bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022‒11‒06
eight papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute
  1. Nociceptor neurons affect cancer immunosurveillance.
  2. Sensory nerves enhance triple-negative breast cancer invasion and metastasis via the axon guidance molecule PlexinB3.
  3. Does memantine show chemopreventive effect against mice 4T1 breast tumor model?
  4. Intramural Component of Venous, Lymphatic, and Perineural Invasion in Colon Cancer: A Threat or an Illusion?
  5. Neuroepithelial Interactions in Cancer.
  6. Role of nerves in neurofibromatosis type 1-related nervous system tumors.
  7. A Rare Case of Neuroendocrine Tumor in a Patient With Neurofibromatosis Type 1: Is There Any Association?
  8. Effect of Propofol and Etomidate on the Proliferation, Cell-cycle Distribution, Apoptosis and Necrosis of Pancreatic Tumour Cells.
  1. Nature. 2022 Nov 02.
    Nociceptor neurons affect cancer immunosurveillance.
    Mohammad Balood, Maryam Ahmadi, Tuany Eichwald, Ali Ahmadi, Abdelilah Majdoubi, Karine Roversi, Katiane Roversi, Christopher T Lucido, Anthony C Restaino, Siyi Huang, Lexiang Ji, Kai-Chih Huang, Elise Semerena, Sini C Thomas, Alexandro E Trevino, Hannah Merrison, Alexandre Parrin, Benjamin Doyle, Daniel W Vermeer, William C Spanos, Caitlin S Williamson, Corey R Seehus, Simmie L Foster, Hongyue Dai, Chengyi J Shu, Manu Rangachari, Jacques Thibodeau, Sonia V Del Rincon, Ronny Drapkin, Moutih Rafei, Nader Ghasemlou, Paola D Vermeer, Clifford J Woolf, Sebastien Talbot.
      Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41586-022-05374-w
  2. NPJ Breast Cancer. 2022 Nov 04. 8(1): 116
    Sensory nerves enhance triple-negative breast cancer invasion and metastasis via the axon guidance molecule PlexinB3.
    Thanh T Le, Samantha L Payne, Maia N Buckwald, Lily A Hayes, Savannah R Parker, Christopher B Burge, Madeleine J Oudin.
      In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis, yet the mechanisms by which different types of peripheral nerves drive tumor progression remain poorly understood. In this study, we identified sensory nerves as more abundant in human triple-negative breast cancer (TNBC) tumors. Co-injection of sensory neurons isolated from the dorsal root ganglia (DRG) of adult female mice with human TNBC cells in immunocompromised mice increased the number of lung metastases. Direct in vitro co-culture of human TNBC cells with the dorsal root ganglia (DRG) of adult female mice revealed that TNBC cells adhere to sensory neuron fibers leading to an increase in migration speed. Species-specific RNA sequencing revealed that co-culture of TNBC cells with sensory nerves upregulates the expression of genes associated with cell migration and adhesion in cancer cells. We demonstrated that lack of the semaphorin receptor PlexinB3 in cancer cells attenuate their adhesion to and migration on sensory nerves. Together, our results identify a mechanism by which nerves contribute to breast cancer migration and metastasis by inducing a shift in TNBC cell gene expression and support the rationale for disrupting neuron-cancer cell interactions to target metastasis.
    DOI:  https://doi.org/10.1038/s41523-022-00485-z
  3. Turk J Med Sci. 2022 Jun;52(3): 841-847
    Does memantine show chemopreventive effect against mice 4T1 breast tumor model?
    Gülşah Albayrak, Elif Burcu Bali, Funda Demirtaş Korkmaz, Emin Ümit Bağrıaçık.
      BACKGROUND: Cancer cells express higher levels of N-methyl-d-aspartate (NMDA) receptor. In this study, we aimed to use memantine as a potential blocker to inhibit the action of the NMDA receptor in cancer cells in vivo in order to investigate the potential chemopreventive effect of memantine in 4T1 tumor-bearing mice.METHODS: To determine the potential chemopreventive effect of the compound, mice weights, tumor volumes, spleen IL-6, and tumor DNA methylation levels were investigated. A total of 26 Balb/c female mice were allocated into three groups. G1 (n = 6): tumor control group, G2 (n = 10): low dose (5mg/kg) memantine group, G3: high dose (10 mg/kg) memantine group (n = 10). G1 was inoculated with 4T1 cells without any memantine treatment. G2 and G3 were pretreated with 5 and 10 mg/kg memantine daily intraperitoneal (ip) injection (weekend off) for 10 days, respectively. Both G2 and G3 were subdivided into two groups as G2a (n = 4) and G3a (n = 4): tumor free groups and G2b (n = 6) and G3b (n = 6) tumor bearing groups.
