bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2021‒10‒17
thirteen papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute
  1. Nerve density in cancer: Less is better.
  2. Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer.
  3. β2-and β3-Adrenergic Receptors Contribute to Cancer-Evoked Pain in a Mouse Model of Osteosarcoma via Modulation of Neural Macrophages.
  4. Catecholamines Mediate Psychologic Stress-Induced Cancer Progression.
  5. Artificial Light at Night Reduces Anxiety-like Behavior in Female Mice with Exacerbated Mammary Tumor Growth.
  6. The Impact of Post-Operative Radiotherapy in Early Stage (pT1-pT2N0M0) Oral Tongue Squamous Cell Carcinoma in Era of DOI.
  7. Impact of Body Mass Index on Tumor Recurrence in Patients Undergoing Liver Resection for Perihilar Cholangiocarcinoma (pCCA).
  8. Long-term Follow-up and Histological Correlation of Peripheral Nervous System Alterations in Neurofibromatosis Type 2.
  9. Poorly Cohesive Carcinoma of the Nonampullary Small Intestine: A Distinct Histologic Subtype With Prognostic Significance.
  10. The role of peripheral nerve signaling in endometriosis.
  11. Endoscopic ultrasound-guided neurolysis in advanced pancreatic cancer: current status.
  12. An Ex Vivo Brain Slice Model to Study and Target Breast Cancer Brain Metastatic Tumor Growth.
  13. A Focused Review of Neural Recording and Stimulation Techniques With Immune-Modulatory Targets.
  1. FASEB Bioadv. 2021 Oct;3(10): 773-786
    Nerve density in cancer: Less is better.
    Ligia B Schmitd, Cindy Perez-Pacheco, Nisha J D'Silva.
      The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. However, usually only a few nerves inside a tumor are affected by perineural invasion, while most nerves are not. Mechanistic studies have shown nerve-secreted factors promote tumor growth and invasion thereby making tumors more aggressive. Therefore, the overall number of nerves in the tumor microenvironment should be more representative of the nerve-tumor biological interaction than perineural invasion. This review summarizes the available clinical information about nerve density as a measure of clinical outcome in cancer and explores the mechanisms underlying nerve density in cancer, specifically, neurogenesis, axonogenesis, and neurotropism.
    Keywords:  neoplasms; nerve tissue/pathology; review; tumor microenvironment
    DOI:  https://doi.org/10.1096/fba.2021-00046
  2. Cancers (Basel). 2021 Sep 28. pii: 4858. [Epub ahead of print]13(19):
    Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer.
    Sengottuvelan Murugan, Bénédicte Rousseau, Dipak K Sarkar.
      Cancer progression is known to be promoted by increased body stress caused by elevated beta-adrenergic and opioidergic nervous system activities. The effects of β2-adrenergic blocker propranolol (PRO) and μ-opioid receptor antagonist naltrexone (NTX) were tested using a preclinical model of human breast cancer. These drugs, individually, and more potently when combined, inhibited the cell growth and progression of breast cancer cells in vitro in cultures, and in vivo in rat xenografts. The antitumor activities of these drugs were associated with direct cell intrinsic effects, including increased cell growth arrest, elevated levels of apoptotic proteins, and reduced production of epithelial-mesenchymal transition factors by the tumor cells, as well as effects on innate immune activation and reduced inflammatory cytokine levels in plasma. These data suggest that the combined treatments of PRO and NTX produce impressive antitumor effects in the preclinical breast cancer model, and thereby may provide a new combinatorial treatment strategy with more clinical treatment modalities.
    Keywords:  apoptosis; beta-adrenergic blocker; breast cancer cells; cell growth arrest; epithelial–mesenchymal transition factors; innate immune system; mu-opioid receptor antagonist; tumor xenograft
    DOI:  https://doi.org/10.3390/cancers13194858
  3. Front Pharmacol. 2021 ;12 697912
    β2-and β3-Adrenergic Receptors Contribute to Cancer-Evoked Pain in a Mouse Model of Osteosarcoma via Modulation of Neural Macrophages.
