bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2024–03–10
twelve papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute



  1. Front Immunol. 2024 ;15 1335387
      The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it.
    Keywords:  cancer; immune cells; neuropeptides; nociceptors; pain; peripheral sensory neurons; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1335387
  2. Am J Cancer Res. 2024 ;14(2): 448-466
      Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC) and link to poor outcome. However, how neural factors affect PDAC prognosis and the underlying mechanism as well as counteracting therapeutic are still unclear. In silico systematic analysis was performed with PROGgene to identify potential neural factor and its receptor in pancreatic cancer. In vitro assays including migration, invasion, 3D recruitment, and gemcitabine resistance were performed to study the effect of neuron-derived neurotensin (NTS) on pancreatic cancer behavior. Orthotopic animal study was used to validate the in vitro findings. Gene set enrichment analysis (GSEA) was performed to confirm the results from in silico to in vivo. Expression of NTS and its receptor 1 (NTSR1) predicted poor prognosis in PDAC. NTS synthetic peptide or neuron-derived condition medium promoted pancreatic cancer invasiveness and recruitment in 2D and 3D assays. NTS-induced effects depended on NTSR1 and PI3K activation. GDC-0941, a clinically approved PI3K inhibitor, counteracted NTS-induced effects in vitro. Inhibition of NTSR1 in pancreatic cancer cells resulted in decreased tumor dissemination and diminished PI3K activation in vivo. NTS boosted gemcitabine resistance via NTSR1 in pancreatic cancer. Our results suggest that neural cell-secreted NTS plays an important role in promoting PDAC.
    Keywords:  Akt; Neuron; neurotensin; neurotensin receptor 1; pancreatic ductal adenocarcinoma
  3. BMC Surg. 2024 Mar 05. 24(1): 80
       BACKGROUND: Perineural invasion (PNI), as the fifth recognized pathway for the spread and metastasis of colorectal cancer (CRC), has increasingly garnered widespread attention. The preoperative identification of whether colorectal cancer (CRC) patients exhibit PNI can assist clinical practitioners in enhancing preoperative decision-making, including determining the necessity of neoadjuvant therapy and the appropriateness of surgical resection. The primary objective of this study is to construct and validate a preoperative predictive model for assessing the risk of perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC).
    MATERIALS AND METHODS: A total of 335 patients diagnosed with colorectal cancer (CRC) at a single medical center were subject to random allocation, with 221 individuals assigned to a training dataset and 114 to a validation dataset, maintaining a ratio of 2:1. Comprehensive preoperative clinical and pathological data were meticulously gathered for analysis. Initial exploration involved conducting univariate logistic regression analysis, with subsequent inclusion of variables demonstrating a significance level of p < 0.05 into the multivariate logistic regression analysis, aiming to ascertain independent predictive factors, all while maintaining a p-value threshold of less than 0.05. From the culmination of these factors, a nomogram was meticulously devised. Rigorous evaluation of this nomogram's precision and reliability encompassed Receiver Operating Characteristic (ROC) curve analysis, calibration curve assessment, and Decision Curve Analysis (DCA). The robustness and accuracy were further fortified through application of the bootstrap method, which entailed 1000 independent dataset samplings to perform discrimination and calibration procedures.
    RESULTS: The results of multivariate logistic regression analysis unveiled independent risk factors for perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC). These factors included tumor histological differentiation (grade) (OR = 0.15, 95% CI = 0.03-0.74, p = 0.02), primary tumor location (OR = 2.49, 95% CI = 1.21-5.12, p = 0.013), gross tumor type (OR = 0.42, 95% CI = 0.22-0.81, p = 0.01), N staging in CT (OR = 3.44, 95% CI = 1.74-6.80, p < 0.001), carcinoembryonic antigen (CEA) level (OR = 3.13, 95% CI = 1.60-6.13, p = 0.001), and platelet-to-lymphocyte ratio (PLR) (OR = 2.07, 95% CI = 1.08-3.96, p = 0.028).These findings formed the basis for constructing a predictive nomogram, which exhibited an impressive area under the receiver operating characteristic (ROC) curve (AUC) of 0.772 (95% CI, 0.712-0.833). The Hosmer-Lemeshow test confirmed the model's excellent fit (p = 0.47), and the calibration curve demonstrated consistent performance. Furthermore, decision curve analysis (DCA) underscored a substantial net benefit across the risk range of 13% to 85%, reaffirming the nomogram's reliability through rigorous internal validation.