    RESULTS: Our results revealed that G3: high dose (10 mg/kg) memantine group, significantly (p = 0.0248) reduced the tumor volumes. We found that spleen IL-6 levels were significantly higher in memantine pretreated tumor free group p = 0.0204 ) We also found that high dose memantine treated tumor free group (G3a) has significantly lower genome-wide DNA methylation levels when compared to tumor control group (G1) p = 0.0012.
    DISCUSSION: To the best of our knowledge, it is the first study that highlights a potential chemopreventive effect of memantine in vivo in the mouse 4T1 breast tumor model. But further investigations should be carried out to explore the chemopreventive mechanism of action for memantine in cancer.
    Keywords:  4T1; DNA methylation; chemoprevention; memantine; triple negative breast cancer
    DOI:  https://doi.org/10.55730/1300-0144.5381
  4. Balkan Med J. 2022 Nov 01.
    Intramural Component of Venous, Lymphatic, and Perineural Invasion in Colon Cancer: A Threat or an Illusion?
    Leyla Özer, Elif Şenocak Taşçı, Arda Ulaş Mutlu, Betül Piyade, Nur Ramoğlu, Miraç Ajredini, Damla Gürleyik, Recep Çeçen, Sena Nur Dinçer, Turan Musevitoğlu, Süha Göksel, Ümit İnce, Cavit Kerem Kayhan, Sibel Erdamar, İbrahim Yıldız, Erman Aytaç.
      Background: Extramural venous invasion is an independent predictor of poor outcome in colorectal cancer, whereas the significance of the intramural component of venous and lymphatic and perineural invasion is unclear.Aims: To evaluate the prognostic impact of intramural components for venous, lymphatic, and perineural invasions and the relation of these invasion patterns with clinicopathological features in patients with colon cancer.
    Study Design: A retrospective cross-sectional study.
    Methods: The analysis included 626 patients with colon cancer in stages II and III. All patients were divided into four categories (no invasion, intramural invasion only, extramural invasion only, or both intramural and extramural invasions) for vascular invasion, lymphatic invasion and perineural invasion. The primary outcomes were 5-year disease-free and overall survival.
    Results: Right-sided (for vascular invasion, 24.7% vs. 33.9%, p = 0.007; for perineural invasion, 34.5% vs. 41.5%, p = 0.034) and dMMR tumors (for vascular invasion, 13.5% vs. 33.5, p < 0.001; for perineural invasion, 25% vs. 41.4%, p = 0.004) exhibited less venous and perineural invasion. Compared with no invasion, presence of intramural invasion only, did not exert any effect on disease-free or overall survival for vascular invasion, lymphatic invasion, and perineural invasion. Multivariate analyses revealed that the presence of both intramural and extramural invasion was independently associated with poor disease-free and overall survival for venous (hazard ratios: 2.39, p = 0.001; hazard ratios: 2.46, p = 0.001), lymphatic (hazard ratios: 2.456, p < 0.001; hazard ratios: 2.13, p = 0.02) and perineural invasion (hazard ratios: 2.99, p < 0.001; hazard ratios: 2.68, p < 0.001), respectively.
    Conclusion: Our data strongly advocates the importance of reporting intramural and extramural components of invasion since the presence of intramural invasion alone may not be considered as a high-risk factor for systemic recurrence.
    DOI:  https://doi.org/10.4274/balkanmedj.galenos.2022.2022-6-94
  5. Annu Rev Pathol. 2022 Nov 02.
    Neuroepithelial Interactions in Cancer.
    Gustavo Ayala.
      Nerves not only regulate the homeostasis and energetic metabolism of normal epithelial cells but also are critical for cancer, as cancer recapitulates the biology of neural regulation of epithelial tissues. Cancer cells rarely develop in denervated organs, and denervation affects tumorigenesis, in vivo and in humans. Axonogenesis occurs to supply the new malignant epithelial growth with nerves. Neurogenesis happens later, first in ganglia around organs or the spinal column and subsequently through recruitment of neuroblasts from the central nervous system. The hallmark of this stage is regulation of homeostasis and energetic metabolism. Perineural invasion is the most efficient interaction between cancer cells and nerves. The hallmark of this stage is increased proliferation and decreased apoptosis. Finally, carcinoma cells transdifferentiate into a neuronal profile in search of neural independence. The latter is the last stage in neuroepithelial interactions. Treatments for cancer must address the biology of neural regulation of cancer. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-031521-023248
  6. Cell Oncol (Dordr). 2022 Nov 03.
    Role of nerves in neurofibromatosis type 1-related nervous system tumors.