    Gennaro Bruno, Francesco De Logu, Daniel Souza Monteiro de Araujo, Angela Subbiani, Federica Lunardi, Sofia Rettori, Romina Nassini, Claudio Favre, Maura Calvani.
      The mechanisms involved in the development and maintenance of cancer pain remain largely unidentified. Recently, it has been reported that β-adrenergic receptors (β-ARs), mainly β2-and β3-ARs, contribute to tumor proliferation and progression and may favor cancer-associated pain and neuroinflammation. However, the mechanism underlying β-ARs in cancer pain is still unknown. Here, we investigated the role of β1-, β2-and β3-ARs in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. Results showed a rapid tumor growth in the soft tissue associated with the development of mechanical allodynia in the hind paw ipsilateral to the injected site. In addition to reduce tumor growth, both propranolol and SR59230A, β1-/β2-and β3-AR antagonists, respectively, attenuated mechanical allodynia, the number of macrophages and an oxidative stress by-product accumulated in the ipsilateral tibial nerve. The selective β1-AR antagonist atenolol was able to slightly reduce the tumor growth but showed no effect in reducing the development of mechanical allodynia. Results suggest that the development of the mechanical allodynia in K7M2 osteosarcoma-bearing mice is mediated by oxidative stress associated with the recruitment of neural macrophages, and that antagonism of β2-and β3-ARs contribute not solely to the reduction of tumor growth, but also in cancer pain. Thus, the targeting of the β2-and β3-ARs signaling may be a promising therapeutic strategy against both tumor progression and the development of cancer-evoke pain in osteosarcoma.
    Keywords:  cancer pain; macrophages; neuroinflammation; osteosarcoma; β-adrenergic receptors
    DOI:  https://doi.org/10.3389/fphar.2021.697912
  4. Cancer Res. 2021 Oct 15. 81(20): 5144-5146
    Catecholamines Mediate Psychologic Stress-Induced Cancer Progression.
    Daniel G Bernabé.
      Catecholamines, which are involved in response to physical or emotional stress, have emerged as one of the main mediators of the relationship between chronic stress and cancer progression. The study in this issue of Cancer Research by Liu and colleagues reveals a new mechanism by which psychologic stress stimulates cancer progression through the D2 dopamine receptor and activation of the oxygen-independent HIF1α pathway. Although most investigations so far have focused on the action of the stress-related catecholamines norepinephrine and epinephrine on tumor cells, this study shows that dopamine and its receptor can be a potential therapeutic target. The findings broaden the understanding of the interaction of catecholamines with the tumor microenvironment and reinforces the need to look at psychologic stress as a modulator of cancer progression.See related article by Liu et al., p. 5353.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3077
  5. Cancers (Basel). 2021 Sep 28. pii: 4860. [Epub ahead of print]13(19):
    Artificial Light at Night Reduces Anxiety-like Behavior in Female Mice with Exacerbated Mammary Tumor Growth.
    William H Walker, Raegan M Kvadas, Laura E May, Jennifer A Liu, Jacob R Bumgarner, James C Walton, A Courtney DeVries, Robert T Dauchy, David E Blask, Randy J Nelson.
      Artificial light at night (ALAN) is a pervasive phenomenon. Although initially assumed to be innocuous, recent research has demonstrated its deleterious effects on physiology and behavior. Exposure to ALAN is associated with disruptions to sleep/wake cycles, development of mood disorders, metabolic disorders, and cancer. However, the influence of ALAN on affective behavior in tumor-bearing mice has not been investigated. We hypothesize that exposure to ALAN accelerates mammary tumor growth and predict that ALAN exacerbates negative affective behaviors in tumor-bearing mice. Adult (>8 weeks) female C3H mice received a unilateral orthotropic injection of FM3A mouse mammary carcinoma cells (1.0 × 105 in 100 μL) into the fourth inguinal mammary gland. Nineteen days after tumor inoculation, mice were tested for sucrose preference (anhedonia-like behavior). The following day, mice were subjected to an open field test (anxiety-like behavior), followed by forced swim testing (depressive-like behavior). Regardless of tumor status, mice housed in ALAN increased body mass through the first ten days. Tumor-bearing ALAN-housed mice demonstrated reduced latency to tumor onset (day 5) and increased terminal tumor volume (day 21). Exposure to ALAN reduced sucrose preference independent of tumor status. Additionally, tumor-bearing mice housed in dark nights demonstrated significantly increased anxiety-like behavior that was normalized via housing in ALAN. Together, these data reaffirm the negative effects of ALAN on tumorigenesis and demonstrate the potential anxiolytic effect of ALAN in the presence of mammary tumors.
