bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022–10–30
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Crosstalk between the peripheral nervous system and breast cancer influences tumor progression.
  2. Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression.
  3. Let-7 microRNAs Are Possibly Associated with Perineural Invasion in Colorectal Cancer by Targeting IGF Axis.
  4. Stress and cancer: The mechanisms of immune dysregulation and management.
  5. The Central Nervous Mechanism of Stress-Promoting Cancer Progression.
  6. Beyond schwannomas and neurofibromas: a radiological and histopathological review of lesser-known benign lesions that arise in association with peripheral nerves.
  7. Malignant Melanotic Nerve Sheath Tumor.
  8. Impact of histopathological type on the prognosis of ampullary carcinoma: A systematic review and meta-analysis.
  9. A broken circadian clock: The emerging neuro-immune link connecting depression to cancer.
  1. Biochim Biophys Acta Rev Cancer. 2022 Oct 22. pii: S0304-419X(22)00153-6. [Epub ahead of print] 188828
    Crosstalk between the peripheral nervous system and breast cancer influences tumor progression.
    Jianming Hu, Wuzhen Chen, Lesang Shen, Zhigang Chen, Jian Huang.
      Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as β-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.
    Keywords:  Breast cancer; Innervation; Neuroactive molecule; Perineural invasion; Peripheral nervous system
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188828
  2. Oxid Med Cell Longev. 2022 ;2022 8445093
    Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression.
    Tao Peng, Yao Guo, Zheng Gan, Yan Ling, Jiongxin Xiong, Xueyi Liang, Jing Cui.
       Background: It has been reported that signaling from the nerve growth factor (NGF) pathway associated with peripheral nerves is able to contribute to perineural invasion (PNI) of pancreatic cancer (PC). Nevertheless, the underlying mechanism by which NGF leads to PNI remained poorly understood.
    Methods: Western blotting was employed to determine NGF level in PC and paracarcinoma tissues and in PC cell lines as well as pancreatic ductal epithelial cells. MiaPaCa-2 and CFPAC-1 cells were treated with 100 ng/ml of NGF or the NGF inhibitor Tanezumab for 24 h, CCK-8 and Transwell assays were employed to test cell proliferation, invasion, and migration, respectively. TrkA expression was knocked down in MiaPaCa-2 and dorsal root ganglion (DRG) cells treated with NGF to determine its effect on the Warburg effect. To reveal that the NGF-TrkA signaling pathway was closely associated with PC PNI, in vitro neuroinvasion model was established by using MiaPaCa-2 cells via coculturing DRG cells in Matrigel. Further, exosomes were extracted from PC cells and identified by examining the levels of specific markers for exosomes. Then RT-qPCR was applied to test miR-21-5p level in tumor derived exosomal (TDE-miR-21-5p). RIP assay was performed to validate NGF and miR-21 binding ability in MiaPaCa-2 cells. Rescue experiments were performed by using coprocessing of Tanezumab and miR-21-5p mimic on MiaPaCa-2 cells, followed by coculture with DRG cells. Subsequently, we used a model of neuroinvasion in nude mice to assess the effect of NGF in vivo on tumor nerve invasion as well as on nociceptive transmission.
    Results: NGF level was preeminently higher in PC tissues and cell lines than in paracarcinoma tissues and normal pancreatic epithelial cell lines. NGF promoted MiaPaCa-2 and CFPAC-1 cell invasion and migration, while Tanezumab treatment showed the opposite results. Besides, NGF binding to TrkA receptors encouraged the intracellular Warburg effect in PC and DRG cells. TrkA blocking-up could restrain NGF induced PC cell migration and neural invasion. Mechanistically, NGF could upregulate TDE-miR-21-5p levels, and DRG cells took up TDE to activate the Warburg effect and stimulate nociceptor gene expression. miR-21-5p inhibitor could abolish the facilitative effect of NGF on PNI in MiaPaCa-2 cells. In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models.
    Conclusions: These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression.
    DOI:  https://doi.org/10.1155/2022/8445093
  3. Life (Basel). 2022 Oct 19. pii: 1638. [Epub ahead of print]12(10):
    Let-7 microRNAs Are Possibly Associated with Perineural Invasion in Colorectal Cancer by Targeting IGF Axis.
