bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022–12–18
twelve papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation.
  2. Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance.
  3. Expectation-maximization algorithm leads to domain adaptation for a perineural invasion and nerve extraction task in whole slide digital pathology images.
  4. Nomogram to predict disease recurrence in patients with locally advanced rectal cancer undergoing rectal surgery after neoadjuvant therapy: retrospective cohort study.
  5. [Research status of the innervation of prostate cancer and its potential clinical applications for nerve-targeted therapy].
  6. 18F-FDG PET/CT and clinicopathological characteristics of neurolymphomatosis in lymphoma patients.
  7. Chronic stress promotes tumor immune evasion via the suppression of MHC-I expression and the upregulation of PD-L1.
  8. Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets.
  9. A 20.5 cm Malignant Peripheral Nerve Sheath Tumor of the Anterior Mediastinum Showing Response to Neoadjuvant Therapy.
  10. Chewing Behavior Attenuates Lung-Metastasis-Promoting Effects of Chronic Stress in Breast-Cancer Lung-Metastasis Model Mice.
  11. A reciprocal feedback between colon cancer cells and Schwann cells promotes the proliferation and metastasis of colon cancer.
  12. The promising prognostic value of vagal nerve activity at the initial management of ovarian cancer.
  1. Int J Mol Sci. 2022 Nov 24. pii: 14695. [Epub ahead of print]23(23):
    An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation.
    Marco Arese, Federico Bussolino, Margherita Pergolizzi, Laura Bizzozero.
      We propose an overview of the molecular cues and their intracellular signaling involved in the crosstalk between cancer and the nervous system. While "cancer neuroscience" as a field is still in its infancy, the relation between cancer and the nervous system has been known for a long time, and a huge body of experimental data provides evidence that tumor-nervous system connections are widespread. They encompass different mechanisms at different tumor progression steps, are multifaceted, and display some intriguing analogies with the nervous system's physiological processes. Overall, we can say that many of the paradigmatic "hallmarks of cancer" depicted by Weinberg and Hanahan are affected by the nervous system in a variety of manners.
    Keywords:  autocrine/paracrine interactions; hallmarks of cancer; signal transduction; tumor–nervous system molecular crosstalk
    DOI:  https://doi.org/10.3390/ijms232314695
  2. Cancers (Basel). 2022 Nov 24. pii: 5793. [Epub ahead of print]14(23):
    Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance.
    Federico Selvaggi, Eugenia Melchiorre, Ilaria Casari, Sebastiano Cinalli, Massimiliano Cinalli, Gitana Maria Aceto, Roberto Cotellese, Ingrid Garajova, Marco Falasca.
      Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting.
    Keywords:  neuropathic pain; pancreas; pancreatic ductal adenocarcinoma; perineural invasion; tumour microenvironment
    DOI:  https://doi.org/10.3390/cancers14235793
  3. Med Biol Eng Comput. 2022 Dec 11.
    Expectation-maximization algorithm leads to domain adaptation for a perineural invasion and nerve extraction task in whole slide digital pathology images.
    Xue Li, Jun Huang, Cuiting Wang, Xiaxia Yu, Tianhao Zhao, Chuan Huang, Yi Gao.
      In addition to lymphatic and vascular channels, tumor cells can also spread via nerves, i.e., perineural invasion (PNI). PNI serves as an independent prognostic indicator in many malignancies. As a result, identifying and determining the extent of PNI is an important yet extremely tedious task in surgical pathology. In this work, we present a computational approach to extract nerves and PNI from whole slide histopathology images. We make manual annotations on selected prostate cancer slides once but then apply the trained model for nerve segmentation to both prostate cancer slides and head and neck cancer slides. For the purpose of multi-domain learning/prediction and investigation on the generalization capability of deep neural network, an expectation-maximization (EM)-based domain adaptation approach is proposed to improve the segmentation performance, in particular for the head and neck cancer slides. Experiments are conducted to demonstrate the segmentation performances. The average Dice coefficient for prostate cancer slides is 0.82 and 0.79 for head and neck cancer slides. Comparisons are then made for segmentations with and without the proposed EM-based domain adaptation on prostate cancer and head and neck cancer whole slide histopathology images from The Cancer Genome Atlas (TCGA) database and significant improvements are observed.