    Keywords:  breast cancer; circadian disruption; circadian rhythms; dim light at night; tumor growth
    DOI:  https://doi.org/10.3390/cancers13194860
  6. Cancers (Basel). 2021 Sep 28. pii: 4851. [Epub ahead of print]13(19):
    The Impact of Post-Operative Radiotherapy in Early Stage (pT1-pT2N0M0) Oral Tongue Squamous Cell Carcinoma in Era of DOI.
    Daniela Alterio, Pasqualina D'Urso, Stefania Volpe, Marta Tagliabue, Rita De Berardinis, Matteo Augugliaro, Sara Gandini, Fausto Antonio Maffini, Roberto Bruschini, Irene Turturici, Stefano Riccio, Luca Calabrese, Alessia Farneti, Anna Starzyńska, Annamaria Ferrari, Barbara Alicja Jereczek-Fossa, Mohssen Ansarin, Giuseppe Sanguineti.
      Background: This study investigated the role of depth of infiltration (DOI) as an independent prognosticator in early stage (T1-T2N0M0) oral cavity tumors and to evaluate the need of postoperative radiotherapy in the case of patients upstaged to pT3 for DOI > 10 mm in the absence of other risk factors. Methods: We performed a retrospective analysis on patients treated with surgery and re-staged according to the 8th edition of malignant tumors classification (TNM). The role of DOI as well as other clinical/pathological features was investigated at both univariable and multivariable analyses on overall survival (OS), disease free survival (DFS), relapse free survival (RFS), and local RFS. Results: Among the 94 included patients, 23 would have been upstaged to pT3 based on DOI. Multivariable analysis showed that DOI was not an independent prognostic factor for any of the considered outcomes. The presence of perineural invasion was associated with a significant worse RFS (p = 0.02) and LRFS (p = 0.04). PORT was found to be significantly associated with DFS (p = 0.04) and RFS (p = 0.06). Conclusions: The increasing DOI alone was not sufficient to impact the prognosis, and therefore, should not be sufficient to dictate PORT indications in early-stage patients upstaged on the sole basis of DOI.
    Keywords:  depth of infiltration; oral tongue cancer; perineural invasion; post-operative radiotherapy
    DOI:  https://doi.org/10.3390/cancers13194851
  7. Cancers (Basel). 2021 Sep 24. pii: 4772. [Epub ahead of print]13(19):
    Impact of Body Mass Index on Tumor Recurrence in Patients Undergoing Liver Resection for Perihilar Cholangiocarcinoma (pCCA).
    Hans-Michael Hau, Mareen Devantier, Nora Jahn, Elisabeth Sucher, Sebastian Rademacher, Daniel Seehofer, Robert Sucher.
      BACKGROUND: The association of body mass index (BMI) and long-term prognosis and outcome of patients with perihilar cholangiocarcinoma (pCCA) has not been well defined. The aim of this study was to evaluate clinicopathologic and oncologic outcomes with pCCA undergoing resection, according to their BMI.METHODS: Patients undergoing liver resection in curative intention for pCCA at a tertiary German hepatobiliary (HPB) center were identified from a prospective database. Patients were classified as normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2) and obese (>30 kg/m2) according to their BMI. Impact of clinical and histo-pathological characteristics on recurrence-free survival (RFS) were assessed using Cox proportional hazard regression analysis among patients of all BMI groups.
