bims-netuvo 2025-08-03 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2025–08–03
thirteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

When human cancer goes neural.
ITGA5-Expressing Tumor Cells Interact with Schwann Cells to Drive Nerve Growth Factor-Mediated Immunosuppression of NK Cells.
Transcriptomic Profiling of Paired Primary Tumors and CNS Metastases in Breast Cancer Reveals Immune Modulation Signatures.
A questionnaire-based cross-sectional study on neuropathic pain in patients with cancer in Japan.
Establishing In Vitro Models of Dorsal Root Ganglia Culture: Complementary Approaches for Investigating Cancer-Nerve Crosstalk.
Neuroimmune axis in gastrointestinal cancers: From mechanisms to therapeutic breakthrough.
Impact of propofol on gastrointestinal cancer outcomes: A review of cellular behavior, growth, and metastasis.
Nociceptor neuron: a novel component directly orchestrates gastric cancer progression.
The Peripheral Tumor Neuro-Microenvironment: Deciphering Neural Landscape and Mechanistic Insights for Therapeutic Innovation.
Preclinical Evaluation of Repurposed Antimalarial Artemisinins for the Treatment of Malignant Peripheral Nerve Sheath Tumors.
Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.
Novel Therapeutics and the Path Toward Effective Immunotherapy in Malignant Peripheral Nerve Sheath Tumors.
Hijacking homeostasis: the brain-body neural circuitry in tumor pathogenesis and emerging therapeutic frontiers.

Cancer Cell. 2025 Jul 16. pii: S1535-6108(25)00275-2. [Epub ahead of print]

When human cancer goes neural.

Christina Nürnberg, Sophie Heuer, Frank Winkler.

Invasion along nerves is prognostically detrimental in pancreatic and other cancers, yet its microenvironmental composition in humans remains poorly understood. In this issue of Cancer Cell, Chen et al. present a patient-derived high-resolution spatial and molecular atlas to reveal significant effects of cancer cell invasion on neuro-immuno-oncological and other nerve features.

DOI: https://doi.org/10.1016/j.ccell.2025.07.004
Mol Ther. 2025 Jul 28. pii: S1525-0016(25)00579-9. [Epub ahead of print]

ITGA5-Expressing Tumor Cells Interact with Schwann Cells to Drive Nerve Growth Factor-Mediated Immunosuppression of NK Cells.

Yingqiao Liu, Guoxu Han, Kang Feng, Xiaoyang Lin, Weijun Zhong, Yilian Liu, Cheng Wang, Caihua Zhang, Xiqiang Liu.

Perineural invasion (PNI) complicates cancer treatment by promoting tumor spread and immune evasion through interactions between tumor cells and peripheral nerves in the tumor microenvironment (TME). This study investigates the role of tumor cells in PNI and their impact on neuro-immunomodulation. We identified a strong correlation between elevated ITGA5 expression and PNI, both associated with poor clinical outcomes due to their contribution to an immunosuppressive TME. Specifically, high ITGA5 expression in tumor cells increased nerve density and reduced NK cell infiltration, facilitating immune evasion. Functional assays revealed that the interaction between ITGA5 on tumor cells and fibronectin (FN1) in the Schwann cell extracellular matrix triggers the reprogramming of Schwann cells to a reparative phenotype, enhancing NGF secretion and promoting tumor neurogenesis. Increased NGF suppresses NK cell cytotoxicity by inhibiting IFN-γ, further supporting tumor growth. Additionally, Cilengitide significantly improves anti-PD-1 immunotherapy efficacy, offering a potential therapeutic strategy to counteract PNI-driven immunosuppression. This study identifies ITGA5 as a key promoter of tumor invasion into nerves, enhancing NGF release from Schwann cells and altering the immune landscape to favor tumor growth. These findings open new avenues for therapies targeting these interactions in cancer progression.

DOI: https://doi.org/10.1016/j.ymthe.2025.07.043
Int J Mol Sci. 2025 Jul 19. pii: 6944. [Epub ahead of print]26(14):

Transcriptomic Profiling of Paired Primary Tumors and CNS Metastases in Breast Cancer Reveals Immune Modulation Signatures.

Ana Julia Aguiar de Freitas, Muriele Bertagna Varuzza, Stéphanie Calfa, Rhafaela Lima Causin, Vinicius Duval da Silva, Cristiano de Pádua Souza, Márcia Maria Chiquitelli Marques.