    Keywords:  Computational pathology; Domain adaptation; Expectation maximization; Whole slide image
    DOI:  https://doi.org/10.1007/s11517-022-02711-z
  4. BJS Open. 2022 Nov 02. pii: zrac138. [Epub ahead of print]6(6):
    Nomogram to predict disease recurrence in patients with locally advanced rectal cancer undergoing rectal surgery after neoadjuvant therapy: retrospective cohort study.
    Jacques-Emmanuel Saadoun, Hélène Meillat, Christophe Zemmour, Serge Brunelle, Alexandra Lapeyre, Cécile de Chaisemartin, Bernard Lelong.
       INTRODUCTION: Prognostic models can be used for predicting survival outcomes and guiding patient management. TNM staging alone is insufficient for predicting recurrence after chemoradiotherapy (CRT) and surgery for locally advanced rectal cancer. This study aimed to develop a nomogram to better predict cancer recurrence after CRT followed by total mesorectal excision (TME) and tailor postoperative management and follow-up.
    MATERIALS AND METHODS: Between 2002 and 2019, data were retrospectively collected on patients with rectal adenocarcinoma. Data on sex, age, carcinoembryonic antigen (CEA) level, tumour location, induction chemotherapy, adjuvant chemotherapy, tumour downsizing, perineural invasion, lymphovascular invasion, pathological stage, resection margins (R0 versus R1), and pelvic septic complications were analysed. The variables significantly associated with cancer recurrence were used to build a nomogram that was validated in both the training and validation cohorts. Model performance was evaluated by receiver operating characteristic curve and area under the curve (AUC) analyses.
    RESULTS: After applying exclusion criteria, 634 patients with rectal adenocarcinoma were included in this study. Eight factors (CEA level, adjuvant chemotherapy, tumour downsizing, perineural invasion, lymphovascular invasion, pathological stage, resection margins (R0 versus R1), and pelvic septic complications) were identified as nomogram variables. Our nomogram showed good performance with an AUC of 0.74 and 0.75 in the training and validation cohorts respectively.
    CONCLUSION: Our nomogram is a simple tool for predicting cancer recurrence in patients with locally advanced rectal cancer after neoadjuvant CRT followed by TME. It provides an individual risk prediction of recurrence to tailor surveillance.
    DOI:  https://doi.org/10.1093/bjsopen/zrac138
  5. Zhonghua Yi Xue Za Zhi. 2022 Dec 13. 102(46): 3663-3666
    [Research status of the innervation of prostate cancer and its potential clinical applications for nerve-targeted therapy].
    R J Mo, J X Luo, Q W Mi, W D Zhong.
      Nerve fibers are important component in tumor microenvironment (TME) and have been shown to promote the early development of the prostate cancer and metastasis of advanced prostate cancer. Besides, it also activates an angio-metabolic switch, altering the endothelial cell metabolism to trigger angiogenesis. Most studies have showed that nerve infiltration in prostate cancer may be regulated by a variety of nerve growth factors secreted by cancer cells.However, surprisingly, neurons in the TME could also be neural progenitors originating from the subventricular zone. Recently, the effects of tumor-associated neuro-immune signal dysfunction on cancer promotion has gradually become a new focus. Therefore, elucidating the molecular and cellular mechanisms of nerve and its signaling in prostate cancer will help improve the value of clinical application of nerve targeted therapy.
    DOI:  https://doi.org/10.3760/cma.j.cn112137-20220527-01167
  6. Hell J Nucl Med. 2022 Dec 14. pii: s002449912517. [Epub ahead of print]
    18F-FDG PET/CT and clinicopathological characteristics of neurolymphomatosis in lymphoma patients.
    Xiaoyue Tan, Xiaolin Sun, Hui Yuan, Li He, Chongyang Ding, Lei Jiang.
       OBJECTIVE: Neurolymphomatosis (NL) is a rare but serious manifestation defined as invasion of peripheral nervous system by malignant lymphocytes. Thus, this study investigated fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and clinicopathological characteristics of NL in lymphoma patients.
