bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2021‒11‒14
eight papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute

  1. FASEB Bioadv. 2021 Nov;3(11): 944-952
      Although the role of nerves in stimulating cellular growth and dissemination has long been described in tissue regeneration studies, until recently a similar trophic role of nerves in disease was not well recognized. However, recent studies in oncology have demonstrated that the growth and dissemination of cancers also requires the infiltration of nerves in the tumor microenvironment. Nerves generate various neurosignaling pathways, which orchestrate cancer initiation, progression, and metastases. Similarly, nerves are increasingly implicated for their regulatory functions in immunity and inflammation. This orchestrator role of nerves in cellular and molecular interactions during regeneration, cancer, immunity, and inflammation offers new possibilities for targeting or enhancing neurosignaling in human health and diseases.
    Keywords:  cancer; immunity; inflammation; nerves; nervous system; regeneration
  2. Br J Pharmacol. 2021 Nov 11.
      BACKGROUND AND PURPOSE: Recently, β-adrenoceptor blockade has emerged as a potential strategy to inhibit melanoma growth. However, it remains to be ascertained whether β-adrenoceptor stimulation by circulating catecholamines increases melanoma growth in mice.EXPERIMENTAL APPROACH: B16F10 melanoma-bearing mice were used to evaluate effects of adrenaline and specific adrenoceptor (AR) ligands on tumor volume. AR expression as well as effects of AR ligands on cell viability, production of mitochondrial reactive oxygen species (mROS) and proliferation activity in B16F10 cells were determined by biochemical analyses.
    KEY RESULTS: qPCR analyses revealed that B16F10 cells express both α- (α1B-, α2A- and α2B-AR) and β-ARs (β2 -AR). We found that treatment with the α- and β-AR agonist adrenaline or with the synthetic catecholamine isoprenaline, that selectively stimulates β-ARs, did not affect melanoma growth. Conversely, adrenaline reduced tumor growth in mice co-treated with propranolol, a β1β2-AR antagonist. Adrenaline had no effect in tumor-bearing β1β2-AR knockout mice, in which β1- and β2-ARs are lacking, but it reduced tumor growth when co-administered with propranolol suggesting that tumor β2-ARs negatively regulate adrenaline antitumor activity. Additionally, we found that α1-AR stimulation with cirazoline yielded a decrease in B16F10 melanoma size. These effects on melanoma growth were paralleled by reduced cell viability and proliferation activity as well as increased mROS production in α1-AR-stimulated B16F10 cells. Decreased viability, proliferation and mitochondrial function in B16F10 cells also occurred after α2-AR stimulation by α2-AR agonist ST-91.
    CONCLUSIONS AND IMPLICATIONS: In B16F10 melanoma model, stimulation of α-AR subtypes yields in vivo and in vitro anticancer activity.
    Keywords:  Melanoma; adrenoceptors; catecholamines; α-adrenoceptor agonists
  3. J Immunol. 2021 Nov 12. pii: ji2100719. [Epub ahead of print]
      The sympathetic nervous system (SNS) is an important regulator of immune cell function during homeostasis and states of inflammation. Recently, the SNS has been found to bolster tumor growth and impair the development of antitumor immunity. However, it is unclear whether the SNS can modulate APC function. Here, we investigated the effects of SNS signaling in murine monocyte-derived macrophages (moMФ) and dendritic cells (DCs) and further combined the nonspecific β-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report that norepinephrine treatment dramatically altered moMФ cytokine production, whereas DCs were unresponsive to norepinephrine and critically lack β2-adrenergic receptor expression. In addition, we show that propranolol plus cancer vaccine enhanced peripheral DC maturation, increased the intratumor proportion of effector CD8+ T cells, and decreased the presence of intratumor PD-L1+ myeloid-derived suppressor cells. Furthermore, this combination dramatically reduced tumor growth compared with vaccination alone. Taken together, these results offer insights into the cell-specific manner by which the SNS regulates the APC immune compartment and provide strong support for the use of propranolol in combination with cancer vaccines to improve patient response rates and survival.