  Breast cancer is a leading cause of central nervous system (CNS) metastases in women, often associated with poor prognosis and limited therapeutic options. However, molecular differences between primary tumors and CNS metastases remain underexplored. We aimed to characterize transcriptomic differences between primary breast tumors and matched CNS metastases and identify immune-related biomarkers associated with metastatic progression and patient outcomes. Transcriptomic profiling was based on 11 matched FFPE sample pairs (primary tumor and CNS metastasis). Paired formalin-fixed paraffin-embedded (FFPE) samples from primary tumors (T1) and CNS metastases (T2) were analyzed using the NanoString nCounter® platform and the PanCancer IO 360™ Gene Expression Panel. Differential gene expression, Z-score transformation, and heatmap visualization were performed in R. In silico survival analyses for overall survival (OS) and recurrence-free survival (RFS) were conducted using publicly available TCGA and GEO datasets. Forty-five genes were significantly differentially expressed between the T1 and T2 samples. Immune-related genes such as CXCL9, IL7R, CD79A, and CTSW showed consistent downregulation in CNS metastases. High expression of CXCL9 and CD79A was associated with improved OS and RFS, whereas high IL7R and CTSW expression correlated with worse outcomes. These findings indicate immune suppression as a hallmark of CNS colonization. Comparative transcriptomic analysis further underscored the distinct molecular landscapes between primary and metastatic tumors. This study highlights transcriptional signatures associated with breast cancer CNS metastases, emphasizing the role of immune modulation in metastatic progression. The identified genes have potential as prognostic biomarkers and therapeutic targets, supporting the need for site-specific molecular profiling in metastatic breast cancer management.

Keywords:  CNS metastases; NanoString; breast cancer; gene expression; immune biomarkers; personalized oncology

DOI:  https://doi.org/10.3390/ijms26146944
Jpn J Clin Oncol. 2025 Aug 01. pii: hyaf116. [Epub ahead of print]

A questionnaire-based cross-sectional study on neuropathic pain in patients with cancer in Japan.

Saori Hashiguchi, Hiroshi Takahashi, Shuhei Yamamoto, Haruhiko Seki, Yaoki Sonohara, Yuko Tanabe.

   BACKGROUND: Some patients with cancer experience cancer-related neuropathic pain. This study investigated the prevalence of possible neuropathic pain in patients with cancer.
METHODS: This observational, cross-sectional, questionnaire-based study recruited adult participants with stage ≥II cancer in Japan between June and November 2024. The primary endpoint was the proportion of participants with suspected neuropathic pain (Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs pain scale [S-LANSS] score ≥ 12 points). Secondary endpoints included pain scores (11-point numeric rating scale [NRS]), communication with healthcare professionals, impact on daily activities, and quality of life (QoL) per the EQ-5D-5L.
RESULTS: Responses from 713 participants were analyzed. Of those, 230 participants (32.3%) reported cancer-related pain and 53 (7.4%) had suspected neuropathic pain. Among participants with suspected neuropathic pain, the mean ± standard deviation (SD) pain intensity (NRS) was 5.1 ± 2.7. Over one-third of participants (37.7% [20/53]) with suspected neuropathic pain reported that no healthcare provider had asked about cancer pain before they sought a consultation, 60.4% (32/53) wished their healthcare provider had noticed their pain sooner, 69.8% (37/53) could no longer perform some daily activities due to cancer pain, and 98.1% (52/53) thought their pain needed to be adequately treated for them to live their life going forward. QoL was lower among participants with suspected neuropathic pain versus the overall population (EQ-5D-L mean ± SD: 0.6065 ± 0.2518 vs 0.8204 ± 0.1788).
CONCLUSIONS: These findings suggest that pain assessment earlier in the cancer treatment process than standard may improve pain management for patients with cancer.

Keywords:  S-LANSS; cancer; neuropathic pain; questionnaire

DOI:  https://doi.org/10.1093/jjco/hyaf116
J Vis Exp. 2025 Jul 11.

Establishing In Vitro Models of Dorsal Root Ganglia Culture: Complementary Approaches for Investigating Cancer-Nerve Crosstalk.

Larissa C B Oliveira, Erica R Pereira, Brandy D Hyndman, Bryanna Thomson, Juliana M Serpeloni, Lois M Mulligan.

