis was used to collate and analyse data, and statistical test was used where necessary. The results were presented on statistical charts and tables.
Result: In this series, 20 cases of MPNSTs were seen with a male predilection. The 3rd and 4th decades were the most frequent decades of occurrence, and most tumours occurred in the gluteal region (eight cases) constituting 40% of all anatomical site's distribution. Borderline/intermediate grade tumours (Grade 2) were the most frequent grade. S100 (25%) and SOX10 (35%) showed low positive immunoexpression. Most of the tumours had low proliferative index or labelling hot spots with Ki67 antibody.
Conclusion: Malignant peripheral nerve sheath tumours are uncommon and tend to be sporadic in our region. Most of these tumours are borderline/intermediate grade tumours (Grade 2) showing low immunoexpression to antibodies employed with varying intensities.

Keywords:  Gluteal Region; Histopathological; Immunohistochemical; Intermediate Grade; MPNSTs; Male

DOI:  https://doi.org/10.71480/nmj.v66i3.898
In Vivo. 2025 Nov-Dec;39(6):39(6): 3428-3436

Heterogeneity of Tumor Glucose Metabolism in Schwannomas Between Trunk and Extremities: An Imaging Study.

Yuta Miyashi, Hiromichi Oshiro, Yoshiro Yoshikawa, Ryo Katsuki, Yasunori Tome, Kotaro Nishida.

   BACKGROUND/AIM: Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) is frequently used to differentiate schwannomas from malignant peripheral nerve sheath tumors. Schwannomas exhibit pathological heterogeneity, with highly cellular (Antoni A) and hypocellular (Antoni B) areas, but current PET/CT methods do not adequately reflect this heterogeneity. This study aimed to compare imaging characteristics of schwannomas in the trunk versus the extremities, with emphasis on metabolic heterogeneity.
PATIENTS AND METHODS: This retrospective study included patients with solitary schwannomas who underwent MRI and 18F-FDG PET/CT before surgical excision (June 2013-September 2023). Exclusion criteria were plexiform, multiple, biopsy-only lesions, and tumors originating from internal organs. Tumors were classified as trunk or extremity lesions. MRI was used to determine size and volume, while PET/CT measured SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Heterogeneity was assessed using three indices: MTV-to-volume ratio (MTV/volume), SUV-based heterogeneity index (HISUV), and metabolic region-adjusted SUV-based heterogeneity index (MRA-HISUV).
RESULTS: Fifty-six patients were included. Trunk schwannomas were larger than extremity tumors in diameter (4.33 cm vs. 2.77 cm; p<0.05) and volume (27.71 cm3 vs. 6.25 cm3; p<0.05). SUVmax (4.09 vs. 3.71) and SUVmean (2.47 vs. 2.22) did not differ significantly. MTV (18.43 cm3 vs. 6.19 cm3, p<0.05) and TLG (58.41 vs. 14.40, p<0.05) were higher in trunk tumors. MTV/volume ratio was lower (0.77 vs. 1.12, p<0.05), while HISUV and MRA-HISUV were higher in trunk schwannomas (1.79 vs. 1.65 and 2.36 vs. 1.49, p<0.05).
CONCLUSION: Trunk schwannomas were larger and exhibited higher metabolic activity and heterogeneity. Novel parameters such as MTV/volume and MRA-HISUV may enhance the characterization of schwannoma heterogeneity.

Keywords:  PET; Positron emission tomography; SUVmax; metabolic tumor volume; schwannoma

DOI:  https://doi.org/10.21873/invivo.14140
Mol Ther Nucleic Acids. 2025 Dec 09. 36(4): 102732

Pan-cancer neural regulation pattern with implications for patient stratification and immunotherapy.

Yueying Gao, Jiyu Guo, Wenyi Yang, Kefan Liu, Qingyi Yang, Si Li, Dezhong Lv, Yangyang Cai, Kang Xu, Weiwei Zhou, Qinghua Jiang, Juan Xu, Yongsheng Li, Haoxiu Sun.

