bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2026–02–15
eleven papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. From neuro-immune command circuits to microbiota-mediated regulation in the gastrointestinal tumor microenvironment.
  2. Sensory Neurons Drive a Fibrotic Immune Microenvironment in Breast Cancer.
  3. Integrating lymphovascular and perineural invasion into TNM staging: a novel ITNM system for enhanced prognostic stratification in colorectal cancer.
  4. Brain metastases from non-small cell lung cancer: molecular subtypes and emerging CNS-directed precision therapies.
  5. LINC01978 drives perineural invasion in cholangiocarcinoma through tumor-neural crosstalk and CCL2-mediated macrophage recruitment.
  6. Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression.
  7. Prognostic factors affecting survival and recurrence in patients undergoing curative surgery for rectal cancer: a 10-year retrospective cohort study from a regional tertiary center in Türkiye.
  8. Diagnostic efficacy of dual-energy computed tomography-based fractal analysis for assessing extramural venous invasion/tumor deposits and peripheral nerve invasion in rectal cancer.
  9. Prelimbic cortex-basolateral amygdala glutamatergic circuit drives cancer-induced bone pain in mice.
  10. Downregulation of ClC-3 chloride channels in dorsal root ganglia neurons contributes to bone metastasis-induced pain.
  11. Bidirectional relationship between cancer and depression: From shared mechanisms to integrated therapeutic strategies.
  1. Front Immunol. 2026 ;17 1739357
    From neuro-immune command circuits to microbiota-mediated regulation in the gastrointestinal tumor microenvironment.
    Yuhan Chen, Dong Tang.
      The nervous system plays a profound role in human health and disease, particularly in regulating cancer development through immune system interactions. The enteric nervous system (ENS), often referred to as the "second brain," comprises millions of neurons and glial cells specialized for the gastrointestinal tract. This system is intimately involved in the growth, infiltration, and metastasis of gastrointestinal tumors. Furthermore, the ENS establishes a bidirectional communication network with the central nervous system via the vagus nerve and spinal afferent nerves, mediating interactions between gut microbiota, the immune system, and the nervous system. Emerging fields like "neuro-immuno-oncology" have introduced neuroimmunomodulatory drugs into clinical practice, but most research focuses on intestinal inflammation, leaving a gap in systematic understanding regarding gastrointestinal tumors. This review systematically summarizes the bidirectional regulatory mechanisms of neuro-immune interactions in gastrointestinal tumors and explores the interplay between nerves, immunity, and microbiota in the gastrointestinal tumor microenvironment. Its aim is to provide a new perspective for understanding the neuro-immune ecology of gastrointestinal tumors and to lay a theoretical foundation for developing cross-scale precision treatment strategies.
    Keywords:  cancer; enteric nervous system; gut microbiota; immunotherapy; neuroimmunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1739357
  2. Cancer Discov. 2026 Feb 10. OF1
    Sensory Neurons Drive a Fibrotic Immune Microenvironment in Breast Cancer.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-020
  3. Front Oncol. 2026 ;16 1745324
    Integrating lymphovascular and perineural invasion into TNM staging: a novel ITNM system for enhanced prognostic stratification in colorectal cancer.
    Jiaqi Hu, Minghao Zhang, Yang Qi, Yun Wang, Dalin Xu, Kejin Zhu, Jun Bu.
       Background: The standard TNM staging system for colorectal cancer (CRC) fails to reflect true tumor biology because it ignores key histopathologic features such as lymphovascular and perineural invasion. We therefore developed and validated an "ITNM" classification that folds these two factors into the N stage, yielding more accurate prognoses and greater clinical value.
    Methods: A retrospective cohort of 442 stage I-III CRC patients underwent radical resection (2015-2021). Propensity score matching (PSM) created balanced exposure (LVI/PNI-positive, n = 185) and control (LVI/PNI-negative, n = 257) groups. The ITNM system was constructed by upstaging the N category based on LVI/PNI status. Predictive performance was evaluated using C-index, ROC-AUC, calibration curves, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).
