bims-netuvo 2025-11-30 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2025–11–30
twelve papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Nerve Adaptations in the Tumor Microenvironment.
TNFR1 Suppression by XPro1595 Reduces Peripheral Neuropathies Associated with Perineural Invasion in Female Mice.
Neural regulation of lung cancer: from mechanisms to clinical implications.
PRC2 Restricts Malignant Peripheral Nerve Sheath Tumorigenesis in a Genetically Engineered Mouse Model of MPNST.
Comparison of 2D and 3D measured iodine concentration of gastric adenocarcinoma on spectral-CT and their relationship with perineural invasion.
Mapping the global research landscape of perineural invasion in gastrointestinal malignancies: a bibliometric visualization analysis.
Research progress on chronic stress stimulation and gastric cancer metastasis.
Cellular senescence in the innervated niche modulates cancer-associated pain: an emerging therapeutic target?
Role of the neurotransmitter-receptor pathway in T-cell tumor immunology and cancer immunotherapy.
Beta-blocker use and survival outcomes in colorectal cancer patients: A systematic review and meta-analysis.
Prognostic nomogram for small-cell lung cancer patients with brain metastasis in China: A population-based real-world analysis.
Colorectal cancer relies on an immunosuppressive cellular topography and genomic adaptations for establishing brain metastases.

Cell Biochem Funct. 2025 Dec;43(12): e70147

Nerve Adaptations in the Tumor Microenvironment.

Aditi Swamy, Karishma Ravikumar, Merlin Pious, Ahina Job, Denny John, Sahadev A Shankarappa.

  The tumor microenvironment (TME) is a complex ecosystem composed of cancer cells, stromal components, immune infiltrates, and neural elements. The presence and growth of nerves within or in close association with tumor tissue, a phenomenon known as tumor innervation, has long been observed. However, recent evidence supports a more active role for peripheral nerves in regulating cancer growth, metastasis, and therapeutic resistance. What remains underappreciated is the reciprocal influence of cancer cells on the nervous system. Accumulating data indicate that cancer cells remodel adjacent nerve terminals, triggering structural, neurochemical, bioelectrical, and transcriptional changes in a tumour-type-specific manner. These adaptations resemble pathways observed in nerve regeneration and suggest a tightly regulated, bidirectional signaling axis between cancer and nerves. In this review, we systematically consolidate emerging literature describing these nerve adaptations and categorize them across multiple levels, from morphological remodeling and neurotransmitter shifts to bioelectrical signaling and neuroimmune crosstalk. We highlight the central role of the tumor secretome in mediating nerve-cancer communication and emphasize how neural elements actively shape tumor behavior. By consolidating and critically examining findings across diverse cancer models and experimental systems, this review provides a mechanistic framework for understanding neural remodeling in cancer and identifies key areas for future investigation, including the potential of targeting nerve-tumor interactions as a therapeutic strategy.

Keywords:  cancer progression; cancer–neuron crosstalk; neural remodeling; perineural invasion; tumor innervation

DOI:  https://doi.org/10.1002/cbf.70147
Cells. 2025 Nov 07. pii: 1749. [Epub ahead of print]14(22):

TNFR1 Suppression by XPro1595 Reduces Peripheral Neuropathies Associated with Perineural Invasion in Female Mice.

Morgan Zhang, Naijiang Liu, Kesava Asam, Charles Meng, Bradley Aouizerat, Yi Ye.

  Perineural invasion (PNI), defined by cancer spreading or invading into the nerve, links to severe pain, recurrence, and poor prognosis. PNI contributes to nerve damage, Schwann cell activation, and sensory neuron dysfunction. Soluble tumor necrosis factor α (solTNFα) binds to TNFR1 to drive inflammation and nerve injury, playing a key role in cancer progression and pain. This study, using a mouse sciatic nerve PNI model, explored whether blocking solTNFα-TNFR1 signaling via TNFR1 knockout or pharmacological inhibition by XPro1595 could reduce PNI-associated pain. Data showed that XPro1595, but not TNFR1 knockout, reduced tumor burden, alleviated mechanical allodynia, and improved muscle function and locomotion, primarily in females. Histological analysis in females showed that XPro1595 increased the number of myelin and dendritic cells while reducing axonal damage that resulted from PNI. In the tumor zone outside the nerve truck, XPro1595 reduced T cell and increased macrophage and dendritic cell numbers. Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling.