    RESULTS: Among a total of 95 patients undergoing liver resection in curative intention for pCCA in the analytic cohort, 48 patients (50.5%) had normal weight, 33 (34.7%) were overweight and 14 patients (14.7%) were obese. After a median follow-up of 4.3 ± 2.9 years, recurrence was observed in totally 53 patients (56%). The cumulative recurrence probability was higher in obese and overweight patients than normal weight patients (5-year recurrence rate: obese: 82% versus overweight: 81% versus normal weight: 58% at 5 years; p = 0.02). Totally, 1-, 3-, 5- and 10-year recurrence-free survival rates were 68.5%, 44.6%, 28.9% and 13%, respectively. On multivariable analysis, increased BMI (HR 1.08, 95% CI: 1.01-1.16; p = 0.021), poor/moderate tumor differentiation (HR 2.49, 95% CI: 1.2-5.2; p = 0.014), positive lymph node status (HR 2.01, 95% CI: 1.11-3.65; p = 0.021), positive resection margins (HR 1.89, 95% CI:1.02-3.4; p = 0.019) and positive perineural invasion (HR 2.92, 95% CI: 1.02-8.3; p = 0.045) were independent prognostic risk factors for inferior RFS.
    CONCLUSION: Our study shows that a high BMI is significantly associated with an increased risk of recurrence after liver resection in curative intention for pCCA. This factor should be considered in future studies to better predict patient's individual prognosis and outcome based on their BMI.
    Keywords:  body mass index; liver resection; obesity; perihilar cholangiocarcinoma; prognosis; recurrence
    DOI:  https://doi.org/10.3390/cancers13194772
  8. Clin Neuroradiol. 2021 Oct 15.
    Long-term Follow-up and Histological Correlation of Peripheral Nervous System Alterations in Neurofibromatosis Type 2.
    Tim Godel, Philipp Bäumer, Said Farschtschi, Klaus Püschel, Barbara Hofstadler, Sabine Heiland, Mathias Gelderblom, Martin Bendszus, Christian Hagel, Victor-Felix Mautner.
      PURPOSE: To examine long-term alterations of the dorsal root ganglia (DRG) and the peripheral nerve in patients with neurofibromatosis type 2 (NF2) by in vivo high-resolution magnetic resonance neurography (MRN) and their correlation to histology.METHODS: In this prospective study the lumbosacral DRG, the right sciatic, tibial, and peroneal nerves were examined in 6 patients diagnosed with NF2 and associated polyneuropathy (PNP) by a standardized MRN protocol at 3 T. Volumes of DRG L3-S2 as well as peripheral nerve lesions were assessed and compared to follow-up examinations after 14-100 months. In one patient, imaging findings were further correlated to histology.
    RESULTS: Follow-up MRN examination showed a non-significant increase of volume for the DRG L3: +0.41% (p = 0.10), L4: +22.41% (p = 0.23), L5: +3.38% (p = 0.09), S1: +10.63% (p = 0.05) and S2: +1.17% (p = 0.57). Likewise, peripheral nerve lesions were not significantly increased regarding size (2.18 mm2 vs. 2.15 mm2, p = 0.89) and number (9.00 vs. 9.33, p = 0.36). Histological analyses identified schwannomas as the major correlate of both DRG hyperplasia and peripheral nerve lesions. For peripheral nerve microlesions additionally clusters of onion-bulb formations were identified.
    CONCLUSION: Peripheral nervous system alterations seem to be constant or show only a minor increase in adult NF2. Thus, symptoms of PNP may not primarily attributed to the initial schwannoma growth but to secondary long-term processes, with symptoms only occurring if a certain threshold is exceeded. Histology identified grouped areas of Schwann cell proliferations as the correlate of DRG hyperplasia, while for peripheral nerve lesions different patterns could be found.