    SUBJECTS AND METHODS: Clinicopathological and 18F-FDG PET/CT findings and treatment regimens were retrospectively investigated in 20 lymphoma patients with NL, and analyzed their correlation with progression-free survival (PFS) and overall survival (OS).
    RESULTS: These 20 lymphoma patients (11 males, 9 females; median age, 49 years) included 10 primary and 10 secondary NL patients. Non-Hodgkin's lymphoma (NHL) was noted in 19 patients, B-cell NHL was associated with 18 cases, and diffuse large B-cell lymphoma was the most common. Notably, 18 patients were aggressive lymphoma while 2 were indolent lymphoma. The affected neural structures included nerve roots (n=17), peripheral nerves (n=3), cranial nerves (n=3), and neural plexus (n=2). Fluorine-18-FDG was avid in all cases, and the median maximum standardized uptake value (SUVmax) of neural and all lesions was 12.2 (range, 3.3-25.6) and 15.0 (range, 4.4-34.2), respectively. The median PFS and OS of all patients were 9.3 and 14.3 months. The 12-month OS rate of 18 patients with aggressive lymphoma receiving intrathecal chemotherapy/autologous stem cell transplants (IT chem/ASCT) was significantly higher than who did not (64.8% vs 15.9%).
    CONCLUSION: The majority of NL occurred in patients with aggressive lymphoma, of which B-cell NHL were the predominant subtypes. Fluorine-18-FDG PET/CT imaging of NL was mainly characterized by intense glucose accumulation alongside peripheral nerves, and IT chem/ASCT was suggested to improve the outcomes of NL.
    DOI:  https://doi.org/10.1967/s002449912517
  7. Am J Cancer Res. 2022 ;12(11): 5286-5299
    Chronic stress promotes tumor immune evasion via the suppression of MHC-I expression and the upregulation of PD-L1.
    Yuzhu Chen, Yazhi Qian, Wei Huang, Yi Zhang, Mo Wu, Yinlong Cheng, Nan Yang, Yanyong Liu.
      Chronic stress induces cancer initiation and progression via regulation of diverse cancer risk factors including immune evasion. Our previous research demonstrated that β-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress, but the underlying mechanism of immune escape remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth and tumor escape from T cell surveillance. Chronic restraint stress reduced intratumor MHC-I expression and enhanced PD-L1 expression, whereas propranolol rectified the changes of MHC-I and PD-L1. Under chronic stress, the activated MAPK pathway suppressed MHC-I production by inactivating STAT1/IRF1 signaling pathway, and promoted PD-L1 translation by elevating eIF2α phosphorylation. These findings support the crucial role of β-adrenergic signaling cascade in the tumor escape from T cell surveillance under chronic restraint stress.
    Keywords:  Chronic restraint stress; MHC-I; PD-L1; T cells; immune evasion; β-adrenergic receptor
  8. Cancer Metastasis Rev. 2022 Dec 14.
    Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets.
    Yu Wang, Haidong Guo, Feng He.
      The circadian clock is a timekeeping system for numerous biological rhythms that contribute to the regulation of numerous homeostatic processes in humans. Disruption of circadian rhythms influences physiology and behavior and is associated with adverse health outcomes, especially cancer. However, the underlying molecular mechanisms of circadian disruption-associated cancer initiation and development remain unclear. It is essential to construct good circadian disruption models to uncover and validate the detailed molecular clock framework of circadian disruption in cancer development and progression. Mouse models are the most widely used in circadian studies due to their relatively small size, fast reproduction cycle, easy genome manipulation, and economic practicality. Here, we reviewed the current mouse models of circadian disruption, including suprachiasmatic nuclei destruction, genetic engineering, light disruption, sleep deprivation, and other lifestyle factors in our understanding of the crosstalk between circadian rhythms and oncogenic signaling, as well as the molecular mechanisms of circadian disruption that promotes cancer growth. We focused on the discoveries made with the nocturnal mouse, diurnal human being, and cell culture and provided several circadian rhythm-based cancer therapeutic strategies.
    Keywords:  BMAL1; CLOCK; Cancer target; Circadian rhythm; Mouse models
    DOI:  https://doi.org/10.1007/s10555-022-10072-0
  9. Cureus. 2022 Nov;14(11): e31299
    A 20.5 cm Malignant Peripheral Nerve Sheath Tumor of the Anterior Mediastinum Showing Response to Neoadjuvant Therapy.