  The interplay between the nervous system and cancer plays a central role in regulating oncogenesis. We depict the pan-cancer landscape of neuro-tumor interactions by integration of >10,000 The Cancer Genome Atlas (TCGA) bulk and 239 pan-cancer spatial transcriptomics, in combination with 115 bulk and >120,000 single-cell checkpoint-inhibitor-treated transcriptomes. Neural signals are significantly correlated with various clinical features, and neural cancer subtypes have been characterized. High neural signals are associated with cancer-associated fibroblast infiltration and immune exclusion. Spatiotemporal transcriptome analysis reveals that tumor core regions present significantly higher neural signals and further unveils the pivotal modulators essential for tumor growth via ligand-receptor interaction networks. Neural signals are predictive biomarkers for drug treatment responses, particularly cancer immunotherapy. We constructed a comprehensive data resource Neuro_Cancer, to investigate neuro-tumor interactions in diverse cancer types. Our systematic dissection of the landscape of the neuronal regulation pattern provides a deeper understanding of tumorigenesis and potential therapeutic opportunities.

Keywords:  MT: Bioinformatics; immunotherapy; neural signals; neuro-tumor interactions; spatial transcriptomics; tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.omtn.2025.102732
Front Immunol. 2025 ;16 1681503

The role of the nervous system in the occurrence, development, and immune response of renal cell carcinoma.

Honghong Sun, Lu Liu, Yuchen Mao, Zhongyu Tan, Xuwen Li, Guangyao Li.

  Renal cell carcinoma (RCC) represents one of the fastest-growing urological malignancies globally, with approximately 30% of patients presenting with metastatic disease at diagnosis. Despite advances in targeted therapy and immune checkpoint inhibitors, treatment resistance remains a critical challenge, largely attributed to the heterogeneous tumor microenvironment (TME). This review systematically examines the emerging role of the neuroimmune system in RCC pathogenesis and progression. The kidney receives dual innervation from sympathetic and parasympathetic systems, which undergo pathological remodeling during tumorigenesis. Novel findings from RCC preclinical models reveal that MANF protein drives sunitinib resistance via IRE1α-XBP1 pathway inhibition, while NPTX2 aberrantly activates PI3K-Akt survival signaling in clear cell renal cell carcinoma (ccRCC). Therapeutic strategies targeting the neuroimmune axis show promise, including β-blockers combined with PD-1 inhibitors to reverse T cell exhaustion, CXCR4 antagonists disrupting nerve- tumor-associated macrophage (TAM) crosstalk, and radiofrequency ablation of perirenal nerve plexus. Future directions involve spatial transcriptomics mapping of the neuroimmune landscape, developing neurotransmitter-targeted delivery systems, and optimizing sequential combination therapies. Understanding the tripartite interaction between nerves, immune cells, and tumor cells opens new avenues for precision medicine in RCC, potentially establishing neuroimmune modulation as a potential new direction of RCC therapy distinct from anti-angiogenesis and immunotherapy.

Keywords:  immunotherapy; nervous system; neuroimmune microenvironment; renal cell carcinoma; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1681503
J Vis Exp. 2025 Oct 10.

An Orthotopic Sciatic Nerve Xenograft for Neurofibromatosis Type 1 Neurofibromas.

Manuela Ye, Aurélien Bore, Sophie Richon, Virginie Dangles-Marie, Eric Pasmant, Raphaël Margueron, Mikael Hivelin.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 gene, leading to the loss of neurofibromin function and the development of benign peripheral nerve sheath tumors known as neurofibromas. While genetically engineered mouse models (GEMMs) have advanced our understanding of NF1 pathophysiology, they often fail to replicate the spontaneous tumorigenesis and microenvironmental complexity of patient-derived neurofibromas. A key challenge in modeling benign neurofibromas is their dependency on the nerve microenvironment, which conventional xenograft approaches do not recapitulate. Here, an optimized orthotopic xenograft model was developed for NF1-associated neurofibromas. Using intraneural injection of immortalized neurofibroma-derived human Schwann cells into the sciatic nerve of NSG immunodeficient mice, this model recapitulates key features of human neurofibroma biology, including nerve-dependent growth and tumor microenvironment interactions. This protocol allows dynamic, real-time monitoring of tumor progression via bioluminescence imaging, providing a reproducible and quantitative method to assess neurofibroma growth. Unlike GEMMs, this model allows for controlled tumor initiation and precise evaluation of preclinical therapeutic strategies. Additionally, it serves as a bridge between GEMMs and patient-derived xenograft models, enhancing the translational relevance of neurofibroma research. By offering a physiologically relevant setting for studying tumor-nerve interactions, this model provides a valuable platform for investigating neurofibroma biology and evaluating potential therapeutic interventions. Future refinements, including the integration of immune components or advanced imaging techniques, may further enhance its application to NF1 research.

