bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022–05–29
eleven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Pan-Cancer Characterization of Intratumoral Autonomic Innervation in 32 Cancer Types in the Cancer Genome Atlas.
  2. The dark side of synaptic proteins in tumours.
  3. A Substance P (SP)/Neurokinin-1 Receptor Axis Promotes Perineural Invasion of Pancreatic Cancer and Is Affected by lncRNA LOC389641.
  4. Understanding the Role of Dopamine in Cancer: Past, Present, and Future.
  5. Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer.
  6. Fadu head and neck squamous cell carcinoma induces hyperexcitability of primary sensory neurons in an in vitro coculture model.
  7. Prognostic Value of Perineural Invasion on Survival and Recurrence in Oral Squamous Cell Carcinoma.
  8. Sporadic nonfunctional pancreatic neuroendocrine tumors: Risk of lymph node metastases and aggressiveness according to tumor size: A multicenter international study.
  9. Surgical outcomes of gastro-entero-pancreatic neuroendocrine tumors G3 versus neuroendocrine carcinoma.
  10. Embracing a curiosity-driven approach in the microneurographic exploration of the human vagus nerves.
  11. Ultrasonographic Evaluation of Peripheral Nerves: Technical Considerations.
  1. Cancers (Basel). 2022 May 21. pii: 2541. [Epub ahead of print]14(10):
    Pan-Cancer Characterization of Intratumoral Autonomic Innervation in 32 Cancer Types in the Cancer Genome Atlas.
    Jeff F Zhang, Haiyang Sheng, Jianhong Chen, Hemn Mohammadpour, Sung Jun Ma, Mark K Farrugia, Shipra Gandhi, Elizabeth G Bouchard, Anurag K Singh, Elizabeth A Repasky, Thaer Khoury, Christine B Ambrosone, Song Yao.
      Over the past two decades, multiple studies have demonstrated the important role that the autonomic nervous system (ANS) plays in tumorigenesis and cancer progression. However, the mechanisms by which this process occurs have only recently begun to be elucidated. Further, the extent of autonomic innervation in various cancer types and its effects on tumor molecular, immunological, and histopathological features, as well as on patient outcomes, are not yet fully characterized. In this study, we analyzed intratumoral ANS gene expression signatures, including overall intratumoral neuron growth and sympathetic and parasympathetic markers, across 32 cancer types using tumor transcriptomic and clinical annotation data available from The Cancer Genome Atlas (TCGA). Our analysis revealed wide variations in intratumoral ANS expression both within and across cancer types. The association of ANS signatures with tumor histopathological characteristics and survival outcomes also varied by cancer type. We found intratumoral ANS expression to be commonly correlated with angiogenesis, TGF-β signaling, and immunosuppression in the tumor microenvironment of many cancer types, which provide mechanistic insights into the involvement of intratumoral innervation in cancer development and progression. Our findings suggest that the potential benefits of cancer therapies targeting β-adrenergic receptor-mediated stress signaling pathways are likely dependent on cancer type.
    Keywords:  TCGA; autonomic nervous system; cancer; innervation
    DOI:  https://doi.org/10.3390/cancers14102541
  2. Br J Cancer. 2022 May 27.
    The dark side of synaptic proteins in tumours.
    Jing Li, Yalan Xu, Hai Zhu, Yin Wang, Peifeng Li, Dong Wang.
      Research in the past decade has uncovered the essential role of the nervous system in the tumour microenvironment. The recent advances in cancer neuroscience, especially the discovery of neuron-tumour synaptic/perisynaptic structures, have revealed the dark side of synaptic proteins in the progression of brain tumours. Here, we provide an overview of the synaptic proteins expressed by tumour cells and analyse their molecular functions and organisation by comparing them with neuronal synaptic proteins. We focus on the studies of neuroligin-3, the glutamate receptors AMPAR and NMDAR and the synaptic scaffold protein DLGAP1, for their newly discovered regulatory role in the proliferation and progression of tumours. Progress in cancer neuroscience has brought novel insights into the treatment of cancers. In the last part of this review, we discuss the therapeutical strategies targeting synaptic proteins and the current challenges and possible toolkits regarding their clinical application in cancer treatment. Our understanding of cancer neuroscience is still in its infancy; deeper investigation of how tumour cells co-opt synaptic signaling will help fulfil the therapeutical potential of the synaptic proteins as promising anti-tumour targets.