    Malika P Ganguli, Jophil Thomas, Mahlon R Kile, Sri Yadlapalli.
      Malignant peripheral nerve sheath tumors (MPNST) are a rare form of sarcoma derived from Schwann cells. Major risk factors for development are neurofibromatosis 1 (NF1) and prior radiation exposure. Tumor location is highly variable. We present a case of an extremely large MPNST tumor in the anterior mediastinum in a 66-year-old male. To the best of our knowledge, the 20.5 cm tumor is the first of its kind in a patient without clinical signs of NF1 or prior radiation exposure. The localization of this tumor to the anterior mediastinum is rarer, as the most common tumors presenting in this area are thyroid neoplasms, thymomas, teratomas, and lymphomas. The patient's tumor responded to doxorubicin-ifosfamide-mesna-based therapy. The tumor decreased from 20.5 cm to 9.0 cm on subsequent imaging. Thus, this is an interesting and valuable case to learn about the presentation and potential treatments of such a rare pathology.
    Keywords:  anterior mediastinum; malignant peripheral nerve sheath tumor (mpnst); neurofibromatosis 1 (nf1); rare tumors; sarcoma
    DOI:  https://doi.org/10.7759/cureus.31299
  10. Cancers (Basel). 2022 Dec 01. pii: 5950. [Epub ahead of print]14(23):
    Chewing Behavior Attenuates Lung-Metastasis-Promoting Effects of Chronic Stress in Breast-Cancer Lung-Metastasis Model Mice.
    Jia-He Zhang, Ke-Yong Wang, Kin-Ya Kubo, Kagaku Azuma.
      We assessed the effects of chewing behavior on the lung-metastasis-promoting impact of chronic psychological-stress in mice. Human breast-cancer cells (MDA-MB-231) were injected into the tail vein of female nude mice. Mice were randomly divided into stress, stress-with-chewing, and control groups. We created chronic stress by placing mice in small transparent tubes for 45 min, 3 times a day for 7 weeks. Mice in the stress-with-chewing group were allowed to chew wooden sticks during the experimental period. The histopathological examination showed that chronic psychological-stress increased lung metastasis, and chewing behavior attenuated the stress-related lung metastasis of breast-cancer cells. Chewing behavior decreased the elevated level of the serum corticosterone, normalized the increased expression of glucocorticoid, and attenuated the elevated expression of adrenergic receptors in lung tissues. We also found that chewing behavior normalized the elevated expression of inducible nitric oxide synthase, 4-hydroxynonenal, and superoxide dismutase 2 in lung tissues, induced by chronic stress. The present study demonstrated that chewing behavior could attenuate the promoting effects of chronic psychological-stress on the lung metastasis of breast-cancer cells, by regulating stress hormones and their receptors, and the downstream signaling-molecules, involving angiogenesis and oxidative stress.
    Keywords:  Glucocorticoid; breast cancer; chewing; metastasis; psychological stress; β2-adrenergic receptor
    DOI:  https://doi.org/10.3390/cancers14235950
  11. J Exp Clin Cancer Res. 2022 Dec 15. 41(1): 348
    A reciprocal feedback between colon cancer cells and Schwann cells promotes the proliferation and metastasis of colon cancer.
    Shengbo Han, Decai Wang, Yan Huang, Zhu Zeng, Peng Xu, Hewei Xiong, Zunxiang Ke, Ya Zhang, Yuhang Hu, Fan Wang, Jie Wang, Yong Zhao, Wenfeng Zhuo, Gang Zhao.
       BACKGROUND: Research has indicated that the emergence of Schwann cells around premalignant lesions of colon cancer might be an early indicator promoting the onset of tumorigenesis. The present study explored the communication between colon cancer cells and Schwann cells.