DOI: https://doi.org/10.3791/68694
Neurobiol Pain. 2025 Jul-Dec;18:18 100200

Unveiling the peripheral nerve hallmarks of chemotherapy-induced neuropathy: insights from paclitaxel treatment in a murine model.

Maria Maiarù, Andrea Petrini, Federica De Angelis, Francesca Nazio, Sara Marinelli.

  Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and debilitating side effect of anticancer drugs like paclitaxel, significantly reducing the quality of life for cancer patients. Paclitaxel-induced peripheral neuropathy (PIPN) is primarily characterized by sensory disturbances such as mechanical allodynia and thermal hyperalgesia. Despite its prevalence, the mechanisms driving PIPN are not fully understood, and current treatment options remain limited. This study explores the impact of varying doses of paclitaxel on neuropathic pain, nerve structural changes, and metabolic alterations in a mouse model. Behavioural assessments demonstrated that paclitaxel induced dose-dependent mechanical allodynia and thermal hyperalgesia, with prolonged symptoms at higher doses. Furthermore, sciatic nerve dysfunction was observed, while metabolic tests revealed significant disruptions in glucose and triglyceride levels, suggesting a link between metabolic imbalances and neuropathy. Histological and molecular analyses identified increased TRPV1 and CGRP expression in skin nerve fibers, accompanied by Schwann cell dysfunction, characterized by myelin disorganization, decreased levels of myelin proteins (P0, MBP), and elevated LC3 levels, pointing to autophagy involvement. Moreover, infiltration of macrophages and mast cells into sciatic nerves indicated an innate immune response. These results emphasize the complex nature of PIPN, which involves sensory nerve sensitization, Schwann cell damage, and metabolic dysregulation. Elucidating these pathways could inform the development of more effective therapies aimed at preventing or alleviating the impact of CIPN.

Keywords:  Inflammation; Innate immunity; Metabolic alterations; Myelin degeneration; Neuropathic pain; Neurotoxicity; Schwann cells

DOI:  https://doi.org/10.1016/j.ynpai.2025.100200
Medicina (Kaunas). 2025 Oct 15. pii: 1843. [Epub ahead of print]61(10):

Prognostic Impact of Concomitant Beta-Blocker Use on Survival in EGFR-Mutant Metastatic Non-Small Cell Lung Cancer Patients Treated with Erlotinib.

Oğuzhan Yıldız, Talat Aykut, Bahattin Engin Kaya, Ömer Genç, Ali Fuat Gürbüz, Fatih Saçkan, Melek Karakurt Eryılmaz, Mehmet Zahid Koçak, Murat Araz, Mehmet Artaç.

  Background and Objectives: Erlotinib, a tyrosine kinase inhibitor (TKI), is an established therapy for patients with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Preclinical and clinical evidence suggests that chronic stress, mediated through β-adrenergic signaling, promotes tumor progression, angiogenesis, and therapy resistance. Furthermore, interactions between β-adrenergic signaling and EGFR pathways have been hypothesized to negatively influence treatment responses. Based on this rationale, we investigated whether concomitant beta-blocker use may improve survival outcomes in EGFR-mutant NSCLC patients treated with erlotinib. Materials and Methods: This retrospective analysis included 103 patients with metastatic EGFR-mutant NSCLC who received erlotinib. Patients were classified according to concurrent beta-blocker use, defined as continuous therapy for at least six months prior to erlotinib initiation, prescribed for cardiovascular indications. Progression-free survival (PFS) and overall survival (OS) were compared between beta-blocker users and non-users. Results: Patients receiving erlotinib with concomitant beta-blocker therapy achieved a median PFS (mPFS) of 21.4 months (95% CI, 13.1-29.7), compared with 9.7 months (95% CI, 6.7-12.7) in non-users (p = 0.003). Median OS (mOS) was 32.4 months (95% CI, 14.8-50.0) in the beta-blocker group versus 19.9 months (95% CI, 14.8-25.0) in the non-beta-blocker group (p = 0.010). Multivariate Cox regression confirmed beta-blocker use as an independent prognostic factor for both PFS (p = 0.004) and OS (p = 0.014). Conclusions: Concomitant beta-blocker use was associated with significantly prolonged survival in patients with EGFR-mutant metastatic NSCLC receiving erlotinib. These findings support the hypothesis that β-adrenergic inhibition enhances the efficacy of EGFR-targeted therapy. Prospective studies are warranted to validate these results and to further elucidate the underlying biological mechanisms.