    CONCLUSION: We have formulated a highly reliable nomogram that provides valuable assistance to clinical practitioners in preoperatively assessing the likelihood of perineural invasion (PNI) among colorectal cancer (CRC) patients. This tool holds significant potential in offering guidance for treatment strategy formulation.
    Keywords:  Colorectal cancer; Nomogram; Perineural invasion; Surgery; Systemic inflammatory markers
    DOI:  https://doi.org/10.1186/s12893-024-02364-9
  4. Signal Transduct Target Ther. 2024 Mar 08. 9(1): 63
      Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a "neural addiction" property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of β-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3β signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
    DOI:  https://doi.org/10.1038/s41392-024-01761-z
  5. Oncogene. 2024 Mar 07.
      Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer. Growing evidence has revealed that pancreatic cancer recurrence and neuropathic pain positively correlate with PNI. Therefore, targeting PNI is a proper strategy for pancreatic cancer treatment. Exosomal lncRNA derived from pancreatic cancer cells is an essential component of the tumor microenvironment. However, whether exosomal lncXIST derived from pancreatic cancer cells can promote PNI and its exact mechanism remains to be elucidated. We show that lncXIST mediates nerve-tumor crosstalk via exosomal delivery. Our data reveal that exosomal lncXIST derived from pancreatic cancer cells is delivered to neural cells and promotes their release of glial-cell-line-derived neurotrophic factor (GDNF), essential in facilitating the PNI of pancreatic cancer. Mechanistically, microRNA-211-5p negatively regulates GDNF, and lncXIST serves as a miR-211-5p sponge. The function of exosomes in the dynamic interplay between nerves and cancer is confirmed in both in vivo and in vitro PNI models. Therefore, targeting pancreatic cancer cell-derived exosomal lncXIST may provide clues for a promising approach for developing a new strategy to combat PNI of pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41388-024-02994-6
  6. Turk J Gastroenterol. 2024 Jan;35(1): 48-60
       BACKGROUND/AIMS: Pancreatic ductal adenocarcinoma is the tumor type with the highest incidence of perineural invasion. This study tries to identify the differentially expressed genes regulated between pancreatic ductal adenocarcinoma tissues with perineural invasion and without perineural invasion.
    MATERIALS AND METHODS: The GSE102238 profile was downloaded. Gene function and pathway analysis were subsequently conducted. A protein-protein interaction network was constructed to search for hub genes. Both univariate Cox analysis and multivariate Cox analysis were calculated to identify prognostic factors. Quantitative real-time polymerase chain reaction (RT-PCR) and overall survival analysis of hub genes were used to verify.
    RESULTS: Our study identified 242 differentially expressed genes including 68 upregulated differentially expressed genes and 174 downregulated differentially expressed genes, which were involved in important functions and pathways. Nine relevant core genes using protein-protein interaction analysis as well as nestin (NES)/vascular endothlial growth factor (VEGF) signaling pathway which is highly related to the pathological process of perineural invasion in pancreatic ductal adenocarcinoma were also discovered. The differentiation was identified as an independent prognostic factor (P < .05) after multivariate Cox analysis. Three upregulated genes (JUP, CALM1, and NES) and 6 downregulated genes (EPHA2, ARF1, ORM2, TERT, IL18, and CXCL3) were validated by quantitative RT-PCR and they all had markedly worse overall survival (P < .05).