    DOI:  https://doi.org/10.1038/s41416-022-01863-x
  3. J Immunol Res. 2022 ;2022 5582811
    A Substance P (SP)/Neurokinin-1 Receptor Axis Promotes Perineural Invasion of Pancreatic Cancer and Is Affected by lncRNA LOC389641.
    Tengfei Ji, Keqiang Ma, Hongsheng Wu, Tiansheng Cao.
      Perineural invasion (PNI) is considered to be a main reason for the poor prognosis of pancreatic cancer. In the present study, we analyzed the roles of substance P (SP)/neurokinin-1 receptor (NK-1R) and lncRNA LOC389641 in pancreatic cancer PNI. Pancreatic cancer cell lines BxPC-3 and MIAPaCa-2 were cocultured with SH-SY5Y cells and then stimulated with SP to simulate the in vivo influence of ganglia on pancreatic cancer. The BxPC-3 and MIAPaCa-2 cells were transfected with a neurokinin-1 receptor (NK-1R) overexpression vector, NK-1R silencing vector, LOC389641 overexpression vector, or LOC389641 silencing vector, respectively. The proliferative abilities of BxPC-3 and MIAPaCa-2 cells were assessed using the cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) assays. Wound-healing and Transwell assays were performed to determine the migration and invasion abilities of the cells. When SP was added to the coculture system, it positively regulated cancer cell proliferation, migration, and PNI and significantly activated the NK-1R/Akt/NF-κB signaling pathway. Incubation with 100 nmol/L SP for 24 h was selected as the optimal condition for treatment. The activated NK-1R positively regulated the proliferation, migration, and invasion of pancreatic cancer cells. However, the levels of lncRNA LOC389641 and tumor necrosis factor receptor SF10A (TNFRSF10A) mRNA in BxPC-3 and MIAPaCa-2 cells were not affected by SP treatment. Overexpression or silencing of LOC389641 changed the effect of SP stimulation on pancreatic cancer PNI. When taken together, these results revealed that SP/NK-1R and LOC389641 promoted the progression of pancreatic cancer PNI. Moreover, we found that pancreatic cancer PNI promoted by the SP/NK-1R axis could be blocked by the TNFRSF10A/NF-κB pathway mediated by LOC389641.
    DOI:  https://doi.org/10.1155/2022/5582811
  4. Carcinogenesis. 2022 May 25. pii: bgac045. [Epub ahead of print]
    Understanding the Role of Dopamine in Cancer: Past, Present, and Future.
    Christopher E Grant, Amy Flis, Bríd M Ryan.
      Dopamine (DA, 3-hydroxytyramine) is member of the catecholamine family and is classically characterized according to its role in the central nervous system as a neurotransmitter. In recent decades, many novel and intriguing discoveries have been made about the peripheral expression of DA receptors (DRs) and the role of DA signaling in both normal and pathological processes. Drawing from decades of evidence suggesting a link between DA and cancer, the DA pathway (DAP) has recently emerged as a potential target in antitumor therapies. Due to the onerous, expensive, and frequently unsuccessful nature of drug development, the repurposing of dopaminergic drugs for cancer therapy has the potential to greatly benefit patients and drug developers alike. However, the lack of clear mechanistic data supporting the direct involvement of DRs and their downstream signaling components in cancer represents an ongoing challenge that has limited the translation of these drugs to the clinic. Despite this, the breadth of evidence linking DA to cancer and non-tumor cells in the tumor microenvironment (TME) justifies further inquiry into the potential applications of this treatment modality in cancer. Herein, we review the literature characterizing the interplay between the DA signaling axis and cancer, highlighting key findings, and then propose rational lines of investigation to follow.
    Keywords:  Dopamine; cancer; chemotherapy; immunotherapy; receptors
    DOI:  https://doi.org/10.1093/carcin/bgac045
  5. Clin Cancer Res. 2022 May 26. pii: clincanres.4543.2021. [Epub ahead of print]
    Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer.