Keywords:  EGFR-mutant metastatic non-small cell lung cancer; beta-blocker; erlotinib; survival

DOI:  https://doi.org/10.3390/medicina61101843
J Thorac Dis. 2025 Sep 30. 17(9): 6759-6770

Perineural invasion as a prognostic factor and the efficacy of upfront surgery for low-risk cT2/T3N0M0 esophageal squamous cell carcinoma patients.

Jicheng Xiong, Simiao Lu, Shuoming Liang, Hainan Chen, Ziwei Wang, Hao Meng, Yan Miao, Qin Xie, Guangyuan Liu, Kangning Wang, Lin Peng, Qiang Fang, Wenguang Xiao, Qifeng Wang, Yongtao Han, Xuefeng Leng.

   Background: Controversy remains as to the need for neoadjuvant therapy in the treatment of cT2/T3N0M0 esophageal squamous cell carcinoma (ESCC), with regional (e.g., China vs. Japan) guidelines making divergent recommendations. Survival data suggest comparable overall survival (OS) rates among cII-stage patients. This study aimed to evaluate the efficacy of upfront surgery for cT2/T3N0M0-stage ESCC patients and to identify prognostic factors in this subgroup.
Methods: We retrospectively collected the data of 786 cT2/T3N0M0-stage ESCC patients treated between January 2010 and December 2017 to assess the survival outcomes and identify risk factors. Additionally, we performed a survival analysis to explore the prognostic factors in this patient subgroup.
Results: The cT2N0-stage and cT3N0-stage ESCC patients had 5-year OS rates of 68.0% and 59.0%, respectively (median OS: 82.7 vs. 78.8 months, P=0.01). Postoperative adjuvant therapy significantly improved the OS of the cT3N0-stage patients compared to the cT3N0-stage patients those did not receive postoperative adjuvant therapy (5-year OS: 65% vs. 53%, P=0.004). Adjuvant therapy yielded comparable survival rates in the cT3N0-stage patients without perineural invasion (PNI) and the cT2N0-stage patients who underwent upfront surgery (5-year OS: 66% vs. 68%, P=0.42). Similarly, no significant difference was observed between the lymphovascular invasion (LVI)-negative cT3N0-stage patients those received adjuvant therapy after surgery and the cT2N0-stage patients those underwent upfront surgery (5-year OS: 66% vs. 68%, P=0.30). The survival analysis revealed no difference in OS between the highly differentiated cT3N0-stage and cT2N0-stage patients (5-year OS: 74% vs. 68%, P=0.79). Conversely, the lowly differentiated cT3N0-stage patients had a poorer prognosis with upfront surgery than the high and moderate differentiation patients and derived no survival benefit from adjuvant therapy (5-year OS: 55% vs. 68%, P=0.02). The multivariate analysis identified PNI as an independent prognostic factor for OS [hazard ratio (HR): 1.382; 95% confidence interval (CI): 1.037-1.841; P=0.03].
Conclusions: Upfront surgery results in favorable long-term survival outcomes in cT2/T3N0M0-stage ESCC patients without PNI. These findings show the importance of tailoring therapeutic strategies to distinct ESCC subgroups, particularly based on PNI status and tumor differentiation.

Keywords:  Esophageal squamous cell carcinoma (ESCC); lymphovascular invasion (LVI); overall survival (OS); perineural invasion (PNI); surgery

DOI:  https://doi.org/10.21037/jtd-2024-1969
Curr Issues Mol Biol. 2025 Sep 23. pii: 789. [Epub ahead of print]47(10):

In Silico Multitarget Profiling of Non-Selective Beta-Blockers Highlights Their Potential as Key Agents in Breast Cancer Adjuvant Therapy via ADRB2, ERBB2, and NPYR Receptors.

