bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2024‒06‒09
eight papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Area postrema neurons mediate interleukin-6 function in cancer cachexia.
  2. N4-acetylcytidine acetylation of neurexin 2 in the spinal dorsal horn regulates hypersensitivity in a rat model of cancer-induced bone pain.
  3. Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models.
  4. Association of cancer and schizophrenia, major depression and bipolar disorder: A Mendelian randomization study.
  5. High-Grade Malignant Peripheral Nerve Sheath Tumor Arising From Common Peroneal Nerve Neurofibroma.
  6. Associations of body composition parameters with postoperative outcome and perineural tumour invasion after oncological pancreatic resection.
  7. Factors predictive of recurrence, metastasis and death in node-negative penile squamous cell carcinoma: A retrospective multicentre cohort study.
  8. Shifting views on cancer pain management: a systematic review and network meta-analysis.
  1. Nat Commun. 2024 Jun 01. 15(1): 4682
    Area postrema neurons mediate interleukin-6 function in cancer cachexia.
    Qingtao Sun, Daniëlle van de Lisdonk, Miriam Ferrer, Bruno Gegenhuber, Melody Wu, Youngkyu Park, David A Tuveson, Jessica Tollkuhn, Tobias Janowitz, Bo Li.
      Interleukin-6 (IL-6) has been long considered a key player in cancer cachexia. It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia. However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, is a critical mediator of IL-6 function in cancer cachexia in male mice. We find that circulating IL-6 can rapidly enter the AP and activate neurons in the AP and its associated network. Peripheral tumor, known to increase circulating IL-6, leads to elevated IL-6 in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons and AP network hyperactivity. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an anti-IL-6 antibody attenuates cachexia and the hyperactivity in the AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra, the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing Gfral-expressing AP neurons also attenuates cancer cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer cachexia.
    DOI:  https://doi.org/10.1038/s41467-024-48971-1
  2. Mol Ther Nucleic Acids. 2024 Jun 11. 35(2): 102200
    N4-acetylcytidine acetylation of neurexin 2 in the spinal dorsal horn regulates hypersensitivity in a rat model of cancer-induced bone pain.
    Longsheng Xu, Shang Zheng, Liping Chen, Lei Yang, Shuyao Zhang, Beibei Liu, Kangli Shen, Qinli Feng, Qinghe Zhou, Ming Yao.
      Cancer-induced bone pain (CIBP) significantly impacts the quality of life and survival of patients with advanced cancer. Despite the established role of neurexins in synaptic structure and function, their involvement in sensory processing during injury has not been extensively studied. In this study using a rat model of CIBP, we observed increased neurexin 2 expression in spinal cord neurons. Knockdown of neurexin 2 in the spinal cord reversed CIBP-related behaviors, sensitization of spinal c-Fos neurons, and pain-related negative emotional behaviors. Additionally, increased acetylation of neurexin 2 mRNA was identified in the spinal dorsal horn of CIBP rats. Decreasing the expression of N-acetyltransferase 10 (NAT10) reduced neurexin 2 mRNA acetylation and neurexin 2 expression. In PC12 cells, we confirmed that neurexin 2 mRNA acetylation enhanced its stability, and neurexin 2 expression was regulated by NAT10. Finally, we discovered that the NAT10/ac4C-neurexin 2 axis modulated neuronal synaptogenesis. This study demonstrated that the NAT10/ac4C-mediated posttranscriptional modulation of neurexin 2 expression led to the remodeling of spinal synapses and the development of conscious hypersensitivity in CIBP rats. Therefore, targeting the epigenetic modification of neurexin 2 mRNA ac4C may offer a new therapeutic approach for the treatment of nociceptive hypersensitivity in CIBP.
    Keywords:  MT: RNA and epigenetic editing Special Issue; N-acetyltransferase 10; RNA acetylation; cancer-induced bone pain; neurexin 2; synaptic remodeling
    DOI:  https://doi.org/10.1016/j.omtn.2024.102200
  3. J Vis Exp. 2024 May 17.
    Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models.
    Dorea P Jenkins, Brittany Turner-Ivey, Jody Fromm Longo, Steven L Carroll.