The contribution of the nervous system to the tumor microenvironment and the importance of neural invasion as a route for cancer dissemination are being increasingly recognized. Interactions of cancer cells with neurons can promote their invasion around and into nerves, a feature of many cancers with poor clinical outcomes. In vitro models to study reciprocal interactions between neurons and cancer cells provide valuable tools for understanding cancer spread and identifying approaches to mitigate it. Here, we describe a protocol for murine dorsal root ganglia (DRG) isolation and the establishment of both whole mount and dissociated monolayer cultures that can be used to visualize neuron morphology and neurite outgrowth over time. Whole DRGs mounted in Matrigel preserve nerve architecture and responses to stimuli in a heterogeneous environment more similar to the in vivo nerve, while dissociated nerve cultures allow assessment of direct cell-cell interactions more closely. Once DRG cultures are established, cancer cells can be added to generate co-cultures that can be used to visualize changes in neurite outgrowth and nerve morphology in response to cancer cells. Growth or motility of cancer cells in response to nerve-derived signals over time or under conditions of growth stimulation or inhibition can be assessed, as well as visualizing the effects of direct contact between cancer cells and nerve extensions. As both co-culture models can be generated simultaneously, this protocol provides a more comprehensive view of the impact of cancer-neuron interactions and facilitates comparisons of treatment conditions and integration of information from the cellular level and whole ganglia. This protocol will facilitate the study of nerve-tumor interactions and can be used for a wide range of applications, including studies of cell signaling, drug screening, or study of the heterogeneity of the tumor-nerve environment and the mechanisms of tumor dissemination along nerves.

DOI: https://doi.org/10.3791/68552
Cell Rep. 2025 Jul 28. pii: S2211-1247(25)00830-7. [Epub ahead of print]44(8): 116059

Neuroimmune axis in gastrointestinal cancers: From mechanisms to therapeutic breakthrough.

Yixuan Zhang, Jintian Chen, Yiwei Zhou, Yanjun Jiang, Jielun Hu, Xiaodong Liu, Jingying Zhou.

  Accumulating evidence has demonstrated that tumor cells can co-opt the nervous and immune systems to facilitate their growth, progression, and metastasis. Tumor innervation has been reported to regulate cancer development either directly or indirectly by modulating immune evasion through the neuroimmune axis. Building on insights into the mechanisms of cancer-neuroimmune interactions, attention is turning to developing novel therapeutics by repurposing neuropsychiatric drugs or using neuromodulation. Given the rich innervation of the gastrointestinal (GI) tract and its accessory organs, we summarize the current understanding of neuroimmune networks in GI cancers, focusing on the most recent updates of neurotransmitter-receptor pathways and tumor-innervating nociceptors. Additionally, we discuss the underlying mechanisms of these pathways and explore their therapeutic implications, which may potentially lead to new approaches for combinatory immunotherapies in GI cancers.

Keywords:  CP: Cancer; CP: Neuroscience; combinatory immunotherapy; gastrointestinal cancer; neuroimmune axis; neuropeptide; neurotransmitter; nociceptors; tumor innervation

DOI:  https://doi.org/10.1016/j.celrep.2025.116059
World J Clin Oncol. 2025 Jul 24. 16(7): 104727

Impact of propofol on gastrointestinal cancer outcomes: A review of cellular behavior, growth, and metastasis.

Funda Arun, Oguzhan Arun.

  Cancer is one of the most important health problems that deeply affects all humanity and will have groundbreaking consequences in human history with its elimination. Gastrointestinal cancers, including colon and rectum, stomach, liver, pancreatic, and esophageal, account for 26% of the global cancer incidence and 35% of cancer-related deaths. Unfortunately, it is estimated that today's high incidence and mortality rates will increase by 58% and 73% by 2040, respectively. Although the treatment process includes novel options such as immunotherapy in addition to classical options with a multidisciplinary approach, surgical treatment under general anesthesia remains the leading option. Considering a long-lasting cancer process, it is quite surprising that a very short-term anesthetic administration can have various effects on cancer cell behavior. Various anesthetic approaches such as regional blocks used in pain management, the use of anesthetic adjuvants such as β-adrenoceptor antagonists, nonsteroidal anti-inflammatory drugs, and intravenous lidocaine, and the choice of anesthetic drugs seem to have potential effects on long-term cancer outcomes. Propofol is an intravenous anesthetic drug that is used for both induction and maintenance of general anesthesia. Many in vitro and clinical studies examining the effects of propofol comparatively with other anesthetic agents on tumor recurrence and metastasis revealed possible effects on tumor cell signaling, the immune response, and the modulation of the neuroendocrine stress response. However, the evidence from all these in vitro and clinical studies is different, complicated, and inconsistent. The general effects of propofol on the behavioral patterns, growth, and metastasis of gastrointestinal tumor cells, as well as the clinical features and consequences resulting from these effects, constitute the subject of this review.