Felipe Muñoz-González, José Correa-Basurto, Iván Ignacio-Mejia, Cindy Bandala.

  Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as inhibitors of well-established protumor signaling pathways related to ADRB2 and their possible affinity for other important protumoral receptors. Our aim was to identify how nsBBs currently prescribed may also interact with receptors other than ADRB2, which are related to the pathophysiology of BC, using bioinformatic intracellular pathway analysis (BIPA). Subsequently, the affinity of nsBBs for both ADRB2 and the targets identified by BIPA was evaluated. We found that, beyond ADRB2, both receptor tyrosine kinase 2 (ERBB2) and neuropeptide Y receptor (NPYR) are promising targets for nsBBs in the adjuvant treatment of BC, according to BIPA. Docking studies showed that the nsBB with the highest binding affinity (ΔG) was carvedilol (-10.5 kcal/mol), followed by propranolol (-8.5 kcal/mol). These in silico findings suggest previously unrecognized pharmacological mechanisms for nsBBs in the possible treatment for BC. Notably, differences in receptor affinity were observed among the nsBBs, with carvedilol exhibiting the strongest binding affinity values on ADRB2, ERBB2, and NPYR as biological targets against BC cells. These promising results require future experimental validation.

Keywords:  beta-blockers; breast cancer; drug repurposing

DOI:  https://doi.org/10.3390/cimb47100789
Neurogastroenterol Motil. 2025 Oct 29. e70190

Microencapsulated Quercetin and Bifidobacterium animalis Independently Preserve Jejunal Enteric Neurons During Colorectal Carcinogenesis.

Lucas Casagrande, Carla Cristina de Oliveira Bernardo, Sabrina Silva Sestak, Maysa Pacheco Alvarez da Silva, Marcos Yudi Nagaoka Godoy, Jean-Pierre Timmermans, Cesar Agostinho Ferreira, Tânia Cristina Alexandrino Becker, Erick Guilherme Stoppa, Waldiceu Aparecido Verri, José Ricardo de Arruma Miranda, Juliana Vanessa Colombo Martins Perles, Jacqueline Nelisis Zanoni.

   BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, significantly disrupting enteric neurotransmission within the colon. While the effects of CRC on the enteric nervous system (ENS) of the colon are well documented, its impact on the small intestine remains underexplored. This study aims to investigate the influence of colorectal carcinogenesis on the small intestine's ENS and evaluate the individual neuroprotective effects of microencapsulated quercetin and Bifidobacterium animalis.
METHODS: Wistar rats were subjected to chemically induced colorectal carcinogenesis, followed by 14 weeks of treatment with microencapsulated quercetin and B. animalis. Gastrointestinal transit times were assessed, and colonic and jejunal samples underwent histopathological and immunohistochemical analyses to evaluate neuronal markers (HuC/D, nNOS, VIP). Cholinergic neurons were not directly assessed.
RESULTS: Aberrant crypt foci confirmed the effectiveness of the colorectal carcinogenesis induction model. The mean gastric emptying time (MGET) was notably shorter in the B. animalis-treated group. Colorectal carcinogenesis significantly reduced the density and size of HuC/D+ neurons in the myenteric and submucosal plexuses of the jejunum. Treatments with either microencapsulated quercetin or B. animalis significantly enhanced neuronal density and size in the jejunum and improved nitrergic neuronal density (nNOS-IR). Additionally, VIPergic neuron density increased in the submucosal plexus, and varicosity size increased in the myenteric plexus in the CR group; treatments reduced this varicosity size.
CONCLUSION: This study provides the first evidence that colorectal carcinogenesis damages jejunal neurons. Treatments with microencapsulated quercetin or B. animalis independently preserved neuronal density and modulated gastrointestinal function. However, their combined administration did not enhance these effects, highlighting the need for further research into therapeutic interventions for preserving ENS integrity during colorectal carcinogenesis.

Keywords:  colorectal carcinogenesis; enteric neuronal density; intestinal transit; microencapsulated quercetin; probiotic

DOI:  https://doi.org/10.1111/nmo.70190
Transl Cancer Res. 2025 Sep 30. 14(9): 5680-5693

Integration analysis of single-cell transcriptome reveals SPP1+ and TFF3+ macrophage subsets contributing to the brain metastasis from lung cancer.