      Patients with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1) commonly develop plexiform neurofibromas (PNs) that subsequently transform into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Understanding the process by which a PN transforms into an MPNST would be facilitated by the availability of genetically engineered mouse (GEM) models that accurately replicate the PN-MPNST progression seen in humans with NF1. Unfortunately, GEM models with Nf1 ablation do not fully recapitulate this process. This led us to develop P0-GGFβ3 mice, a GEM model in which overexpression of the Schwann cell mitogen neuregulin-1 (NRG1) in Schwann cells results in the development of PNs that progress to become MPNSTs with high frequency. However, to determine whether tumorigenesis and neoplastic progression in P0-GGFβ3 mice accurately model the processes seen in NF1 patients, we had to first prove that the pathology of P0-GGFβ3 peripheral nerve sheath tumors recapitulates the pathology of their human counterparts. Here, we describe the specialized methodologies used to accurately diagnose and grade peripheral nervous system neoplasms in GEM models, using P0-GGFβ3 and P0-GGFβ3;Trp53+/- mice as an example. We describe the histologic, immunohistochemical, and histochemical methods used to diagnose PNs and MPNSTs, how to distinguish these neoplasms from other tumor types that mimic their pathology, and how to grade these neoplasms. We discuss the establishment of early-passage cultures from GEM MPNSTs, how to characterize these cultures using immunocytochemistry, and how to verify their tumorigenicity by establishing allografts. Collectively, these techniques characterize the pathology of PNs and MPNSTs that arise in GEM models and critically compare the pathology of these murine tumors to their human counterparts.
    DOI:  https://doi.org/10.3791/65740
  4. J Psychosom Res. 2024 May 23. pii: S0022-3999(24)00218-6. [Epub ahead of print]183 111806
    Association of cancer and schizophrenia, major depression and bipolar disorder: A Mendelian randomization study.
    Xinyue Han, Xiangying Lin, Guanhong Li, Jingnan Wang, Xiangxue Meng, Tongyu Chen, Yanbo Zhang, Xiaoling Fu.
      BACKGROUND: Schizophrenia, bipolar disorder and major depression have been reported to be associated with some cancers. However, the magnitude of the causal relationship between them remains unclear. This study aims to explore the potential association between three major mental diseases and the risk of some cancers.METHODS: We performed the two-sample Mendelian randomization(MR) analysis using publicly available genome-wide association studies (GWAS) statistics to investigate the causal relationship between these three mental diseases and some common types of cancers, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, bladder cancer, prostate cancer, thyroid cancer, pancreatic cancer, malignant melanoma and glioma. We obtained genetic association estimates for schizophrenia, bipolar disorder and depression from the Psychiatric Genomics Consortium.The genetic association estimates for cancers were obtained from the UK Biobank, the MRC-IEU consortium and the GliomaScan consortium.
    RESULTS: After correction for heterogeneity and horizontal pleiotropy, we detected suggestive evidence for the association between thyroid cancer and genetically predicted schizophrenia (OR = 1.543, 95% CI: 1.023-2.328, P = 0.039), and thyroid cancer and major depression (OR = 3.573, 95% CI: 1.068-11.953, P = 0.039). No evidence of causal effects of schizophrenia, major depression and bipolar disorder on other types of cancers.
    CONCLUSIONS: Our findings suggest the association of schizophrenia and major depression and the development of thyroid cancer.
    Keywords:  Bipolar disorder; Major depression; Mendelian randomization; Schizophrenia; cancer
    DOI:  https://doi.org/10.1016/j.jpsychores.2024.111806
  5. Cureus. 2024 May;16(5): e59607
    High-Grade Malignant Peripheral Nerve Sheath Tumor Arising From Common Peroneal Nerve Neurofibroma.
    Jian-Jiun Chen, Chien-Kuan Lee, Chen-Yuan Yang.
      This article presents a case report of a 45-year-old male with neurofibromatosis type I (NF1) who developed a high-grade malignant peripheral nerve sheath tumor (MPNST) originating from a neurofibroma within the common peroneal nerve over popliteal fossa. MPNSTs are aggressive tumors associated with NF1, causing significant mortality. The patient underwent tumor resection surgery and received postoperative radiation therapy. Follow-up examinations showed no impairment of motor function and no tumor recurrence after regular MRI evaluation for four years. This article explores the challenges of distinguishing benign neurofibromas from malignant MPNST via MRI image and biopsy, and achieving a balance between tumor excision and preserving nerve functionality during surgical treatment. However, caution is warranted due to the risk of recurrence.
    Keywords:  common peroneal nerve; malignant peripheral nerve sheath tumor; neurofibroma; neurofibromatosis; popliteal mass
    DOI:  https://doi.org/10.7759/cureus.59607
  6. BMC Surg. 2024 Jun 04. 24(1): 175
    Associations of body composition parameters with postoperative outcome and perineural tumour invasion after oncological pancreatic resection.
    Tara C Mueller, Martin Henselmann, Stefan Reischl, Carsten Jaeger, Charlotte Trefzer, Ihsan Ekin Demir, Helmut Friess, Marc E Martignoni.
      BACKGROUND: Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss.METHODS: A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities.
    RESULTS: Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters.
    CONCLUSIONS: This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions.