Keywords:  Gastrointestinal cancer; General anesthesia; Morbidity; Outcomes; Propofol; Survival

DOI:  https://doi.org/10.5306/wjco.v16.i7.104727
J Mol Med (Berl). 2025 Jul 31.

Nociceptor neuron: a novel component directly orchestrates gastric cancer progression.

Xiaoyu Wang, Yu Cheng, Yongjie Wang.

DOI: https://doi.org/10.1007/s00109-025-02582-5
Crit Rev Oncol Hematol. 2025 Jul 29. pii: S1040-8428(25)00259-8. [Epub ahead of print] 104871

The Peripheral Tumor Neuro-Microenvironment: Deciphering Neural Landscape and Mechanistic Insights for Therapeutic Innovation.

Xiaoxiao Wang, Yuetong Pan, Yanting Zhou, Tianjing Tang, Fei Li, Hongyan Li.

  As the nascent field of cancer neuroscience experiences explosive growth, the critical importance of the peripheral nervous system (PNS) in the onset, progression, and therapeutic approaches of cancer has garnered considerable attention from researchers in recent years. The neural-tumor interactions mediated by PNS components in the tumor microenvironment (TME) constitute the neural landscape of peripheral cancers, where neural activity regulates metastatic competence through structural innervation networks, neurochemical signaling cascades, and immune microenvironment remodeling. Within the TME, the synergistic interplay among cancer cells, neurons, and schwann cells establishes a dynamic neural ecological niche that orchestrates both oncogenic expansion and aberrant neural reorganization. This reflects an innovative theoretical framework of microenvironment-driven neural plasticity in cancer pathogenesis. We pioneer the conceptualization of "tumor neuro-microenvironment (TNME)", elucidating the pivotal roles of the PNS in orchestrating TNME dynamics via intricate neural-tumor interactions. By deeply dissecting the interactive networks between the PNS and TNME, as well as their mechanistic insights, we articulate the latest advancements in targeted PNS interventions for cancer therapy. This showcases its tremendous potential in anti-cancer efforts, paving the way for novel perspectives and therapeutic approaches in neuroscience-oriented cancer treatment strategies.

Keywords:  Cancer neuroscience; Cancer therapy; Neural-immune modulation; Peripheral nervous system; Tumor neuro-microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104871
Int J Mol Sci. 2025 Jul 10. pii: 6628. [Epub ahead of print]26(14):

Preclinical Evaluation of Repurposed Antimalarial Artemisinins for the Treatment of Malignant Peripheral Nerve Sheath Tumors.

Heather M Duensing, Jalen M Dixon, Owen R Hunter, Nicolina C Graves, Nickalus C Smith, Andersen J Tomes, Cale D Fahrenholtz.

  Malignant peripheral nerve sheath tumors (MPNSTs) are a rare type of soft tissue sarcoma associated with poor prognoses. The standard of care for non-resectable tumors consists of surgical excision followed by radiation and chemotherapy. MPNSTs are most common in patients with neurofibromatosis type 1 but can also occur sporadically. Regardless of origin, MPNSTs most often rely on signaling pathways that increase basal oxidative stress. This provides the basis for developing therapeutics with mechanisms that can potentiate oxidative stress to selectively eradicate tumor cells at doses that are tolerable for normal cells. Artemisinin derivatives are a mainstay of malaria therapy worldwide, with a well-established safety profile. Artemisinin's antimalarial effects are due to an endoperoxide bridge in its chemical structure that induces oxidative stress. We found that artesunate (ARS) and metabolite dihydroartemisinin (DHA) are selectively cytotoxic to MPNST cells relative to normal Schwann cells with the endoperoxide bridge required for activity. Mechanistically, DHA induced oxidative stress, lipid peroxidation, and DHA-mediated cytotoxicity could be prevented with co-administration of the antioxidant N-acetyl-cysteine. Furthermore, we found that DHA was able to selectively remove MPNST from co-culture with normal Schwann cells. These data supports the further development of artemisinins for the clinical management of MPNST.