Keywords:  Schwann cell; XPro1595; extracellular matrix; inflammation; locomotion; mitochondrial; myelination; pain; perineural invasion; tumor necrosis factor

DOI:  https://doi.org/10.3390/cells14221749
Eur J Med Res. 2025 Nov 28. 30(1): 1190

Neural regulation of lung cancer: from mechanisms to clinical implications.

Lijia Xu, Xiaokui Sun, Yundan Yao, Hao Fang.

  Lung cancer exhibits extremely high incidence and mortality rates among all malignancies, and its behavior is closely associated with the nervous system. Researchers have found that the nervous system influences the hallmark capabilities of lung cancer, such as proliferation, stemness, invasion, metastasis, treatment resistance, metabolic reprogramming, immune surveillance evasion, and angiogenesis. Conversely, lung cancer and anti-tumor therapies also affect the nervous system. The emergence of this knowledge has in turn provided new opportunities for lung cancer treatment and the innovation of therapeutic concepts. This review comprehensively summarizes the interaction between the nervous system and lung cancer based on the logical framework of cancer hallmarks. What's more, we also conclude several novel anti-tumor strategies based on cancer neuroscience to facilitate further implication and clinical transition.

Keywords:  Cancer hallmark; Cancer neuroscience; Drug repurposing; Lung cancer

DOI:  https://doi.org/10.1186/s40001-025-03464-9
bioRxiv. 2025 Nov 13. pii: 2025.11.12.687881. [Epub ahead of print]

PRC2 Restricts Malignant Peripheral Nerve Sheath Tumorigenesis in a Genetically Engineered Mouse Model of MPNST.

Woo Hyun Cho, Amish J Patel, Makzhuna Khudoynazarova, Sarah Warda, Juan Yan, Dan Li, Dana Schoeps, Eve Fishinevich, Mohini R Pachai, Cindy J Lee, Zoe Jacobs, Kae Kristoff, Jessica J Sher, Cristina R Antonescu, Yu Chen, Ping Chi.

Polycomb Repressive Complex 2 (PRC2), which normally regulates transcriptional silencing, chromatin compaction, and stem cell biology, has both oncogenic and tumor suppressor roles in cancer development depending on tumor type. Malignant peripheral nerve sheath tumor (MPNST), characterized by NF1, CDKN2A and PRC2 loss, is an aggressive subtype of sarcoma with poor prognosis and no effective therapy. In high-grade human MPNSTs, inactivating mutations in PRC2 core components SUZ12 or EED are prevalent and contributes to oncogenic transformation and progression of MPNST. How PRC2 inactivation contributes to MPNST pathogenesis, however, remains incompletely understood. Here we show that genetic inactivation of Eed in addition to Nf1 and Cdkn2a in the Schwann-progenitor lineage leads to widespread tumorigenesis within the sciatic nerve compartment of mice. In contrast, loss of Nf1 and Cdkn2a is insufficient to drive tumorigenesis in the sciatic nerve but leads to MPNST development in other anatomic locations with a longer latency. Single-nucleus multiome sequencing of the sciatic nerves revealed that PRC2-loss reprograms Nf1 / Cdkn2a -deficient Schwann-lineage cells toward a dedifferentiated, neural crest stem cell-like state that resembles the transcriptomic signatures of human PRC2-loss MPNST. Together, these findings suggest a context-dependent tumor suppressive role for PRC2 within the sciatic nerve and establish a novel mouse model that recapitulates human PRC2-loss MPNST.
SIGNIFICANCE: We present a novel genetically engineered mouse model that faithfully recapitulates human PRC2-loss MPNST, enabling mechanistic and preclinical studies of malignant transformation in the context of PRC2 loss.

DOI: https://doi.org/10.1101/2025.11.12.687881
BMC Med Imaging. 2025 Nov 26. 25(1): 490

Comparison of 2D and 3D measured iodine concentration of gastric adenocarcinoma on spectral-CT and their relationship with perineural invasion.

Tianxia Bei, Xiaoqiang Yao, Xuejun Chen, Yue Wu, Jing Li, Jinrong Qu.