    Keywords:  Body composition; Malnutrition; Pancreatic cancer; Perineural tumour invasion; Postoperative complications
    DOI:  https://doi.org/10.1186/s12893-024-02457-5
  7. J Eur Acad Dermatol Venereol. 2024 Jun 06.
    Factors predictive of recurrence, metastasis and death in node-negative penile squamous cell carcinoma: A retrospective multicentre cohort study.
    Katie A O'Connell, Jacob L Thomas, Fadi Murad, Guohai Zhou, Guru P Sonpavde, Matthew Mossanen, Timothy N Clinton, Antonio Ji-Xu, Philippe E Spiess, Anthony M Rossi, Chrysalyne D Schmults.
      BACKGROUND: Penile squamous cell carcinoma (PSCC) carries significant morbidity and mortality. Literature is limited regarding prognostic factors, especially prognostic factors for development of metastasis.OBJECTIVES: To identify independent prognostic factors associated with poor outcomes, defined as local recurrence (LR), metastasis and disease-specific death (DSD) in clinically node-negative PSCC undergoing local therapy.
    METHODS: Thirty-two-year Retrospective Multicenter Cohort Study of 265 patients with histologically diagnosed PSCC at three tertiary care centres. Predictive models based on patient or tumour characteristics were developed.
    RESULTS: Local recurrence occurred in 56 patients, metastasis in 52 patients and DSD in 40 patients. In multivariable models, the following five factors were independent prognostic factors based on subhazard ratio (SHR): history of balanitis (LR SHR: 2.3; 95% CI 1.2-4.2), poor differentiation (metastasis SHR 1.9; 95% CI 1.0-3.6), invasion into the corpora (metastasis SHR: 3.0; 95% CI 1.5-5.8 and DSD SHR: 4.5; 95% CI 1.7-12.1), perineural invasion (PNI) (metastasis SHR: 2.8; 95% CI 1.4-5.5 and DSD SHR: 3.5; 95% CI, 1.6-7.8) and a history of phimosis (DSD SHR: 2.5; 95% CI 1.2-5.3). The 5-year cumulative incidence of metastasis was higher for tumours with PNI [cumulative incidence function (CIF) = 55%, 95% CI 38-75 vs. CIF 15%, 95% CI 11-22], corporal invasion (CIF: 35%, 95% CI 26-47 vs. 12%, 95% CI 7-19) and poorly differentiated tumours (CIF = 46%, 95% CI 31-64 vs. CIF 15%, 95% CI 11-22).
    CONCLUSIONS: History of balanitis, history of phimosis, PNI, corporal invasion and poor differentiation are independent risk factors associated with poor outcomes. Since poor differentiation and PNI currently constitute only T1b disease, prognostic staging can likely be improved.
    DOI:  https://doi.org/10.1111/jdv.20093
  8. J Pain Symptom Manage. 2024 Jun 03. pii: S0885-3924(24)00790-5. [Epub ahead of print]
    Shifting views on cancer pain management: a systematic review and network meta-analysis.
    Maike S V Imkamp, Maurice Theunissen, Wolfgang Viechtbauer, Sander M J van Kuijk, Marieke H J van den Beuken-van Everdingen.
      CONTEXT: Strong opioids are the cornerstone in the treatment of cancer-related pain.OBJECTIVES: This study aims to compare analgesic effectiveness of different strong opioids for the treatment of cancer-related pain.
    METHODS: PubMed and Embase were searched for RCTs that compared strong opioids for treatment of cancer-related pain against one another. A network meta-analysis was conducted and the related Surface Under the Cumulative RAnking (SUCRA)-based treatment ranks were calculated. Primary outcome was pain intensity (numerical rating scale (NRS)) and/or the percentage of patients with ≥50% pain reduction, after 1 and 2-4 weeks.
    RESULTS: Sixteen RCTs (1813 patients) were included. Methadone showed, with a high certainty of evidence, increased ORs for treatment success at 1 week, compared with morphine, buprenorphine, fentanyl, and oxycodone, range 3.230-36.833. Methadone had the highest likelihood to be the treatment of preference (ToP) (SUCRA 0.9720). For fentanyl, ORs were lower, however significant and with high certainty. After 2-4 weeks, methadone again showed the highest likelihood for ToP, however, with moderate certainty and non-significant ORs. The combination of morphine/methadone, compared with morphine, buprenorphine, fentanyl, hydromorphone, methadone, and oxycodone achieved a treatment effect of mean NRS difference after 2-4 weeks between -1.100 and -1.528 and had the highest likelihood for ToP.
    CONCLUSION: The results suggest that methadone possibly deserves further promotion as first-line treatment for the treatment of cancer-related pain.
    Keywords:  Cancer pain; Drug therapy; Pain management; Palliative care; Statistics
    DOI:  https://doi.org/10.1016/j.jpainsymman.2024.05.022
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