    Results: Multivariate analysis confirmed LVI (HR = 2.10, p = 0.018) and PNI (HR = 2.28, p = 0.025) as independent predictors of overall survival (OS). The LVI/PNI-positive group had significantly lower 5-year OS (69.5% vs. 88.2%, p < 0.001). The ITNM system demonstrated superior discriminative ability for 5-year OS (C-index = 0.715; AUC = 0.735, 95% CI: 0.691-0.776), excellent calibration (p = 0.489), and higher net benefit on DCA. Significant reclassification improvement was confirmed (NRI = 0.306, p < 0.001; IDI = 0.061, p < 0.001).
    Conclusion: The ITNM system significantly enhances prognostic accuracy by integrating LVI and PNI into TNM staging, enabling risk-adapted therapeutic decision-making and representing a paradigm shift in CRC stratification.
    Keywords:  TNM staging; colorectal cancer; lymphovascular invasion; perineural invasion; prognosis model
    DOI:  https://doi.org/10.3389/fonc.2026.1745324
  4. Front Oncol. 2026 ;16 1717432
    Brain metastases from non-small cell lung cancer: molecular subtypes and emerging CNS-directed precision therapies.
    Mehek Sharma, Anvay Shah, Kimberly A Rivera-Caraballo, Girindra Raval, Balveen Kaur, Gerald C Wallace.
      Non-small-cell lung cancer (NSCLC) is a leading cause of morbidity and mortality globally, due in large part to the development of NSCLC-associated brain metastases (L-BM). Upon initial presentation, 11-26% of patients with NSCLC will have L-BM, while half of patients with NSCLC will develop L-BM over the course of their disease. The emergence of PD-1/PD-L1 immunotherapy and targeted therapies for EGFR, ALK, and ROS1 mutations has transformed the treatment landscape and improved outcomes for select patient populations. CNS progression remains a major challenge due to therapy resistance, the blood-brain barrier (BBB), and the unique molecular and transcriptomic adaptations exhibited by NSCLC brain metastases which differs markedly from primary lung tumors. In this review, we examine the molecular drivers of CNS metastasis, oncogenic signaling-targeted therapies, and next-generation CNS drug-delivery strategies including intraventricular or intranasal administration, focused ultrasound, nanocarriers, and efflux transporter modulation. Furthermore, we provide a comprehensive update on recent and ongoing preclinical and clinical studies, highlighting novel CNS-penetrant agents with demonstrated intracranial efficacy. Understanding these mechanisms and refining targeted approaches are critical to improving CNS disease control, survival outcomes, and quality of life for NSCLC patients with brain involvement.
    Keywords:  BBB penetration; brain metastases; molecular biomarkers; non-small cell lung cancer; patient-centered outcomes; targeted therapies
    DOI:  https://doi.org/10.3389/fonc.2026.1717432
  5. Cancer Lett. 2026 Feb 06. pii: S0304-3835(26)00067-4. [Epub ahead of print]643 218304
    LINC01978 drives perineural invasion in cholangiocarcinoma through tumor-neural crosstalk and CCL2-mediated macrophage recruitment.
    Haoran Li, Runhe Zhou, Xueling Wang, Zhaowei Sun, Kai Ma, Bingyuan Zhang, Qinlei Wang, Chuan Feng, Bin Zhou, Yujie Feng.
      Perineural invasion (PNI) is a major contributor to the aggressiveness and poor prognosis of cholangiocarcinoma (CCA). However, the crosstalk among tumor cells, the peripheral nervous system, and tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) remains incompletely defined. Using in vitro and in vivo models of PNI, we demonstrate that tumor-derived exosomal LINC01978 mediates neural reprogramming and TAM-associated extracellular matrix (ECM) remodeling. Subsequent analyses of clinical cohorts confirm that high LINC01978 expression is significantly associated with PNI and poorer survival. This mechanism is further validated in human specimens by IHC and IF. Mechanistically, we propose a nerve-coupled dual-loop model that drives PNI in CCA. In the first loop, tumor-derived exosomes deliver LINC01978 to neural cells. This process promotes neurite outgrowth via autocrine glial cell line-derived neurotrophic factor (GDNF) signaling, which in turn activates the RET/STAT3 signaling pathway in CCA cells, thereby promoting malignant phenotypes. After this loop is established, a second loop emerges at the invasive front. Invaded nerves secrete CCL2, thereby preferentially recruiting CCR2+ inflammatory monocytes (IMs) to PNI sites, where they differentiate into TAMs and secrete CTSB to degrade the perineural ECM. Together, the two loops act sequentially and reinforce each other, creating a self-amplifying program that escalates PNI.