   BACKGROUND: To determine the optimal region of interest (ROI) measurement strategy in spectral computed tomography (CT) for the preoperative prediction of perineural invasion (PNI) in gastric adenocarcinoma.
METHODS: This retrospective study analyzed 91 gastric adenocarcinoma patients undergoing triple-phase (arterial, venous, and delayed phase; AP/VP/DP) contrast-enhanced spectral CT within two weeks before surgery. Patients were divided into PNI-positive and PNI-negative groups based on pathological findings. Iodine concentration (IC) values were measured using two free-hand ROI approaches: a two-dimensional ROI (2D-ROI) and a three-dimensional volumetric ROI (3D-ROI). Normalized IC (nIC) was also calculated. Consistency and correlation between the two ROI measurements were assessed. Differences in clinicopathological and CT features between the PNI-positive and PNI-negative groups were analyzed. The area under the receiver operating characteristic curve (AUC) was used to evaluate predictive performance. Logistic regression identified independent risk factors for PNI.
RESULTS: The ICs measured by 2D and 3D-ROI showed excellent consistency (ICC = 0.803-0.853) and correlation (r = 0.777-0.797), though 2D-ROI yielded higher values (all P < 0.05). 2D-ICVP, 2D-ICDP, 2D-nICVP, 2D-nICDP and 3D-nICDP, were significantly higher in PNI-positive GC (P < 0.05). 2D-nICDP had the highest predictive AUC (0.761), outperforming other parameters (AUC = 0.622-0.670; P < 0.05). Multivariable analysis confirmed 2D-nICDP as the only independent PNI predictor.
CONCLUSIONS: Although the consistency and correlation between 2D and 3D-ROIs were excellent, only 2D-nICDP was an independent predictor for PNI in gastric cancer (GC) and demonstrated superior predictive performance.

Keywords:  Iodine concentration; Perineural invasion; Region of interest; Stomach neoplasms

DOI:  https://doi.org/10.1186/s12880-025-02042-z
Discov Oncol. 2025 Nov 27.

Mapping the global research landscape of perineural invasion in gastrointestinal malignancies: a bibliometric visualization analysis.

Shijie Yang, ChengZhang Zhu, Hui Cai.



Keywords:  Bibliometrics; Enteric nervous system; Gastrointestinal malignancies; Perineural invasion; Visualization

DOI:  https://doi.org/10.1007/s12672-025-04044-3
Discov Oncol. 2025 Nov 25. 16(1): 2160

Research progress on chronic stress stimulation and gastric cancer metastasis.

Juntao Chen, Yanling Zhang, Tianyou Zhang, Zhipeng Wen, Yongfeng Li, Yinzhuo Ye, Zili Zhou, Guiqing Jia.

  Gastric cancer remains a major clinical challenge due to its propensity for metastasis and poor five-year survival rates. Emerging evidence implicates chronic psychological stress as a critical promoter of tumor dissemination. Stress signals engage both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), leading to sustained elevations of cortisol and catecholamines. These mediators act on glucocorticoid receptors (GR) and β-adrenergic receptors (ADRB2) in gastric cancer cells, thereby activating downstream cAMP/PKA and NF-κB/STAT3 pathways. The resulting cascade enhances epithelial-mesenchymal transition (EMT), upregulates matrix metalloproteinases, and promotes neovascularization, while concurrently inducing an immunosuppressive microenvironment characterized by CD8⁺ T-cell exhaustion, M2-polarized TAMs, and Treg expansion. Moreover, stress-driven epigenetic and metabolic reprogramming amplifies the Warburg effect and synergizes with Helicobacter pylori infection to accelerate tumor invasion. Clinical and cohort studies consistently associate elevated stress markers with increased metastasis risk, and interventions-ranging from β-blockers and GR antagonists to cognitive-behavioral therapy-show promise in mitigating these effects. Future advances in multi-omics, spatial profiling, smart probiotics, and optogenetic tools are poised to unravel the complex "stress-tumor" interface and enable precise, integrative mind-body therapeutic strategies.

Keywords:  Chronic stress; Epithelial–mesenchymal transition; Gastric cancer; Helicobacter pylori; Immunosuppression; Metabolic reprogramming; Metastasis; Neuroendocrine

DOI:  https://doi.org/10.1007/s12672-025-03950-w
Front Immunol. 2025 ;16 1694567

Cellular senescence in the innervated niche modulates cancer-associated pain: an emerging therapeutic target?

Fabrizio Antonangeli, Edoardo Arcuri, Angela Santoni.

  Crosstalk between cancer cells and the nervous system establishes the so-called "innervated niche". This component of the tumor microenvironment (TME) influences tumor progression and variably regulates the genesis and maintenance of cancer-related pain. Senescence is a cellular stress response emerging as a hallmark of cancer and aging. Through the inflammatory secretome referred to as the senescence-associated secretory phenotype (SASP), senescent cells execute immunomodulation and tissue remodeling, participating in many physio-pathological processes. As inflammation is a key determinant of the TME as well as of neuropathies, in this review article we try to outline the possible role of senescence in the innervated niche. We argue that senescence can contribute to neuroinflammation, which is nowadays recognized as the initial factor triggering both cancer and non-cancer pain, by boosting local inflammation in the TME. At the same time, senescent cells can become targetable elements of the innervated niche to control cancer pain. We describe how the immune system supports the resolution of pain, and we suggest the possibility of harnessing natural killer (NK) cells, the prototype of innate immunity lymphocytes, for therapeutic approaches aimed at pain relief.