  4. Curr Protoc. 2021 Nov;1(11): e285
      In vivo rodent, whole peripheral nerve models are useful for studying the electrical conduction of sensory and motor fibers under normal physiological conditions as well as for assessing neurological outcomes after the application of physical alterations or pharmacological agents to the nervous system. Significant literature has focused on single-neuron and central nervous system electrophysiology protocol development. However, creation and development of in vivo whole-nerve electrophysiological recording protocols are sparse in the scientific literature. Here, detailed protocols for designing and building an in vivo whole-nerve electrophysiology system are described, including straightforward techniques to create working stimulation and recording electrodes that may be adapted to numerous study designs. Further, we include details for rodent anesthesia, surgical dissection (for the sciatic nerve), compound action potential signal optimization, data acquisition, data analyses, and troubleshooting tips. © 2021 Wiley Periodicals LLC. Basic Protocol 1: In vivo electrophysiology system wiring, hardware, and software setups Support Protocol 1: Design and 3D printing of electrophysiology base electrodes Support Protocol 2: Building needle electrodes Basic Protocol 2: Rodent anesthesia and surgery for nerve exposure Basic Protocol 3: Compound action potential recording and troubleshooting using WinWCP Basic Protocol 4: Compound action potential data analysis using WinWCP.
    Keywords:  compound action potential; electrophysiology; in vivo; rodent; sciatic nerve
  5. J Endocrinol Invest. 2021 Nov 13.
      PURPOSE: Patients submitted to curative surgery for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) exhibit a variable risk of disease relapse. Aims of this meta-analysis were to estimate the rate of disease recurrence and to investigate the risk factors for disease relapse in patients submitted to curative surgery for NF-PanNENs.METHODS: Medline/Pubmed and Web of Science databases were searched for relevant studies. A meta-regression analysis was performed to investigate the source of recurrence rate heterogeneity. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CI) were used to assess the effect of each possible prognostic factor on disease-free survival.
    RESULTS: Fifteen studies, involving 2754 patients submitted to curative surgery for NF-PanNENs, were included. The pooled rate of disease recurrence was 21% (95% CI 15-26%). Study quality (Odds ratio, OR 0.94, P = 0.016) and G3-PanNENs rate (OR 2.18, P = 0.040) independently predicted the recurrence rate variability. Nodal metastases (HR 1.63, P < 0.001), tumor grade G2-G3 (G1 versus G2: HR 1.72, P < 0.001, G1 versus G3 HR 2.57, P < 0.001), microvascular (HR 1.25, P = 0.046) and perineural (HR 1.29, P = 0.019) invasion were identified as significant prognostic factors. T stage (T1-T2 versus T3-T4, P = 0.253) and status of resection margins (R0 versus R1, P = 0.173) did not show any significant relationship with NF-PanNENs recurrence.
    CONCLUSION: Disease relapse occurs in approximately one out of five patients submitted to curative surgery for NF-PanNENs. Nodal involvement, tumor grade, microvascular and perineural invasion are relevant prognostic factors, that should be taken into account for follow-up and for possible trials investigating adjuvant or neoadjuvant treatments.
    Keywords:  Curative surgery; Nonfunctioning; Pancreatic neuroendocrine neoplasms; Prognostic factors; Recurrence; Relapse
  6. FASEB Bioadv. 2021 Nov;3(11): 953-966
      The gut immune system in the healthy intestine is anti-inflammatory, but can move to a pro-inflammatory state when the gut is challenged by pathogens or in disease. The nervous system influences the level of inflammation through enteric neurons and extrinsic neural connections, particularly vagal and sympathetic innervation of the gastrointestinal tract, each of which exerts anti-inflammatory effects. Within the enteric nervous system (ENS), three neuron types that influence gut immune cells have been identified, intrinsic primary afferent neurons (IPANs), vasoactive intestinal peptide (VIP) neurons that project to the mucosa, and cholinergic neurons that influence macrophages in the external muscle layers. The enteric neuropeptides, calcitonin gene-related peptide (CGRP), tachykinins, and neuromedin U (NMU), which are contained in IPANs, and VIP produced by the mucosa innervating neurons, all influence immune cells, notably innate lymphoid cells (ILCs). ILC2 are stimulated by VIP to release IL-22, which promotes microbial defense and tissue repair. Enteric neurons are innervated by the vagus, and, in the large intestine, by the pelvic nerves. Vagal nerve stimulation reduces gut inflammation, which may be both by stimulation of efferent (motor) pathways to the ENS, and stimulation of afferent pathways that connect to integrating centers in the CNS. Efferent pathways from the CNS have their anti-inflammatory effects through either or both vagal efferent neurons and sympathetic pathways. The final neurons in sympathetic pathways reduce gut inflammation by the action of noradrenaline on β2 adrenergic receptors expressed by immune cells. Activation of neural anti-inflammatory pathways is an attractive option to treat inflammatory bowel disease that is refractory to other treatments. Further investigation of the ways in which enteric reflexes, vagal pathways and sympathetic pathways integrate their effects to modulate the gut immune system and gut inflammation is needed to optimize neuromodulation therapy.