    Keywords:  CCL2; LINC01978; Macrophages; Perineural invasion; RET
    DOI:  https://doi.org/10.1016/j.canlet.2026.218304
  6. Cancer Discov. 2026 Feb 09.
    Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression.
    Jérémy Nigri, Wenjun Lan, Melanie L Fung, Charlotte Kayser, Astrid Deschênes, Juliene Hinds, Sanjeev Kaushalya, Sara A Pawlak, Jennifer S Thalappillil, Sandeep Nadella, Marc Hilmi, Wungki Park, Rajya Kappagantula, Youngkyu Park, Zhen Zhao, Jonathan Preall, Christine A Iacobuzio-Donahue, Kevin J Tracey, Jeremy C Borniger, David A Tuveson.
      Pancreatic ductal adenocarcinoma (PDAC) co-opts the peripheral nervous system through nerve hypertrophy, axonogenesis and perineural invasion, and these processes correlate with patient morbidity and mortality. Prior work has shown that autonomic nerves directly modulate neoplastic cells in PDAC, but whether cancer-associated fibroblasts (CAFs) participate in neural remodeling is unknown. Using thick tissue sections, we identified dense neo-innervation near myofibroblastic CAFs (myCAFs) in preinvasive Pancreatic Intraepithelial Neoplasms (PanINs). Mechanistically, TGF-β produced during inflammation and neoplasia triggers myofibroblast formation, and myCAFs produce axon guidance molecules that recruit sympathetic nerves. Norepinephrine released by sympathetic nerves activates myofibroblast cultures in vitro, and sympathetic nerve depletion impairs stromal activation and PDAC growth in vivo. A chemogenetic model confirmed that fibroblast-specific α1-adrenergic signaling exacerbated pancreatic inflammation and neoplasia. Therefore, beyond direct epithelial effects, sympathetic nerves promote pancreatitis and PDAC by co-opting myofibroblasts and myCAFs as disease amplifiers, highlighting CAF subtype-specific stromal interactions as putative therapeutic targets.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1337
  7. Front Oncol. 2025 ;15 1679585
    Prognostic factors affecting survival and recurrence in patients undergoing curative surgery for rectal cancer: a 10-year retrospective cohort study from a regional tertiary center in Türkiye.
    Merve Yumak, Mehmet Salim Demir.
       Background: Rectal cancer remains a major health burden worldwide, with significant morbidity and mortality despite advances in multimodal treatment. Identifying factors associated with postoperative mortality and recurrence is crucial for improving long-term outcomes.
    Objective: To evaluate clinical, pathological, and treatment-related predictors of overall survival (OS) and disease-free survival (DFS) in patients who underwent curative surgery for rectal cancer at a regional tertiary care center in Türkiye.
    Methods: This retrospective cohort study included 122 patients who underwent rectal cancer surgery between 2013 and 2023 at Van Training and Research Hospital. Demographic, clinical, and pathological variables were recorded, including tumor location, differentiation, lymphovascular invasion (LVI), perineural invasion (PNI), neoadjuvant/adjuvant therapy, and resection margin status. Survival analysis was performed using the Kaplan-Meier method, and independent prognostic factors were identified through multivariate Cox regression.
    Results: The median overall survival was 156.0 months (95% CI, 132.4-179.6), and the median disease-free survival was 28.5 months (95% CI, 22.0-36.5). Mortality was significantly associated with LVI (p=0.001), PNI (p=0.007), poor differentiation (p<0.001), R1 resection (p=0.013), emergency surgery (p=0.043), and follow-up metastasis (p<0.001). Patients with LVI had a 3.89-fold increased mortality risk, while follow-up metastasis increased mortality risk 8.75-fold. Recurrence was significantly associated with mid-rectal tumors, advanced T/N stage, LVI, PNI, and positive margins. Elevated carcinoembryonic antigen (CEA) levels were also predictive of poor outcomes.