Keywords:  NK cell; SASP; cancer; neuroinflammation; neuropathy; pain; senescence; senolysis

DOI:  https://doi.org/10.3389/fimmu.2025.1694567
Acta Biochim Biophys Sin (Shanghai). 2025 Nov 26.

Role of the neurotransmitter-receptor pathway in T-cell tumor immunology and cancer immunotherapy.

Mingyu Fan, Xiang Zhao.

  This review synthesizes how neurotransmitters-including glutamate, acetylcholine (ACh), γ-aminobutyric acid (GABA), serotonin (5-HT), and catecholamines-modulate T-cell immunity in the tumor microenvironment through activation, differentiation, trafficking, and checkpoint dependence. Glutamate amplifies T-cell receptor signaling but is counterbalanced by tumor-derived glutamate export. Cholinergic pathways exert dual effects through nicotinic and muscarinic receptors, whereas GABA generally imposes metabolic and signaling brakes that favor regulatory programs. Serotonin shows spatial divergence-suppressing peripheral responses but enhancing intratumoral cytotoxicity-and chronic β-adrenergic stress dampens effector function and limits immunotherapy efficacy. Advances in spatial multi-omics, single-cell profiling, and neuromodulation will help discover new targets across these axes. This review provides mechanistic insights and translational implications, highlighting emerging strategies such as glutamate receptor, metabotropic glutamate receptor 4 (mGluR4) or xCT (SLC7A11) inhibition, receptor subtype modulation, and β-blockade. Integrating neurotransmitter-receptor targeting with checkpoint inhibitors or cell therapies may improve the depth and durability of cancer immunotherapy.

Keywords:  T cell; cancer immunotherapy; immune checkpoint blockade; immunometabolism; neuroimmune crosstalk; neurotransmitter; receptor signaling; tumor microenvironment

DOI:  https://doi.org/10.3724/abbs.2025216
J Int Med Res. 2025 Nov;53(11): 3000605251397839

Beta-blocker use and survival outcomes in colorectal cancer patients: A systematic review and meta-analysis.

Rui Li, Jie Chen, Yingkai Chen, Kai Jin, Yong Chen, Changyu Deng, Xuefen Liu, Yue Li.

  ObjectiveWe aimed to investigate the associations between beta-blocker use and survival outcomes, including cancer-specific mortality, all-cause mortality, median overall survival, and median progression-free survival, in patients with colorectal cancer. The findings are intended to inform evidence-based strategies for optimizing adjuvant therapy in clinical practice.MethodsWe conducted a comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library to identify studies assessing the effect of beta-blockers on survival outcomes in patients with colorectal cancer. Studies reporting hazard ratios and 95% confidence intervals for cancer-specific mortality, all-cause mortality, median overall survival, or median progression-free survival were included. Adjusted hazard ratios were pooled using meta-analytic techniques. Subgroup and sensitivity analyses were performed to explore the potential sources of heterogeneity and assess result robustness.ResultsOverall, 13 high-quality cohort studies including >93,000 patients with colorectal cancer were included. Beta-blocker use was marginally associated with reduced cancer-specific mortality (hazard ratio = 0.90; 95% confidence interval: 0.81-1.00), with a more pronounced effect among patients who had not undergone surgery (hazard ratio = 0.86; 95% confidence interval: 0.75-0.98). Although no overall association was observed for all-cause mortality (hazard ratio = 0.76), a significant reduction was noted in the subgroup that underwent curative surgery (hazard ratio = 0.65; 95% confidence interval: 0.42-1.00). Among patients receiving bevacizumab, beta-blocker use was linked to improved median overall survival (hazard ratio = 0.70; 95% confidence interval: 0.56-0.87), whereas a nonsignificant trend toward improved median progression-free survival was observed (hazard ratio = 0.79; 95% confidence interval: 0.60-1.05). Sensitivity analyses supported the robustness and consistency of the pooled results.ConclusionsThis meta-analysis indicates that beta-blocker use is significantly associated with a reduced risk of cancer-specific mortality in patients with colorectal cancer, with the most pronounced benefit observed among those who did not undergo surgery. Additionally, patients undergoing radical resection or bevacizumab-based therapy may also experience improved survival with beta-blocker use. Given the well-established cardiovascular safety, affordability, and broad clinical availability, beta-blockers may serve as promising adjuncts for comprehensive colorectal cancer treatment. However, further randomized controlled trials are warranted to validate these findings and define optimal patient populations, timing, and combination strategies. This study was registered with PROSPERO (CRD420251079257).