Zhenli Liu, Xueli Wang, Yuanhui Wang, Guangning Zhang.

   Background: The death of lung cancer patients is closely linked to brain metastasis. While tumor-associated macrophages (TAMs) have been extensively studied in the context of lung cancer metastasis, their role and mechanism in brain metastasis remain unclear. In this study, we analyzed and explored the heterogeneity and differential gene expression of TAM subsets associated with brain metastasis of lung cancer using single-cell transcriptome data.
Methods: Single-cell RNA sequencing datasets related to brain metastasis of lung cancer were acquired from the Gene Expression Omnibus (GEO) database and ArrayExpress platform. Through standard single-cell data analysis and visualization, we investigated the differential gene expression and signal pathway enrichment of macrophage subsets associated with brain metastasis of lung cancer, focusing on the unique microenvironment and cell component differences in brain metastasis tissues.
Results: Compared with normal lung tissue, brain tissue, and tumor focus of primary lung cancer, we observed a significant up-regulation in the cell proportions of SPP1+ macrophages and TFF3+ macrophages in brain metastasis tissues of lung cancer. These macrophage subsets up-regulated various factors promoting tumor progression and metastasis. SPP1+ macrophages significantly up-regulated the expressions of SPP1, CCL2, MIF, and AREG, while TFF3+ macrophages up-regulated the expressions of TFF3, TFF1, CCL4, CCL3, AGR2, CCL3L3, and CCL4L2. Signal pathway analysis revealed obvious enrichment in the NOD-like receptor signaling pathway, Chemokine signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway in these two macrophage subsets.
Conclusions: Our findings demonstrate the close association of SPP1+ and TFF3+ macrophage subsets with brain metastasis of lung cancer. Our differential gene and signaling pathway analysis revealed the potential tumor-promoting mechanisms. These insights may offer new perspectives for clinical strategies targeting macrophages or the tumor microenvironment to treat brain metastasis of lung cancer.

Keywords:  Brain metastasis from lung cancer; SPP1+; TFF3+; macrophage; tumor-associated macrophage (TAM)

DOI:  https://doi.org/10.21037/tcr-2024-2489
Medicina (Kaunas). 2025 Oct 13. pii: 1828. [Epub ahead of print]61(10):

Subtype- and Site-Specific Innervation of Melanocytic Nevi as Revealed by PGP 9.5 and CGRP Expression.

Bruno Minigo, Marin Ogorevc, Nela Kelam, Ante Čizmić, Sandra Zekić Tomaš, Katarina Vukojević, Sandra Kostić, Dubravka Vuković, Snježana Mardešić.

  Background and objectives: Melanocytic nevi are among the most common skin lesions, yet their relationship with the peripheral nervous system has remained understudied. Given the neural crest origin of melanocytes and Schwann cells, and the neurotrophic signaling capabilities of pigment cells, this study aimed to investigate the density of nerve fibers within nevi and assess how it varies with respect to histological subtype and anatomical location. Materials and Methods: A total of 90 nevi were analyzed, including junctional, compound, and intradermal types, distributed across the head, trunk, and limbs. Immunofluorescence staining for the pan-neuronal marker PGP 9.5 and for CGRP were performed and nerve fiber density was quantified. Statistical evaluation using two-way ANOVA revealed that both nevus type and anatomical site significantly influenced the degree of total innervation. Results: Junctional nevi demonstrated the highest total nerve fiber density, significantly exceeding that of compound and intradermal nevi. Likewise, nevi located on the head exhibited a significantly greater density of PGP 9.5-positive nerve fibers compared to those on the trunk and limbs. No significant correlation was observed between nevus type and location, suggesting that both factors contribute independently to the differences in innervation. CGRP-positive innervation was uniform regardless of the histological type of nevus and anatomical location. Conclusions: These findings likely reflect the facts that junctional nevi reside at the dermo-epidermal junction, where nerve fibers are most abundant, while the skin of the head and neck is well known to be more richly innervated than other regions. In contrast, analysis of CGRP-positive fibers suggests that the heterogeneity detected with PGP 9.5 is primarily driven by other neuronal populations. The results support the hypothesis of a dynamic relationship between nevi and the peripheral nervous system, potentially mediated by neurotrophic factors. Understanding this interaction may provide insight into nevus biology, sensory symptoms reported in some lesions, and the evolving role of nerves in the tumor microenvironment.