    Ling-Ling Ge, Ming-Yan Xing, Hai-Bing Zhang, Qing-Feng Li, Zhi-Chao Wang.
      BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that affects nearly 1 in 3000 infants. Neurofibromin inactivation and NF1 gene mutations are involved in various aspects of neuronal function regulation, including neuronal development induction, electrophysiological activity elevation, growth factor expression, and neurotransmitter release. NF1 patients often exhibit a predisposition to tumor development, especially in the nervous system, resulting in the frequent occurrence of peripheral nerve sheath tumors and gliomas. Recent evidence suggests that nerves play a role in the development of multiple tumor types, prompting researchers to investigate the nerve as a vital component in and regulator of the initiation and progression of NF1-related nervous system tumors.CONCLUSION: In this review, we summarize existing evidence about the specific effects of NF1 mutation on neurons and emerging research on the role of nerves in neurological tumor development, promising a new set of selective and targeted therapies for NF1-related tumors.
    Keywords:  Glioma; Nerve; Nervous system tumors; Neurofibromatosis type 1; Peripheral nerve sheath tumor
    DOI:  https://doi.org/10.1007/s13402-022-00723-3
  7. Cureus. 2022 Sep;14(9): e29621
    A Rare Case of Neuroendocrine Tumor in a Patient With Neurofibromatosis Type 1: Is There Any Association?
    Fatima Zahra Baddi, Fatima Zohra Ahsayen, Hiba Ramdani, Meriem Rhazari, Imane Skiker, Afaf Thouil, Hatim Kouismi.
      Neurofibromatosis type 1 (NF1) is an autosomal dominant condition characterized by café-au-lait spots, cutaneous neurofibromas, axillary and inguinal freckling, and iris Lisch nodules; however, the presentations vary greatly, even within families. NF1 is also a recognized risk factor for the development of malignancy particularly malignant peripheral nerve sheath tumors (MPNST), optic gliomas, other gliomas, and leukemia. Nevertheless, the occurrence of lung cancer in a patient with neurofibromatosis type 1 is a rare phenomenon. Here we present a case of neuroendocrine tumor in a patient with neurofibromatosis type 1, highlighting the association between the two diseases. This case report also aimed to raise awareness of possible malignancies in patients with neurofibromatosis type 1.
    Keywords:  lung cancer; malignancies; neuroendocrine tumor; neurofibromatosis type 1 (nf1); risk factor
    DOI:  https://doi.org/10.7759/cureus.29621
  8. In Vivo. 2022 Nov-Dec;36(6):36(6): 2722-2729
    Effect of Propofol and Etomidate on the Proliferation, Cell-cycle Distribution, Apoptosis and Necrosis of Pancreatic Tumour Cells.
    Manuela Malsy, Bernhard Graf, Veronika Hofer, Diane Bitzinger, Anika Bundscherer.
      BACKGROUND/AIM: The influence of surgical interventions and anaesthesiological procedures on tumour progression was investigated as early as the 1920s. In current cancer management, the perioperative phase is increasingly being considered a vulnerable period with an increased risk of tumour cell dissemination due to medication, surgical manipulation, and immunosuppression. The extent to which narcotics administered in the perioperative setting influence the oncological outcomes of patients with pancreatic cancer is still unclear.MATERIALS AND METHODS: To investigate the effect of propofol and etomidate on the proliferation, cell-cycle distribution, apoptosis, and necrosis of pancreatic tumour cells in vitro, PaTu 8988t and Panc-1 pancreatic cancer cells were treated with 0-1,000 μM propofol or etomidate for 24 h each. Cell proliferation was measured with enzyme-linked immunosorbent-bromodeoxyuridine assay. The apoptosis rate was analysed with annexin V staining and the cell-cycle distribution with flow cytometry.
    RESULTS: Propofol at 1,000 μM induced apoptosis and inhibited cell proliferation. The cell cycle showed an increased S-phase and reduced cells in the G1-phase. At 100 μM, propofol significantly inhibited proliferation of the pancreatic cancer cell line PaTu 8988t and reduced cells in the G2-phase in the cell cycle. Etomidate had no effects on cell-cycle distribution, proliferation, apoptosis, and necrosis at the concentrations used.
    CONCLUSION: In this study, propofol was shown to have anticancer effects by induction of apoptosis and inhibition of cell proliferation, while etomidate did not affect pancreatic cancer cells. However, it is too early to make any recommendation for changes in clinical practice and further clinical studies are warranted to investigate the effect of anaesthetics on cancer progression.
    Keywords:  Propofol; apoptosis; cancer; cell-cycle distribution; etomidate; necrosis; pancreatic cancer; proliferation
    DOI:  https://doi.org/10.21873/invivo.13008
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