Keywords:  Beta-blockers; cancer-specific mortality; colorectal cancer; meta-analysis; overall survival; progression-free survival

DOI:  https://doi.org/10.1177/03000605251397839
Medicine (Baltimore). 2025 Nov 21. 104(47): e45367

Prognostic nomogram for small-cell lung cancer patients with brain metastasis in China: A population-based real-world analysis.

Weili Wang, Hongwei Li, Sufang Jia, Xiaqin Zhang, Wei Bai, Sijin Li.

  Small-cell lung cancer (SCLC) is one of the top malignancies that leads to brain metastasis (BM), and the prognosis for SCLC patients tends to be abysmal. However, there is a notable amount of heterogeneity among these patients, and a subset of them can be expected to survive much longer than average. Therefore, we aimed to develop a model to predict the prognosis of SCLC patients with BM. This retrospective study collected data from the medical records of 697 SCLC patients with brain malignancies treated at Shanxi Provincial Cancer Hospital from January 2008 to December 2018. Among them, 526 patients were used as the training cohort. Univariate and multivariate analyses were performed in this cohort to select independent risk factors that affect the prognosis of SCLC patients with BM, and a nomogram model was established. The remaining 171 patients were used as the validation cohort to verify the model. Our analysis showed that 7 pretreatment variables were related to the overall survival of SCLC patients with BM. These variables were incorporated into the model. Our predictive model performed well in validation and outperformed the lung diagnostic specific graded prognostic assessment. It may serve as a practical tool to guide individualized treatment decisions for SCLC patients with BM, helping to identify those suited for aggressive therapy versus supportive care. Future multicenter prospective studies are needed to validate its generalizability and explore optimized treatment strategies.

Keywords:  brain metastasis; case series; nomogram; overall survival; small-cell lung cancer

DOI:  https://doi.org/10.1097/MD.0000000000045367
bioRxiv. 2025 Nov 16. pii: 2025.11.14.688538. [Epub ahead of print]

Colorectal cancer relies on an immunosuppressive cellular topography and genomic adaptations for establishing brain metastases.

Anuja Sathe, Mengrui Zhang, Xiangqi Bai, Ji In Kang, Rithika Meka, Huiyun Sun, Susan M Grimes, Aparajita Khan, Mingen Liu, Andrew S Luksik, Michael Lim, Claudia K Petrisch, Christopher M Jackson, Hannes Vogel, Jeanne Shen, Melanie Gephart, Summer Han, Hanlee P Ji.

Colorectal cancer ( CRC ) brain metastases have a poor prognosis and limited treatment options, including resistance to radiation therapy. Little is known about the molecular and cellular mechanisms that enable CRC tumor cells to adapt to the brain and establish a supportive tumor microenvironment. To address this gap we used spatial transcriptomics to analyze 51 CRC brain metastases. A subset had matched primary colon tumors and longitudinally paired metastatic resections before and after radiation treatment. We identified the critical spatial cellular features of the tumor epithelium and the surrounding tumor microenvironment that support metastatic growth in the brain. CRC brain metastases developed a stromal microenvironment with abundant fibroblasts and tumor-associated macrophages. A fibroblast-macrophage cellular neighborhood promoted angiogenesis, extracellular matrix remodeling, and immune suppression. Tumor cells showed local adaptations. In endothelial-rich regions, they were proliferative whereas in macrophage-rich regions, they were more differentiated and immune evasive. Compared with paired primary tumors, CRC brain metastases showed increased chromosomal instability, with activation of RNA-processing, stress response, and junctional remodeling pathways. After radiation treatment, resistant clones had increased epithelial-mesenchymal transition, while the immunosuppressive stroma remained intact. We identified tumor-derived MIF , GDF15 , PRSS3 and SEMA3C ligands and macrophage-derived SPP1 that have the potential to affect multiple cell types in the metastatic niche. These ligand-receptor interactions drive angiogenesis, stromal activation and immune suppression. In a macrophage-tumor-fibroblast co-culture model, knockout of SPP1 in macrophages led to reduced expression of lipid-metabolism related genes and disrupted tumor-promoting interactions. Together, these results indicate that CRC growth in the brain is sustained by a specific cellular organization with immunosuppressive multicellular interactions.

DOI: https://doi.org/10.1101/2025.11.14.688538