    Andrei Marian Niculae, Maria Dobre, Vlad Herlea, Teodora Ecaterina Manuc, Bogdan Trandafir, Elena Milanesi, Mihail Eugen Hinescu.
      Increased insulin-like growth factor (IGF) axis activity is associated with the development and progression of different types of malignancies, including colorectal cancer (CRC). MicroRNAs (miRNAs) belonging to the let-7 family have been reported to target genes involved in this axis and are known as tumor suppressors. In this study, in silico bioinformatic analysis was performed to assess miRNA-mRNA interactions between eight miRNAs belonging to the let-7 family and genes involved in the IGF signaling pathway, coding for receptors and substrates. miRNAs' expression analysis revealed that hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let- 97 7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, and hsa-let-7g-5p were significantly down-regulated in 25 CRC tumoral tissues (T) compared to the corresponding adjacent peritumoral tissues (PT). Moreover, our results showed an upregulation of miR-let-7e-5p in CRC tissues with mutations in KRAS codon 12 or 13, and, for the first time, found a specific dysregulation of let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, and let-7i-5p in CRC with perineural invasion. Our results sustain the relationship between the IGF axis, let-7 miRNAs, and CRC and suggest an association between the expression of these miRNAs and perineural invasion.
    Keywords:  colorectal cancer; insulin-like growth factor; let-7 microRNAs; perineural invasion
    DOI:  https://doi.org/10.3390/life12101638
  4. Front Immunol. 2022 ;13 1032294
    Stress and cancer: The mechanisms of immune dysregulation and management.
    Yixin Liu, Sheng Tian, Biao Ning, Tianhe Huang, Yi Li, Yongchang Wei.
      Advances in the understanding of psychoneuroimmunology in the past decade have emphasized the notion that stress and cancer are interlinked closely. Durable chronic stress accelerated tumorigenesis and progression, which is unfavorable for clinical outcomes of cancer patients. Available evidence has provided unprecedented knowledge about the role and mechanisms of chronic stress in carcinogenesis, the most well-known one is dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). With abnormal activation of neuroendocrine system, stress-related hormones contribute to increased oncogenes expression, exacerbated chronic inflammation and impaired immunologic function. In addition, accumulating studies have demonstrated that diverse stress interventions including pharmacological approaches, physical exercises and psychological relaxation have been administered to assist in mental disorders reduction and life quality improvement in cancer patients. In this review, we systematically summarize the connection and mechanisms in the stress-immune-cancer axis identified by animal and clinical studies, as well as conclude the effectiveness and deficiencies of existing stress management strategies.
    Keywords:  chronic stress; hypothalamic-pituitary-adrenal axis; immunity; stress management; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1032294
  5. Int J Mol Sci. 2022 Oct 21. pii: 12653. [Epub ahead of print]23(20):
    The Central Nervous Mechanism of Stress-Promoting Cancer Progression.
    Yuchuan Hong, Lu Zhang, Nian Liu, Xirong Xu, Dan Liu, Jie Tu.
      Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body's immune response, causing tumor cells to escape the "surveillance" of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.
    Keywords:  HPA axis; adrenergic receptor; cancer; central nervous system; glucocorticoid receptor; neuropeptide Y receptor; stress; sympathetic nervous system
    DOI:  https://doi.org/10.3390/ijms232012653
  6. Skeletal Radiol. 2022 Oct 25.
    Beyond schwannomas and neurofibromas: a radiological and histopathological review of lesser-known benign lesions that arise in association with peripheral nerves.
    Marco G Aru, Jessica L Davis, Gregory S Stacy, Megan K Mills, Corrie M Yablon, Christopher J Hanrahan, Raluca McCallum, Eric C Nomura, Barry G Hansford.
      Peripheral nerve sheath tumors comprise a significant percentage of both benign and malignant soft tissue tumors. The vast majority of these lesions are schwannomas and neurofibromas, which most radiologists are familiar with including the well-described multimodality imaging features. However, numerous additional often under-recognized benign entities associated with nerves exist. These rarer entities are becoming increasingly encountered with the proliferation of cross-sectional imaging, particularly magnetic resonance imaging (MRI). It is important for the radiologist to have a basic understanding of these entities as many have near-pathognomonic MR imaging features as well as specific clinical presentations that when interpreted in concert, often allows for a limited differential or single best diagnosis. The ability to provide a prospective, pre-intervention diagnosis based solely on imaging and clinical presentation is crucial as several of these entities are "do not touch" lesions, for which even a biopsy may have deleterious consequences. To our knowledge, the majority of these benign entities associated with nerves have only been described in scattered case reports or small case series. Therefore, the aim of this article is to provide a radiopathologic comprehensive review of these benign entities that arise in association with nerves with a focus on characteristic MRI features, unique histopathologic findings, and entity specific clinical exam findings/presentation.