    Ligia B Schmitd, Cindy Perez-Pacheco, Emily L Bellile, Weisheng Wu, Keith Casper, Michelle Mierzwa, Laura S Rozek, Gregory T Wolf, Jeremy M G Taylor, Nisha J D'Silva.
       PURPOSE: Perineural invasion (PNI), a common occurrence in oral squamous cell carcinomas, is associated with poor survival. Consequently, these tumors are treated aggressively. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. To address these knowledge gaps, we investigated spatial and transcriptomic profiles of PNI-positive and PNI-negative nerves.
    EXPERIMENTAL DESIGN: Tissue sections from 142 patients were stained with S100 and cytokeratin antibodies. Nerves were identified in two distinct areas; tumor bulk and margin. Nerve diameter and nerve-to-tumor distance were assessed; survival analyses were performed. Spatial transcriptomic analysis of nerves at varying distances from tumor was performed with NanoString GeoMx Digital Spatial Profiler Transcriptomic Atlas.
    RESULTS: PNI is an independent predictor of poor prognosis among patients with metastasis-free lymph nodes. Patients with close nerve-tumor distance have poor outcomes even if diagnosed as PNI-negative using current criteria. Patients with large nerve(s) in the tumor bulk survive poorly, suggesting that even PNI-negative nerves facilitate tumor progression. Diagnostic criteria were supported by spatial transcriptomic analyses of >18,000 genes; nerves in proximity to cancer exhibit stress and growth response changes that diminish with increasing nerve-tumor distance. These findings were validated in vitro and in human tissue.
    CONCLUSIONS: This is the first study in human cancer with high-throughput gene-expression analysis in nerves with striking correlations between transcriptomic profile and clinical outcomes. Our work illuminates nerve-cancer interactions suggesting that cancer-induced injury modulates neuritogenesis, and supports re-classification of PNI based on nerve-tumor distance rather than current subjective criteria.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-4543
  6. Pain Rep. 2022 May-Jun;7(3):7(3): e1012
    Fadu head and neck squamous cell carcinoma induces hyperexcitability of primary sensory neurons in an in vitro coculture model.
    Megan L Uhelski, Aysegul Gorur, Ted Shi, German Corrales, Kim N Du, Yan Li, Moran Amit, Claudio E Tatsui, Laurence D Rhines, Patrick M Dougherty, Juan P Cata.
       Introduction: Currently, cancer pain is viewed as a process orchestrated by the release of pronociceptive molecules and the invasion of neural structures, referred to as perineural invasion (PNI). Cancer pain resulting from PNI is well-documented, but the mechanisms leading to peripheral sensitization because of tumor growth are not fully known.
    Methods: A retrospective study was used to examine how the use of anti-inflammatory medications affected preoperative pain in patients with oral squamous cell carcinoma cancer. We then used an in vitro coculture model in which dorsal root ganglion (DRG) neurons were incubated together with Fadu human head and neck squamous cell carcinoma cancer cells to explore how cancer cells affect the electrical membrane properties of sensory neurons.
    Results: We found that inflammation contributes to preoperative pain in patients with oral squamous cell carcinoma. After coculture with Fadu human head and neck squamous cell carcinoma cancer cells, we identified markers of inflammation in coculture media and found evidence of neuronal sensitization, including spontaneous activity, reduced current thresholds, depolarized resting membrane potential, and enhanced responses to current stimulation in human and rat DRG neurons. In rats, these effects were influenced by sex and age: neurons from young adult female rats were resistant to changes in neuronal activity, in contrast to neurons from older adult female rats or male rats of either age group.
    Conclusions: Pro-inflammatory substances released in cancer cell-DRG coculture promoted neuronal hyperexcitability and may contribute to cancer pain after PNI, and these effects may differ across age groups and sexes.
    Keywords:  Dorsal root ganglia; Perineural invasion; Sensitization
    DOI:  https://doi.org/10.1097/PR9.0000000000001012
  7. Diagnostics (Basel). 2022 Apr 24. pii: 1062. [Epub ahead of print]12(5):
    Prognostic Value of Perineural Invasion on Survival and Recurrence in Oral Squamous Cell Carcinoma.