Keywords:  antimalarials; artemisinins; artesunate; dihydroartemisinin; malignant peripheral nerve sheath tumors; neurofibromatosis type 1; redox balance

DOI:  https://doi.org/10.3390/ijms26146628
J Transl Med. 2025 Jul 25. 23(1): 836

Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.

Chen Sun, Yuqing Shen, Fuhua Wang, Tian Lu, Jianqiong Zhang.

  Tumor progression is characterized by profound metabolic alterations and dynamic interactions within the tumor microenvironment (TME), which enable rapid proliferation, immunoinvasion, and metastasis. The sympathetic nervous system (SNS), which has been best known for its role in stress regulation, has emerged as a critical regulator of tumor metabolism. The SNS influences glucose, lipid and glutamine metabolism in tumor cells and stromal components by releasing neurotransmitters such as norepinephrine (NE), creating a pro-tumor metabolic and immunosuppressive microenvironment. SNS signaling enhances glycolysis via upregulation of glucose transporter 1 (GLUT1) and glycolytic enzymes, and supports lipid metabolism through fatty acid synthesis and oxidation. In immune cells, SNS-driven metabolic shifts promote immunosuppressive phenotypes, particularly in T cells and macrophages. Concurrently, SNS signaling enhances glycolysis in endothelial cells, thereby facilitating angiogenesis within the TME. Together, these processes collectively sustain tumor growth, invasion, and resistance to therapy. Therapeutic strategies targeting SNS signaling, such as adrenergic receptors (ARs) blockers, show promise in disrupting these tumor-supportive networks. However, challenges such as the non-specific nature of SNS blockade and the complexity of TME interactions necessitate further research into ARs subtypes, tumor-specific metabolic vulnerabilities, and predictive biomarkers. This review highlights the therapeutic potential of targeting SNS signaling to reshape tumor metabolism and the microenvironment. By elucidating the metabolic impacts of its systemic and local arms, it provides a framework for integrating SNS-directed strategies with existing treatments to improve clinical outcomes.

Keywords:  Cancer therapy; Metabolic reprogramming; Sympathetic nervous system; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1186/s12967-025-06657-2
Cancers (Basel). 2025 Jul 21. pii: 2410. [Epub ahead of print]17(14):

Novel Therapeutics and the Path Toward Effective Immunotherapy in Malignant Peripheral Nerve Sheath Tumors.

Joshua J Lingo, Elizabeth C Elias, Dawn E Quelle.

  Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently "cold" tumor microenvironment into a "hot" immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy.

Keywords:  MPNST; immunotherapy; targeted therapy

DOI:  https://doi.org/10.3390/cancers17142410
Mol Cancer. 2025 Jul 25. 24(1): 206

Hijacking homeostasis: the brain-body neural circuitry in tumor pathogenesis and emerging therapeutic frontiers.

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

  Cancer research is undergoing a paradigm shift from solely studying tumor cells to investigating systemic effects of cancer in the tumor macroevironment, with an emphasis on the interactions between host organs and tumors. The theory of homeostasis is an important basis for explaining biological functions from the perspective of the organism. Organic homeostasis relies on brain-body crosstalk through interception, immunoception, nociception and other supervisory processes, guaranteeing normal physiological function. Recent studies reveal that malignant tumors can hijack and exploit the brain and its central-peripheral neuronal networks to disrupt the body's homeostasis. Tumors likely disrupt normal brain-body crosstalk by establishing bidirectional brain-tumor connections. On the contrary, organism utilize these mechanisms to hinder tumorigenesis and progression. Standing at the perspective of brain-body crosstalk also promotes the conceptional evolution of cancer initiation and development, and more importantly, provides additional insight for cancer treatment. In this review, we summarize current knowledge about brain-body crosstalk under tumor-bearing contexts and propose some novel anti-cancer strategies.

Keywords:  Brain-body; Cancer neuroscience; Drug repurposing; Homeostatic disruption; Neural circuity; Neuroimmune

DOI:  https://doi.org/10.1186/s12943-025-02396-6