    Keywords:  Dorsal root ganglia hyperplasia; Magnetic resonance neurography; Neurocutaneous syndrome; Peripheral nerve lesions; Polyneuropathy
    DOI:  https://doi.org/10.1007/s00062-021-01102-5
  9. Am J Surg Pathol. 2021 Oct 11.
    Poorly Cohesive Carcinoma of the Nonampullary Small Intestine: A Distinct Histologic Subtype With Prognostic Significance.
    Alessandro Vanoli, Camilla Guerini, Federica Grillo, Catherine Klersy, Matteo Fassan, Giovanni Arpa, Giuseppe Neri, Ombretta Luinetti, Marco V Lenti, Paola Ulivi, Gianluca Tedaldi, Daniela Furlan, Erica Quaquarini, Sandro Ardizzone, Gianluca Sampietro, Livia Biancone, Giovanni Monteleone, Enrico Solcia, Fausto Sessa, Marco Paulli, Nazmi V Adsay, Antonio Di Sabatino.
      Poorly cohesive carcinomas (PCCs) are neoplasms characterized by a dyshesive cell invasion pattern featuring single-cell or cord-like stromal infiltration. Although they have been extensively studied in the stomach and other digestive system organs, limited data regarding nonampullary small bowel poorly cohesive carcinomas (SB-PCCs) are hitherto available. The aims of our study were to analyze the clinicopathologic and immunophenotypical features of SB-PCCs (PCC pattern accounting for >50% of the neoplasm) and to compare them with small bowel adenocarcinomas (SBAs), not otherwise specified (SBAs-NOS) and with cancers with a histologically distinct PCC component accounting for 10% to 50% of the neoplasm (mixed-poorly-cohesive-glandular-SBAs). Fifteen SB-PCCs were identified and compared with 95 SBAs-NOS and 27 mixed-poorly-cohesive-glandular-SBAs. Most SB-PCCs (67%) were composed of <10% of signet-ring cells, and all but 1 SB-PCCs exhibited loss of membranous expression of E-cadherin. Compared with SBAs-NOS, SB-PCCs showed a significantly younger patient age at diagnosis, and a stronger association with Crohn disease, and both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs featured a higher rate of lymphovascular and perineural invasion and a lower percentage of mismatch repair-deficient cases. Importantly, the cancer-specific survival of SB-PCC (hazard ratio: 3.81; 95% confidence interval: 1.90-7.64; P<0.001) and mixed-poorly-cohesive-glandular-SBA (4.12; 2.20-7.71; P<0.001) patients was significantly worse compared with SBAs-NOS cases. This study provides objective evidence to the World Health Organization (WHO) 2019 introduction of SB-PCC as a distinctive subtype of nonampullary SBA, by virtue of its unique clinical and histologic features, and suggests that both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs should be separated from SBAs-NOS.
    DOI:  https://doi.org/10.1097/PAS.0000000000001821
  10. FASEB Bioadv. 2021 Oct;3(10): 802-813
    The role of peripheral nerve signaling in endometriosis.
    Stephen Kenneth Godin, John Wagner, Pearl Huang, Dara Bree.
      A hallmark of endometriosis - a chronic debilitating condition whose causes are poorly understood - is neuronal innervation of lesions. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with endometriosis but also contribute to a pro-growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. The diverse array of contributions that neurons play in endometriosis indicate that it should be considered as a nerve-centric disease. This review is focused on the emerging field of exoneural biology and how it applies to the field of endometriosis, in particular the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the mechanisms of neuronal contribution to endometriosis, as well as their interactions with accompanying stromal and immune cells, will unearth novel disease-relevant pathways and targets, providing additional, more selective therapeutic horizons.
    Keywords:  endometriosis; lesion; nerve signaling; nociceptor; peripheral nerves
    DOI:  https://doi.org/10.1096/fba.2021-00063
  11. BMJ Support Palliat Care. 2021 Oct 11. pii: bmjspcare-2021-002905. [Epub ahead of print]
    Endoscopic ultrasound-guided neurolysis in advanced pancreatic cancer: current status.
    Katy Hickman, Edmund Godfrey, Thankamma Ajithkumar.