    Keywords:  enteric nervous system; inflammatory bowel disease; innate lymphoid cells; neuropeptides; sympathetic nerves; vagus nerve
  7. Urol Ann. 2021 Oct-Dec;13(4):13(4): 391-396
      Introduction: The association between inflammation and malignancies is being recognized. In this study, we assessed the use of preoperative neutrophil-lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) in predicting cancer-specific survival (CSS) and inguinal node involvement in patients with carcinoma penis.Methods: Sixty-nine patients operated for squamous cell carcinoma penis with inguinal node dissection between 2012 and 2020 were identified. We recorded the type of surgery (partial/total penectomy), T stage, grade, lymphovascular invasion (LVI), perineural invasion (PNI), pathological status of inguinal nodes and nodal stage (pN1-3), extranodal extension (ENE), and CSS. The hemogram performed within 2 weeks of surgery was used for calculating NLR and LMR.
    Results: Partial penectomy was the most common surgery (65.22%) and pT2 was the most common stage (53.62%). Grade 2 was seen in 66.67%, LVI in 34.78%, PNI in 37.68%, 52.17% had inguinal node involvement with pN3 being the most common (36.23%), and 36.23% had ENE. Kaplan-Meier analysis revealed that NLR of >3 and the LMR ≤3 indicated an inferior CSS (P = 0.05 and 0.04, respectively). T stage, inguinal node involvement, LVI, pN stage, and ENE were also associated with inferior CSS (P < 0.05). On multivariate analysis, T stage was significantly associated with CSS (P = 0.02). The NLR >3 and LMR ≤3 were also significantly associated with the presence of pathological inguinal node involvement (P = 0.001 and 0.026).
    Conclusion: NLR and LMR may help in predicting CSS and inguinal node involvement in patients of carcinoma penis.
    Keywords:  Cancer-specific survival; inflammation; lymph nodes; metastasis; penile cancer
  8. Oral Surg Oral Med Oral Pathol Oral Radiol. 2021 Aug 30. pii: S2212-4403(21)00597-6. [Epub ahead of print]
      OBJECTIVE: The objective of this study was to investigate the association between survival rate and lymphovascular invasion (LVI) and perineural invasion (PNI) in the tumor invasive front (TIF) of squamous cell carcinoma of the tongue (TSCC).STUDY DESIGN: Seventy patients with TSCC were included. The retrospective analysis included demographic, clinical, and histopathologic data. Tissue blocks containing the TIF were stained with anti-α-smooth muscle actin and anti-S100 to detect LVI and PNI, respectively. Overall survival (OS) and disease-specific survival (DSS) were assessed using Pearson's chi-square test, Kaplan-Meier method, and Cox regression.
    RESULTS: LVI and PNI were detected in 61.4% and 78.6% of the TSCC samples at the TIF, respectively. LVI and PNI were present in 54.3% of the cases and were associated with advanced clinical stage, lymph node resection, metastatic nodes, and lower survival (P < .05). The 5-year OS and DSS rates were 44% and 52%, respectively. Multivariate analysis showed that primary tumors >3.0 cm (hazard ratio = 4.29; P = .004) and a concomitant presence of LVI and PNI at the TIF (hazard ratio = 4.0; P = .012) were independent predictors for worse DSS.
    CONCLUSION: LVI and PNI, identified by immunostaining at the TIF, are potential prognostic markers of TSCC.