Keywords:  CGRP; PGP 9.5; UCHL1; cutaneous innervation; melanocytic nevi

DOI:  https://doi.org/10.3390/medicina61101828
Mol Pain. 2025 Oct 29. 17448069251395641

EXPRESS: Amino Acid Transporter SLC38A3 Mediates Bone Cancer Pain in Rats Via the PI3K/AKT/TRPV1 Signaling Pathway.

Yu-Na Cheng, Ming-Zhu Zhang, Cui-Qing Xie, Zhi-Qi Li, You-Feng Ge, Zhao-Hui Jin, Zhi-Hua Luo, Chen-Yang Zheng, Liang Chen, Dong Fang, Chen-Guang Niu, Jin-Jin He.

  Bone cancer pain (BCP), one of the most intractable symptoms in patients with cancer, remains poorly understood and lacks effective therapeutic interventions. In this study, we employed an established rat model of BCP induced by intratibial injection of MRMT-1 mammary carcinoma cells. Transcriptomic profiling of the L4-L6 dorsal root ganglia (DRGs) revealed an upregulation of the amino acid transporter SLC38A3. This finding was further confirmed by time-dependent increases in both its mRNA and protein levels. Immunofluorescence co-localization indicated that SLC38A3 was expressed in NF200-, CGRP-, and IB4-positive neurons within the L4-L6 DRGs, and its expression was upregulated in the BCP model. Concomitantly, the transient receptor potential vanilloid 1 (TRPV1) expression in BCP rat DRGs was dynamically upregulated at both the mRNA and protein levels, aligning temporally with pain hypersensitivity. Lentivirus-mediated overexpression or knockdown of SLC38A3 in the DRGs led to a corresponding upregulation or downregulation of TRPV1-expression. Activation of the PI3K/AKT signaling pathway corresponds with BCP-related pain behaviors and expression patterns of SLC38A3 and TRPV1. Bexarotene alleviates BCP in rats by suppressing the aberrant overexpression of SLC38A3, thereby blocking the PI3K/AKT signaling pathway-mediated upregulation of TRPV1. These findings indicate that SLC38A3, through its downstream PI3K/AKT-TRPV1 axis, may serve as a potential molecular mechanism for analgesia in BCP.

Keywords:  PI3K/AKT; SLC38A3; TRPV1; bone cancer pain; dorsal root ganglion

DOI:  https://doi.org/10.1177/17448069251395641
Front Oncol. 2025 ;15 1580640

Optoacoustic imaging of the brain in a cachexia-inducing pancreatic cancer xenograft.

Saleem Yousf, Marie-France Penet, Andrew Brannen, Paul Winnard, Yelena Mironchik, Balaji Krishnamachary, Zaver M Bhujwalla.

  Pancreatic cancer-induced cachexia drives co-morbidities that result in a poor quality of life. To expand understanding of the effects of cachexia on the brain here, for the first time, we used noninvasive oxygen enhanced (OE) multispectral optoacoustic tomography (MSOT) to evaluate the ability of the brain vasculature to respond to oxygen breathing in an established xenograft model of pancreatic cancer-induced cachexia. Studies were performed with mice bearing cachexia inducing Pa04C tumors, non-cachexia inducing Panc1 tumors and non-tumor bearing mice. OE-MSOT identified a reduced oxygen carrying capacity in the brain vasculature of mice with cachexia inducing Pa04C tumors, compared to non-tumor bearing mice, and mice with non-cachexia inducing Panc1 tumors. Brain volumes, quantified in mice with MSOT, were significantly reduced in Pa04C tumor-bearing mice compared to non-tumor bearing mice. Our data have identified the inability of brain vasculature to increase oxygenation in response to oxygen breathing in cachectic mice as a new mechanism that may contribute to cachexia-induced morbidity.

Keywords:  brain; cachexia; optoacoustic imaging; pancreatic ductal adenocarcinoma; vascular oxygenation

DOI:  https://doi.org/10.3389/fonc.2025.1580640