    Conclusion: LVI, PNI, tumor grade, margin status, and follow-up metastasis are strong predictors of recurrence and mortality in rectal cancer surgery. Incorporating these parameters into postoperative risk stratification may enhance surveillance and therapeutic strategies, especially in regional healthcare settings.
    Keywords:  CEA; cox regression; lymphovascular invasion; neoadjuvant therapy; perineural invasion; rectal cancer; recurrence; surgical oncology
    DOI:  https://doi.org/10.3389/fonc.2025.1679585
  8. Quant Imaging Med Surg. 2026 Feb 01. 16(2): 154
    Diagnostic efficacy of dual-energy computed tomography-based fractal analysis for assessing extramural venous invasion/tumor deposits and peripheral nerve invasion in rectal cancer.
    Changjiang Zhang, Yinglan Shu, Junfan Chen, Tianqi Feng, Lifeng Lu, Hongjing Wang, Weijuan Chen, Xinjie Liu, Yindeng Luo.
       Background: Extramural venous invasion (EMVI), tumor deposits (TDs), and peripheral nerve invasion (PNI) are high-risk pathological features in patients with rectal cancer (RC), but their preoperative assessment with conventional computed tomography (CT) is limited. This study aimed to evaluate the value of dual-energy computed tomography (DECT)-based fractal analysis for predicting EMVI/TD and PNI in patients with RC.
    Methods: A total of 130 patients with histologically confirmed RC who underwent preoperative DECT were consecutively enrolled and divided into a retrospective development cohort (n=85) and a prospective validation cohort (n=45). Fractal dimensions (FDs) from conventional mixed-energy images (FD-Con), iodine maps [FD-iodine concentration (FD-IC)], and effective atomic number (Zeff) maps (FD-Zeff) were calculated. Patients were classified as PNI-positive/-negative and EMVI/TD-positive/-negative according to surgical pathology. Group comparisons, receiver operating characteristic (ROC) curve analysis, and multivariable logistic regression were used to identify independent predictors and build combined models, which were tested in the validation cohort.
    Results: Among the 130 patients, 59 were PNI-positive and 35 were EMVI/TD-positive. FD-IC and FD-Zeff were significantly higher in positive than in negative groups for both PNI and EMVI/TD (all P values ≤0.019). In the validation cohort, FD-IC and FD-Zeff achieved areas under the ROC curves (AUCs) of 0.752 and 0.771 for predicting PNI and 0.795 and 0.855 for predicting EMVI/TD, respectively. FD-IC was an independent risk factor for PNI [odds ratio (OR) =77.873; P=0.039], and FD-Zeff was an independent predictor of EMVI/TD (OR =1.109×104; P=0.006). In the validation cohort, the combined model yielded AUCs of 0.771 and 0.879 for PNI and EMVI/TD, respectively.
    Conclusions: DECT-based fractal analysis, particularly FD-IC and FD-Zeff, provides quantitative markers for preoperative prediction of PNI and EMVI/TD in patients with RC and improves diagnostic performance as compared with conventional CT-based fractal parameters.
    Keywords:  Rectal cancer (RC); computed tomography (CT); fractals
    DOI:  https://doi.org/10.21037/qims-2025-862
  9. iScience. 2026 Feb 20. 29(2): 114753
    Prelimbic cortex-basolateral amygdala glutamatergic circuit drives cancer-induced bone pain in mice.
    Qi-Yan Feng, Jin-Rong Wei, Meng-Xue Song, Zi-Yue Deng, Yong-Chang Li, Shu-Fen Hu, Fu-Chao Zhang, Hai-Long Zhang, Guang-Yin Xu, Guo-Qin Jiang.