    METHODS: Immunofluorescence analyses were conducted to examine the differential distribution of Schwann cells within colon cancer tissues and normal colon tissues. CCK8 assay, colony formation assay, wound healing assay, and transwell assay were performed to investigate the interaction between colon cancer cells and Schwann cells. Exosomes derived from colon cancer cells were isolated to further explore the effect of colon cancer cells on Schwann cells. Gain- and loss-of function experiments, luciferase reporter assays, chromatin immunoprecipitation assays, and immunohistochemistry assays were performed to reveal the cross-talk between colon cancer cells and Schwann cells. Furthermore, colon cancer cells co-cultured with Schwann cells were transplanted into nude mice for evaluating their effect on tumor proliferation and metastasis in vivo.
    RESULTS: The clinicopathological characteristics indicated that Schwann cells were enriched in colon cancer tissues and were associated with tumor metastasis and poor prognosis. The co-culture of Schwann cells with colon cancer cells promoted the proliferation and migration of colon cancer cells and Schwann cells, which was mediated by nerve growth factor (NGF) secreted from Schwann cells. Exosomal miR-21-5p released by colon cancer cells inhibited VHL expression in Schwann cells, which in turn stabilized the HIF-1α protein and increased the transcription of NGF. Meanwhile, the Schwann cells-derived NGF activated TrkA/ERK/ELK1/ZEB1 signaling pathway in colon cancer cells, which further enhanced the expression of exosomal miR-21-5p. Inhibition of either NGF or miR-21-5p significantly inhibited the proliferation and metastasis of transplanted colon cancer cells in nude mice. Coincidently, miR-21-5p was positively associated with the expression of NGF, p-ERK, p-ELK1, and ZEB1 in human colon cancer tissues.
    CONCLUSIONS: Our results implicated a reciprocal communication between colon cancer cells and Schwan cells that promoted the proliferation and metastasis of colon cancer, and identified NGF and exosomal miR-21-5p as potential therapeutic targets for the treatment of colon cancer.
    Keywords:  Colon cancer; EMT; Exosomes; Metastasis; NGF; Schwann cells
    DOI:  https://doi.org/10.1186/s13046-022-02556-2
  12. Front Oncol. 2022 ;12 1049970
    The promising prognostic value of vagal nerve activity at the initial management of ovarian cancer.
    François Cherifi, Sophie Lefevre Arbogast, Jonaz Font, Cyril Abdeddaim, Stephanie Becourt, Nicolas Penel, Elodie Coquan, Justine Lequesne, Yori Gidron, Florence Joly.
       Objective: Identifying new modifiable prognostic markers is important for ovarian cancer (OC). Low parasympathic activity is associated with inflammation, oxidative stress and sympathetic nervous system activation. Previous studies reported that low vagal nerve activity, measured by low heart rate variability (HRV), may predict poor cancer prognosis. We aimed to examine the prognostic value of HRV in OC.
    Methods: This bicentric retrospective study included patients diagnosed with serous OC FIGO stage ≥IIB, between January 2015 and August 2019, with electrocardiograms (ECG) available around diagnosis. HRV was measured from ECG using the time domain parameter of standard deviation of all normal-to-normal heartbeat intervals (SDNN). Optimal SDNN cut-off was determined using the Youden index criteria of time-dependent ROC curves. We used multivariate cox proportional hazard models to investigate the association between HRV and overall survival (OS), while adjusting for well-known OC prognostic factors.
    Results: The 202 patients included were 65.7 years-old on average, 93% had stage FIGO IIIC/IV, 56% had complete surgical resection. Median OS was 38.6 months [95%CI:34.4-47.4]. The median SDNN was 11.1ms, with an optimal cut-off of 10ms to predict OS. OS was shorter for patients with low HRV compared to high HRV (26.4 vs 45.1 months; p<0.001). In multivariate analysis, HRV remained an independent prognostic factor with a two-fold higher risk of death among patients with low SDNN compared to those with high SDNN (HR=2.03, 95%CI=1.35-3.06, p<0.001).
    Conclusion: Low HRV, was associated with worse OS in OC patients, supporting previous studies on the prognostic role of HRV in cancer. If replicated in prospective studies, vagal nerve activity may be a new therapeutic target in OC.
    Keywords:  autonomic nervous system; heart rate variability (HRV); ovarian cancer; parasympathetic activity; prognostic factor and survival; vagus nerve
    DOI:  https://doi.org/10.3389/fonc.2022.1049970
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