    Steffen Spoerl, Silvia Spoerl, Stephanie Reil, Michael Gerken, Nils Ludwig, Juergen Taxis, René Fischer, Tobias Ettl, Torsten E Reichert, Gerrit Spanier.
      A diagnosis of perineural invasion (PNI) is widely accepted as an unfavorable prognostic factor in various solid malignancies. Although PNI has been described as a high-risk parameter in oral squamous cell carcinoma (OSCC), its role in the current staging manuals of the American Joint Committee on Cancer (AJCC) is rather subordinate. We analysed the prognostic value of PNI on survival and recurrence in a large, multicenter OSCC cohort and a population-based approach. A total of 493 OSCC patients with primary tumor resection to negative margins and concomitant neck dissection between 2010 and 2017 were enrolled. PNI was evaluated in relation to overall survival (OAS) and recurrence-free survival (RFS) using uni- and multi-variable Cox regression. The median follow-up time was 5.0 years and PNI was diagnosed in 48 patients (9.7%). A pathohistological verification of PNI correlated significantly with a deteriorated OAS in uni- (HR 2.312; 95% CI 2.312-3.493, p = 0.001) and multivariable Cox regression (HR 1.820; 95% CI 1.164-2.847, p = 0.009). Additionally, a diagnosis of PNI correlated with increased cumulative, as well as distant, metastasis 5-year-recurrence rates (p = 0.027 and p = 0.011, respectively). The application of adjuvant radiotherapy (RT) or radiochemotherapy (RCT) in patients with PNI did not alter OAS or RFS in survival analysis when compared to patients without PNI. The results underline the adverse impact of PNI on the survival and recurrence of surgically treated OSCC patients. Based on our findings, we highly recommend an emphasis on PNI in the TNM staging concept.
    Keywords:  PNI; oral cancer; oral squamous cell carcinoma; perineural invasion; recurrence; survival
    DOI:  https://doi.org/10.3390/diagnostics12051062
  8. Surgery. 2022 May 24. pii: S0039-6060(22)00243-4. [Epub ahead of print]
    Sporadic nonfunctional pancreatic neuroendocrine tumors: Risk of lymph node metastases and aggressiveness according to tumor size: A multicenter international study.
    Julie Perinel, Gennaro Nappo, Alessandro Zerbi, Charlotte M Heidsma, Elisabeth J M Nieveen van Dijkum, Ho Seong Han, Yoo-Seok Yoon, Sohei Satoi, Ihsan Ekin Demir, Helmut Friess, Yogesh Vashist, Jakob Izbicki, Alexandra Charlotte Muller, Beat Gloor, Marta Sandini, Luca Gianotti, Fabien Subtil, Mustapha Adham.
       BACKGROUND: Although the correlation between tumor size and aggressiveness is clearly established in sporadic nonfunctional pancreatic neuroendocrine tumors, the management of tumors ≤2 cm remains debated. In recent guidelines, the cut-off size to operate ranged from 1 to 2 cm. The aim of this retrospective study was to report the rate of lymph nodes metastases in resected sporadic nonfunctional pancreatic neuroendocrine tumors, according to tumor size and, second, to identify risk factors of lymph node metastases and disease-free survival.
    METHODS: Resected sporadic nonfunctional pancreatic neuroendocrine tumors from 9 international expert centers were included (1999-2017). Functional pancreatic neuroendocrine tumors, genetic syndromes, and R2 resection were excluded. Aggressiveness was defined as microvascular invasion, perineural invasion, lymph node metastases, G3 grading, distant metastases, and/or recurrence.
    RESULTS: Overall, 495 resected sporadic nonfunctional pancreatic neuroendocrine tumors were included. For tumors up to 5 cm, the risk of lymph node metastases was increased by 1.73 for every 1 cm increase in size (odds ratio = 1.73; 95% confidence interval = 1.46-2.03). Tumor size >2 cm (P < .001), perineural invasion (P = .002), microvascular invasion (P < .001), and distant metastases (P = .008) were independently associated with lymph node metastases. Tumor size >2 cm (P = .003), R1 status (P = .004), lymph node metastases (P < .001), and World Health Organization grade 3 (P = .002) were independently associated with disease-free survival. Aggressiveness rate was 13.1% in tumors ≤1 cm and 29% in tumors between 1.1 and 2 cm.
