bims-netuvo 2025-05-25 papers

Cancer Lett. 2025 May 21. pii: S0304-3835(25)00384-2. [Epub ahead of print] 217817

Neurodegeneration of Local Sympathetic Inputs Promotes Colorectal Cancer Progression.

Xin Chen, Ying Cao, Yifei Zhao, Yao Ma, Xiangchao Shi, Junwei Wang, Zhaoyu Jiang, Renjie Luo, Zhangyuzi Deng, Xin Zhou, Jing Yang, Wei Fu.

The nervous system can profoundly influence cancer prognosis, and this frontier of cancer neuroscience has increasingly garnered research attention. However, the involvement of neural signals in colorectal cancer remains incompletely understood. In this study, we exploit advanced three-dimensional imaging and conventional immunohistochemistry to observe a transitional loss of local sympathetic inputs from colorectal adenomas to adenocarcinomas in human patients. This negative correlation similarly occurs in the mouse models of colorectal cancer. Of importance, the pharmacologic ablation of sympathetic innervations significantly exaggerates the progression of colorectal tumors in the chemical-induced mouse model. We then demonstrate that the sympathetic neurotransmitter norepinephrine acts via α2-adrenergic receptors to elevate the cancer cell expression of chemokines to recruit CD8+ T cells, and the destruction of sympathetic signals leads to their reduction within the tumor microenvironment. Together, these results have elucidated a novel aspect of the neurodegeneration of local sympathetic inputs in promoting colorectal cancer progression.

Keywords: Axonal degeneration; CCL5; antitumor immunity; colitis; lightsheet microscopy; malignant transformation; tissue inflammation

DOI: https://doi.org/10.1016/j.canlet.2025.217817

Int J Colorectal Dis. 2025 May 16. 40(1): 120

Neural influences in colorectal cancer progression and therapeutic strategies.

Zhibin Zeng, Shirong Cai, Chenle Ye, Tongduan Li, Yan Tian, Enyuan Liu, Junbin Cai, Xiaojun Yuan, Heng Yang, Quanqi Liang, Kaishu Li, Cui Peng.

PURPOSE: This review aims to elucidate the neural mechanisms driving colorectal cancer (CRC) growth, metastasis, and therapeutic resistance, summarizing the roles of neurotransmitters, neurotrophic factors, and neural signaling in carcinogenesis. It further explores therapeutic strategies targeting neural dependencies in CRC.
METHODS: A comprehensive PubMed search was conducted using the keywords colorectal cancer and tumor innervation, focusing on studies published between 2000 and 2024. The review synthesizes evidence across four domains: neurotransmitter-receptor interactions, gut-brain-microbiota axis dynamics, neuroimmune modulation, and neural regulation of cancer stem cells, discussing their collective impact on CRC pathophysiology.
RESULTS: Neural innervation significantly influences CRC progression. For instance, the neurotransmitter serotonin promotes tumor growth and metastasis via paracrine and autocrine stimulation, while neurotrophic mediators like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) activate oncogenic signaling through receptor tyrosine kinases (RTKs). Downstream pathways, such as Wnt/β-catenin signaling, are modulated by neural inputs, underscoring CRC's neurodevelopmental dependency and highlighting their potential as therapeutic targets.
CONCLUSION: Neural mechanisms are pivotal in CRC progression, revealing novel therapeutic avenues. Strategies targeting neurotransmitter synthesis, neurotrophic signaling, or neuroimmune crosstalk may disrupt tumorigenic loops while preserving systemic nervous system integrity. Future research must prioritize translating these insights into clinical interventions to improve patient outcomes. Elucidating the intricate interplay between neural mediators and cancer pathogenesis, coupled with developing therapies specifically targeting the neurogenic basis of CRC aggressiveness, represents a critical frontier in oncology.

Keywords: Colorectal cancer; Gut-brain axis; Mechanism; Neural innervation; Targeted therapy

DOI: https://doi.org/10.1007/s00384-025-04887-w

Eur J Nucl Med Mol Imaging. 2025 May 19.

First clinical investigation to predict lymphovascular and/or perineural invasion in gastric cancer using 18F-FAPI-42 PET/CT parameters.

Lilan Fu, Fei Xie, Penghui Sun, Ye Dong, Kemin Zhou, Li Jiang, Ruihe Wu, Yanjiang Han, Hubing Wu, Ganghua Tang, Wenlan Zhou.

OBJECTIVE: This study was conducted to explore the predictive value of PET parameters derived from 18F-FAPI-42 PET/CT in assessing lymphovascular and/or perineural invasion (LVI/PNI) in gastric cancer (GC) patients.
METHODS: 72 GC patients who underwent 18F-FAPI-42 PET/CT prior to surgical resection were included. Clinicopathological factors and PET parameters were collected and analyzed in LVI/PNI-negative and LVI/PNI-positive groups. The predictive value of PET parameters for LVI/PNI status was evaluated using the receiver operating characteristic (ROC) curve. A nomogram was developed using significant predictors from multivariate stepwise regression analysis and its performance was assessed by decision curve analysis (DCA).
RESULTS: Univariate analysis indicated a significant association between LVI/PNI status and PET parameters (SUVmax, SUVmean, and TBR) (all p < 0.001). The area under the ROC curve (AUC) values for predicting LVI/PNI were 0.932 [95% CI (0.877-0.987)] for SUVmax, 0.923 [95% CI (0.861-0.984)] for SUVmean, and 0.925 [95% CI (0.865-0.985)] for TBR. The optimal cutoff values for prediction, along with their corresponding sensitivity and specificity, were 3.86 (93.3% and 81.5%) for SUVmax, 2.04 (93.3% and 81.5%) for SUVmean, and 9.75 (91.1% and 81.5%) for TBR. Multivariate analysis identified histological grade and SUVmax as independent risk factors for LVI/PNI prediction. Our nomogram had good discriminatory ability (AUC = 0.934) and offered net benefits in predicting LVI/PNI status by DCA.
CONCLUSION: This study demonstrates that FAPI uptake parameters exhibit an exceptionally high capacity and serve as a noninvasive preoperative tool for predicting LVI/PNI status in GC, with SUVmax emerging as the most suitable predictive indicator.