      Pancreatic cancer has a very poor prognosis with patients often presenting with locally advanced, inoperable or metastatic disease. A significant proportion of patients have visceral pain due to perineural infiltration or coeliac plexus involvement by the tumour. This pain is difficult to control and may become refractory to conventional pain management. Therefore, coeliac plexus neurolysis (CPN) has been proposed to ablate the neuronal transmission pathway of pain permanently. CPN is recommended for those who have uncontrolled pain, are experiencing unacceptable opioid adverse effects or are receiving escalating doses of analgesics. It is not known whether CPN performed at diagnosis as the first-line treatment ('early') would impact short-term and long-term pain control and quality of life. NICE has recommended (2018) a randomised trial comparing early endoscopic ultrasound-guided coeliac plexus neurolysis (EUS-CPN) with on-demand EUS-CPN in pancreatic cancer. In this context, we will review the current evidence on its clinical benefits.
    Keywords:  pain; pancreatic; quality of life; symptoms and symptom management
    DOI:  https://doi.org/10.1136/bmjspcare-2021-002905
  12. J Vis Exp. 2021 Sep 22.
    An Ex Vivo Brain Slice Model to Study and Target Breast Cancer Brain Metastatic Tumor Growth.
    Lorela Ciraku, Rebecca A Moeller, Emily M Esquea, Wiktoria A Gocal, Edward J Hartsough, Nicole L Simone, Joshua G Jackson, Mauricio J Reginato.
      Brain metastasis is a serious consequence of breast cancer for women as these tumors are difficult to treat and are associated with poor clinical outcomes. Preclinical mouse models of breast cancer brain metastatic (BCBM) growth are useful but are expensive, and it is difficult to track live cells and tumor cell invasion within the brain parenchyma. Presented here is a protocol for ex vivo brain slice cultures from xenografted mice containing intracranially injected breast cancer brain-seeking clonal sublines. MDA-MB-231BR luciferase tagged cells were injected intracranially into the brains of Nu/Nu female mice, and following tumor formation, the brains were isolated, sliced, and cultured ex vivo. The tumor slices were imaged to identify tumor cells expressing luciferase and monitor their proliferation and invasion in the brain parenchyma for up to 10 days. Further, the protocol describes the use of time-lapse microscopy to image the growth and invasive behavior of the tumor cells following treatment with ionizing radiation or chemotherapy. The response of tumor cells to treatments can be visualized by live-imaging microscopy, measuring bioluminescence intensity, and performing histology on the brain slice containing BCBM cells. Thus, this ex vivo slice model may be a useful platform for rapid testing of novel therapeutic agents alone or in combination with radiation to identify drugs personalized to target an individual patient's breast cancer brain metastatic growth within the brain microenvironment.
    DOI:  https://doi.org/10.3791/62617
  13. Front Immunol. 2021 ;12 689344
    A Focused Review of Neural Recording and Stimulation Techniques With Immune-Modulatory Targets.
    Lorenzo Carnevale, Marialuisa Perrotta, Giuseppe Lembo.
      The complex interactions established between the nervous and immune systems have been investigated for a long time. With the advent of small and portable devices to record and stimulate nerve activity, researchers from many fields began to be interested in how nervous activity can elicit immune responses and whether this activity can be manipulated to trigger specific immune responses. Pioneering works demonstrated the existence of a cholinergic inflammatory reflex, capable of controlling the systemic inflammatory response through a vagus nerve-mediated modulation of the spleen. This work inspired many different areas of technological and conceptual advancement, which are here reviewed to provide a concise reference for the main works expanding the knowledge on vagus nerve immune-modulatory capabilities. In these works the enabling technologies of peripheral nervous activity recordings were implemented and embody the current efforts aimed at controlling neural activity with modulating functions in immune response, both in experimental and clinical contexts.
    Keywords:  bioelectronic medicine; immunity; inflammatory reflex; microneurography; neuro-immune interface
    DOI:  https://doi.org/10.3389/fimmu.2021.689344
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