    CONCLUSION: This analysis showed that 9 core genes including JUP, CALM1, NES, EPHA2, ARF1, ORM2, TERT, IL18, and CXCL3, as well as NES/VEGF signaling pathway, have a relationship with the development process of perineural invasion in pancreatic ductal adenocarcinoma. Cox analysis and overall survival analysis suggested differentiation as an independent prognostic factor and key roles for these 9 hub genes in perineural invasion prognosis in pancreatic ductal adenocarcinoma.
    DOI:  https://doi.org/10.5152/tjg.2024.21430
  7. Cytopathology. 2024 Mar 05.
      The cytomorphology of MPNST in effusion specimens is rarely described. In this paper, the detailed cytopathological and immunohistochemical characteristics of metastatic MPNST has been described in pleural effusion. Patients' medical history and the judicious utilization of ancillary studies contribute to ensure precise cytological diagnoses. The cytomorphology of malignant peripheral nerve sheath tumour (MPNST) in effusion specimens can be diagnostically challenging. The author presents detailed cytopathological and immunohistochemical characteristics of a case of metastatic MPNST in pleural effusion.
    Keywords:  cytology; malignant peripheral nerve sheath tumour; pleural effusion; pleural fluid
    DOI:  https://doi.org/10.1111/cyt.13371
  8. Mol Neurobiol. 2024 Mar 04.
      Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. Patients with NF1 often have complications with tumors, such as neurofibroma. In order to investigate the pathogenesis of human neurofibroma, a systematic comparison of protein expression levels between Schwann cell-like sNF96.2 cells, which originated from malignant peripheral nerve sheath tumors (MPNST), and normal Schwann cells was performed using 4-D label-free proteomic analysis. In addition, the expression levels and localization of dysregulated proteins were confirmed using a Gene Expression Omnibus (GEO) transcriptomic dataset, Western blot analysis, and immunofluorescence labeling. The effects of SRY-box transcription factor 9 (SOX9) in the neurofibroma and surrounding microenvironment were evaluated in vivo using a tumor transplantation model. The present study observed that SOX9 and procollagen C-endopeptidase enhancer (PCOLCE) were significantly altered. NF1 mutation promoted the nuclear translocation and transcriptional activity of SOX9 in neurofibromas. SOX9 increased collagen VI secretions by enhancing the activation of PCOLCE in neurofibroma cells. These findings might provide new perspectives on the pathophysiological significance of SOX9 in neurofibromas and elucidate a novel molecular mechanism underlying neurofibromas.
    Keywords:  Collagen Secretion; Fibroblasts; Neurofibroma; PCOLCE; SOX9
    DOI:  https://doi.org/10.1007/s12035-024-04036-4
  9. Cureus. 2024 Feb;16(2): e53619
      Adrenal schwannomas are exceptionally rare tumors affecting about 0.2%, originating from the adrenal gland, presenting diagnostic challenges due to their nonspecific clinical features and overlapping radiological characteristics with other adrenal masses. Here, we report the case of a 49-year-old female with no significant medical history presenting with diffuse abdominal pain. Imaging studies, including contrast-enhanced computerized tomography (CECT), revealed a well-defined mass within the right adrenal gland. Given inconclusive radiological findings and persistent symptoms, surgical exploration was performed, leading to the identification and resection of the mass. Microscopic examination, including immunohistochemistry, confirmed the schwannomatous origin of the tumor. The final diagnosis of an adrenal schwannoma was established after a histopathological examination. Postoperatively, the patient was treated with antibiotics and discharged on oral antibiotics after suture removal on advised follow-up after 15 days. This case highlights the diagnostic complexities associated with adrenal schwannomas and emphasizes the necessity of surgical intervention for conclusive diagnosis. The report aims to contribute to the limited literature on adrenal schwannomas, enhancing our understanding of their clinical presentation and reinforcing the importance of a multidisciplinary approach in their diagnosis and management.