Keywords: Fibroblast activating protein inhibitor; Gastric cancer; Lymphovascular invasion; Perineural invasion; Positron emission tomography

DOI: https://doi.org/10.1007/s00259-025-07325-9

J Gastrointest Oncol. 2025 Apr 30. 16(2): 549-567

Prognostic nomogram for T3-T4 primary colorectal cancer patients with perineural invasion after surgery: a Surveillance, Epidemiology, and End Results program database analysis.

Hui Wu, Xue Liu, Haitao Chen, Qinghua Yao.

Background: Colorectal cancer (CRC) is a common malignancy, with T3-T4 primary CRC characterized by perineural invasion (PNI), representing an aggressive subtype with poor prognosis. This study aimed to develop and validate prognostic nomograms for predicting overall survival (OS) and cancer-specific survival (CSS) in patients with T3-T4 primary CRC and PNI after surgery.
Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on patients diagnosed with T3-T4 primary CRC and PNI between 2000 and 2019. Eligible patients were randomly divided into training and validation cohorts. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors, which were integrated into nomograms for OS and CSS. The nomograms were assessed using the concordance index (C-index), receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA).
Results: A total of 7,808 patients met the inclusion criteria. Significant prognostic factors identified in the multivariate analysis included age, sex, race, marital status, site, Tumor (T) stage of the Tumor, Node, Metastasis (TNM) staging system, radiation, regional node positive, liver and lung metastasis, tumor size, histologic type, median household income, and SEER summary stage. The nomograms exhibited good predictive accuracy, with C-indexes of 0.7422 for OS in the training cohort and 0.7428 in the validation cohort. The nomograms were validated using ROC curves, calibration plots, and DCA, which confirmed the models' reliability and clinical utility.
Conclusions: The developed nomograms are robust tools for predicting 3-, 5-, and 10-year OS and CSS in patients with T3-T4 primary CRC and PNI after surgery. These tools help clinicians create personalized treatment plans and improve patient outcomes.

Keywords: Colorectal cancer (CRC); Surveillance, Epidemiology, and End Results (SEER); cancer-specific survival (CSS); overall survival (OS); perineural invasion (PNI)

DOI: https://doi.org/10.21037/jgo-24-709

Int J Nanomedicine. 2025 ;20 6023-6041

Bupivacaine Nanoparticles Inhibit Triple-Negative Breast Tumor Growth by Suppressing the Noradrenergic Nerves in Tumor Microenvironment.

Haixuan Wu, Xiaoyan Huang, Hui Xu, Hongmei Yang, Zhongqi Liu, Fan Liu, Fengtao Ji, Minghui Cao.

Background: Nerves in the tumor microenvironment (TME) promote malignant phenotypes of cancer. Neuron-targeting cancer treatment strategies have garnered significant attention. However, existing pharmacological or surgical methods of denervation can lead to side effects such as pain and respiratory system issues. Targeted delivery of local anesthetics to the TME using nanotechnology to suppress nerves appears to be a promising approach.
Methods: NP-BUP, an acid-responsive nanoparticle encapsulating the local anesthetic bupivacaine, was synthetized using a nano-precipitation method. Immunofluorescence staining was employed to identify the primary types of nerves in breast tumors. In vitro, the impact of the neurotransmitter on the recruitment of macrophages by tumor supernatant is assessed using the transwell assay. ELISA assays and intracellular Ca2+ measurement experiments were conducted to evaluate the inhibitory effect of NP-BUP on noradrenergic neurons. In vivo, the impact of NP-BUP on noradrenergic neurons, tumor-associated macrophages (TAMs) infiltration, and tumor growth within the TME were assessed.
Results: The predominant type of neuron within breast tumor tissues was found to be noradrenergic neuron. Noradrenergic neuronal uptake of NP-BUP at pH 6.5 was 2.4 times higher than at pH 7.4. In vitro, NP-BUP significantly inhibited the release of norepinephrine (NE), a neurotransmitter that promotes macrophage migration, from adrenergic cells. In vivo, tumor tissues from 4T1 tumor-bearing mice treated with NP-BUP showed a significant reduction in NE content and macrophage infiltration, with tumor volume and weight decreasing by approximately 70% compared to the PBS group.
Conclusion: Our study provides a TME pH-responsive nanoplatform for targeted suppression of neuronal control within the TME. Our results demonstrate that specifically modulating innervation within the TME can influence the growth of breast cancer.

Keywords: neuromodulation; noradrenergic neurons; pH-responsive nanoparticles; triple negative breast cancer; tumor-associated macrophage

DOI: https://doi.org/10.2147/IJN.S515895