      Cancer-induced bone pain (CIBP), resulting from bone metastases, is excruciating and lacks effective treatment. Previous studies on CIBP mechanisms mainly focused on the peripheral nervous system and spinal cord, with limited attention to the brain. This study investigates the prelimbic cortex (PrL) to basolateral amygdala (BLA) circuit in regulating CIBP in female mice. CIBP models were established by injecting E0771 cells into the tibias of C57BL/6J female mice. c-Fos expression and calcium activity in BLAGlu neurons were significantly elevated in CIBP models. Optogenetic inhibition of either BLAGlu neurons or PrLGlu neurons projecting to BLA increased pain thresholds. The PrLGlu-BLAGlu projection was activated by CIBP, and chemogenetic inhibition of BLAGlu neurons reversed this overactivation and pain thresholds. Glutamate probe analysis showed excessive glutamate release in the BLA, which was reduced by the chemical inhibition of the PrL-BLA circuit. This study identifies a PrLGlu-BLAGlu circuit controlling CIBP, offering new therapeutic insights.
    Keywords:  Biological sciences; Cancer; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.114753
  10. J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00138-9. [Epub ahead of print] 111268
    Downregulation of ClC-3 chloride channels in dorsal root ganglia neurons contributes to bone metastasis-induced pain.
    Zi-Xian Zhang, Ying-Shuang Qiu, Xian-Zhen Yin, Jin Xi, Qi You, Gang Xu, Jian-Zhong Guan.
      Bone metastasis-induced pain is a debilitating condition that remains a pervasive clinical challenge, with effective treatments still lacking. Although ClC-3 chloride channels are known to play an important role in synaptic transmission within the central nervous system, their expression and function in peripheral sensory neurons are poorly understood. Here, we found that the downregulation of ClC-3 in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and contributed to bone metastasis-induced pain. Overexpressing Clc-3 in DRG neurons attenuated tumor-induced neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas knocking down Clc-3 induced neuronal hyperexcitability and pain hypersensitivity in naïve rats. Mechanistically, tumor-associated production of insulin-like growth factor 1 (IGF1) activated the receptor IGF1R on DRGs, leading to an upregulation of histone deacetylase 2 (HDAC2), thereby suppressing the transcription of Clc-3 gene. Activation of the IGF1/IGF1R-AKT signaling pathway promotes HDAC2-mediated epigenetic silencing of Clc-3, thereby enhancing neuronal excitability and pain hypersensitivity in tumor-bearing rats. Our findings reveal a new and targetable mechanism underlying bone metastasis-induced pain, offering promising therapeutic avenues for pain management in cancer patients.
    Keywords:  ClC-3 chloride channels; bone metastasis-induced pain; histone deacetylase 2; insulin-like growth factor 1
    DOI:  https://doi.org/10.1016/j.jbc.2026.111268
  11. Cancer Lett. 2026 Feb 09. pii: S0304-3835(26)00081-9. [Epub ahead of print]643 218318
    Bidirectional relationship between cancer and depression: From shared mechanisms to integrated therapeutic strategies.
    Zichen Liu, Jiaming Wan, Shupeng Liu.
      Cancer and depression exhibit a clinically significant bidirectional association, as evidenced by the key findings: cancer patients are prone to depression, and depressed patients are prone to cancer. This may help explain why depression is commonly observed in cancer populations, where it is associated with poorer treatment adherence, diminished quality of life, and elevated mortality. Conversely, depression associated with an elevated cancer risk, potentially mediated by factors, such as neuroimmune dysregulation, chronic inflammation, and unhealthy lifestyles. Shared mechanisms include stress-induced β-adrenergic signaling, neuroinflammation, kynurenine pathway activation, and gut-brain-tumor axis disruptions involving bacterial metabolites like acetate. Common lifestyle factors such as smoking and sleep disruption, may further link both conditions through pathways like Wnt/β-catenin and JAK/STAT. Integrated treatment strategies combining anti-inflammatory medications such as non-steroidal anti-inflammatory drugs (NSAIDs) or tumor necrosis factor-α (TNF-α) inhibitors, psychotropic medications such as selective serotonin reuptake inhibitors (SSRIs), lifestyle modifications (e.g., exercise, Mediterranean diet) and psychotherapy (e.g., CBT) are promising for breaking the potential depression-cancer cycle and improving outcomes.
    Keywords:  Cancer; Depression; Gut-brain axis; Immunotherapy; Lifestyle interventions; Microbiota; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.canlet.2026.218318
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