    Keywords:  abdominal pain; adrenal schwannoma; diagnostic challenges; histopathological examination; multidisciplinary approach; surgical exploration
    DOI:  https://doi.org/10.7759/cureus.53619
  10. Case Rep Womens Health. 2024 Mar;41 e00590
      The retroperitoneum is the rarest site for Schwannomas, tumors that originate from Schwann cells and usually present as benign, slowly growing masses. During pregnancy, the routine application of ultrasound for fetal assessment has led to an increased rate of detection of maternal asymptomatic masses, notably including the retroperitoneal ones. While most of these masses prove to be benign, it is imperative to consider the potential for malignancy. This report presents a rare case involving a woman diagnosed with bilateral adnexal cysts and a pre-sacral retroperitoneal mass during the first trimester of pregnancy. Surgical intervention was employed to remove ovarian tumors, and a biopsy was performed on the non-adnexal tumor to determine its nature. The histological examination revealed a bilateral borderline seromucinous tumor in the ovaries and identified a Schwannoma in the sacral mass. Despite the considerable size of the pre-sacral mass, which significantly impacted the patient's quality of life, successful measures were taken to achieve a near-term pregnancy, culminating in the delivery of a healthy baby. Subsequently the patient underwent neurosurgical treatment of the substantial pre-sacral Schwannoma. The discovery of a Schwannoma during pregnancy can evoke concerns among healthcare practitioners, touching upon potential malignancy risks, accelerated tumor growth, and impacts on fetal well-being. This paper provides a comprehensive, practice-based overview of these critical aspects.
    Keywords:  Magnetic resonance imaging; Pregnancy; Schwannoma; Ultrasound
    DOI:  https://doi.org/10.1016/j.crwh.2024.e00590
  11. J Surg Case Rep. 2024 Mar;2024(3): rjae101
      We report a case of a robotic-assisted excision of a retrocaval ancient schwannoma. A 40-year-old female presented with generalized weakness and abdominal pain that led to the diagnosis of a retroperitoneal mass adjacent to the pancreas and inferior vena cava. Because of the clinical, imaging, and needle biopsy findings, the patient underwent an elective robotic-assisted retroperitoneal exploration. We provide an overview of the pathology and highlight the significance of utilizing a minimally invasive approach for excision of retroperitoneal masses.
    Keywords:  ancient schwannoma; case report; ganglioneuroma; retrocaval schwannoma; robotic surgery
    DOI:  https://doi.org/10.1093/jscr/rjae101
  12. Heliyon. 2024 Mar 15. 10(5): e26089
       Background: Intraneural perineurioma is a rare, benign slow-growing lesion that usually involves a single main trunk nerve during childhood and young adulthood. The treatment of intraneural perineurioma is still a subject of controversy, especially in fast-growing children. To date, there was no systemic analysis of intraneural perineurioma in children.
    Method: A case of Intraneural perineurioma affecting the left sciatic nerve with 2 years of follow-up was presented. A systematic review was performed on literature published before June 2023, focusing on intraneural perineurioma diagnosed at no older than 18 years old.
    Result: A 9-year-old boy presented with progressive left foot-drop and abnormal gait for 2 years. The electromyography and magnetic resonance neurography study confirmed neuropathy involving the left sciatic nerves and its branches. Pathological investigation of the left sural nerve confirmed the diagnosis of intraneural perineurioma. The boy received physical therapy, and the disease was stable during the 2 years of follow-up. Fifty-seven childhood cases were identified in literature. Five patients with oral intraneural perineurioma underwent excision of the mass with good outcomes. In the other 52 patients with peripheral nerve involvement, 25 of them received surgical treatment, with different outcomes according to different operations. Out of 33 cases with precise lesion sizes, the length of the lesion in patients without nerve resection was significantly longer than that in patients with nerve resection (12.86 ± 7.44 cm vs 4.57 ± 4.5 cm. p < 0.05).
    Conclusions: Intraneural perineuriomas are rare benign tumors with slow progression. The options for surgery should be cautiously considered in childhood patients with long segmental peripheral nerve involvement.
    Keywords:  Case report; Childhood; Intraneural perineuriomas; Peripheral neuropathy; Surgical treatment
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e26089