    CONCLUSION: In resected sporadic nonfunctional pancreatic neuroendocrine tumors, the risk of lymph node metastases is correlated to tumor size. Considering that sporadic nonfunctional pancreatic neuroendocrine tumors between 1.1 and 2 cm had a higher risk of lymph node metastases and recurrence compared to tumors ≤1 cm, the decision to perform surgery in this subgroup of patients should be individualized in surgically fit patients.
    DOI:  https://doi.org/10.1016/j.surg.2022.04.013
  9. J Surg Oncol. 2022 May 26.
    Surgical outcomes of gastro-entero-pancreatic neuroendocrine tumors G3 versus neuroendocrine carcinoma.
    Mu-Xing Li, Alexandra G Lopez-Aguiar, George Poultsides, Flavio Rocha, Sharon Weber, Ryan Fields, Kamran Idrees, Cliff Cho, Shishir K Maithel, Xu-Feng Zhang, Timothy M Pawlik.
       BACKGROUND: To define surgical outcomes of patients with high-grade gastro-entero-pancreatic neuroendocrine neoplasm grade G3 (GEP-NEN G3).
    METHODS: Patients who underwent surgical resection between 2000 and 2016 were identified. The overall survival (OS) and recurrence-free survival (RFS) of patients with gastro-entero-pancreatic neuroendocrine tumors grade G3 (GEP-NET G3) versus neuroendocrine carcinoma (NEC) were evaluated.
    RESULTS: Fifty-one out of 2182 (2.3%) patients who underwent surgical resection were diagnosed as GEP-NEN G3. The pancreas was the most common primary site (n = 3772.5%). A majority of patients had lymph node metastasis (n = 3262.7%); one in three (n = 1631.4%) had distant metastasis. The median OS and RFS of the entire cohort were 56.4 and 34.5 months, respectively. Perineural invasion was a strong prognostic factor associate with OS after surgical resection. Patients with NEC had a worse survival outcome versus patients with NET G3 (median OS: 33.1 months vs. not attained, p = 0.088). In contrast, among patients who underwent curative-intent resection, patients with NEC had comparable RFS versus patients with NET G3 (median RFS: 35.6 vs. 33.9 months, p = 0.774).
    CONCLUSIONS: Surgical resection provided acceptable short- and long-outcomes for well-selected patients with resectable GEP-NEN G3. NEC was associated with a worse OS versus NET G3.
    Keywords:  WHO grade 3; gastro-entero-pancreatic; neuroendocrine neoplasm; outcome; surgery
    DOI:  https://doi.org/10.1002/jso.26928
  10. J Physiol. 2022 May 27.
    Embracing a curiosity-driven approach in the microneurographic exploration of the human vagus nerves.
    Michael J Joyner, Stephen A Klassen.
      
    Keywords:  autonomic nervous system; heart rate; lung volume; parasympathetic; regulation; sympathetic activity; vagus nerve
    DOI:  https://doi.org/10.1113/JP283281
  11. Semin Musculoskelet Radiol. 2022 Apr;26(2): 105-113
    Ultrasonographic Evaluation of Peripheral Nerves: Technical Considerations.
    Antje L Greenfield, Mannan Parrikh, Riti Kanesa-Thasan.
      Advances in ultrasonographic (US) technology featuring high-resolution transducers have revolutionized US over recent years as a modality increasingly used in the evaluation of musculoskeletal structures and peripheral nerves. A wide variety of nerve pathologies can be detected, such as neoplastic and tumorlike lesions, entrapment syndromes, posttraumatic injuries, and inflammatory conditions. US can serve as an imaging tool for guiding percutaneous treatments, such as injection therapies or hydrodissection, and assist with perioperative nerve marking and visualization of peripheral nerves in the operating room. This article describes the normal US appearance of peripheral nerves, US imaging techniques, common peripheral nerve pathologies, and interventional applications.
    DOI:  https://doi.org/10.1055/s-0042-1742606
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