    Keywords:  Benign; Histopathology; Neuroma; Peripheral nerve sheath tumor
    DOI:  https://doi.org/10.1007/s00256-022-04207-1
  7. AJNR Am J Neuroradiol. 2022 Oct 27.
    Malignant Melanotic Nerve Sheath Tumor.
    J C Benson, M D Marais, P M Flanigan, M Bydon, C Giannini, R J Spinner, A L Folpe.
      Malignant melanotic nerve sheath tumors are uncommon pigmented tumors of Schwann cell origin, most often found along the spinal nerves. Although well-described in the literature, the tumors are quite rare, making up <1% of nerve sheath tumors. Physicians are, therefore, often unfamiliar with both the appearance and the optimal treatment of such tumors. Morphologically, many imaging features overlap with schwannomas and neurofibromas. Nevertheless, the malignant melanotic nerve sheath tumors are crucial to identify. They can be extremely aggressive, and the management of these tumors is considerably different from their benign counterparts. In this radiology-pathology review, we will highlight the imaging appearance, histologic features, surgical resection, and subsequent therapeutic strategies in a patient with a lumbar malignant melanotic nerve sheath tumor.
    DOI:  https://doi.org/10.3174/ajnr.A7691
  8. Eur J Surg Oncol. 2022 Oct 09. pii: S0748-7983(22)00693-X. [Epub ahead of print]
    Impact of histopathological type on the prognosis of ampullary carcinoma: A systematic review and meta-analysis.
    Dong Woo Shin, Sihyun Kim, Kwangrok Jung, Jae Hyup Jung, Bomi Kim, Jinwoo Ahn, Jaihwan Kim, Jin-Hyeok Hwang, Jong-Chan Lee.
      Histologically, ampullary carcinomas (ACs) can be classified into intestinal (INT-AC) and pancreatobiliary (PB-AC) subtypes. However, the prognostic implications of these subtypes remain unclear. This study aimed to evaluate the impact of the histopathologic phenotype of ACs on survival following pancreaticoduodenectomy. We searched PubMed, Embase, and Medline for studies published in English from 1994 to 2021. A meta-analysis was performed using Review Manager 5.3. The primary endpoint was overall survival (OS). We identified 3,890 articles; of these, 37 articles involving 3,455 participants (1,659 INT-ACs and 1,796 PB-ACs) were included. Patients in the PB-ACs group had significantly shorter OS than those in the INT-ACs group (hazard ratio [HR]: 1.79, 95% confidence interval [95% CI]: 1.51-2.13, p < 0.001, I2 = 61%). A similar tendency was observed in the immunohistochemistry staining group (HR: 1.76, 95% CI: 1.33-2.33, p < 0.001, I2 = 67%), which included 24 studies and 1,638 patients, and the non-immunohistochemistry group (HR: 1.84, 95% CI: 1.53-2.22, p = 0.04, I2 = 46%), which included 13 studies and 1,817 patients. Subgroup analysis revealed that patients with PB-AC had higher frequencies of advanced (III, IV) and pT3-4 stage AC, lymph node metastasis, poorly differentiated tumor, positive surgical margins, lymphovascular invasion, and perineural invasion, than those with INT-AC. Patients with PB-AC had a significantly shorter OS than those with INT-AC due to a higher aggressiveness. Because the histopathologic subtype is a major prognostic factor in patients with resected AC, routine histopathologic classification should be considered even in clinical settings without immunohistochemistry.
    Keywords:  Ampulla of vater cancer; Intestinal type; Pancreatobiliary type
    DOI:  https://doi.org/10.1016/j.ejso.2022.10.001
  9. Brain Behav Immun Health. 2022 Dec;26 100533
    A broken circadian clock: The emerging neuro-immune link connecting depression to cancer.
    Keyu Su, Zaheer Ud Din, Bai Cui, Fei Peng, Yuzhao Zhou, Cenxin Wang, Xiaoyu Zhang, Jinxin Lu, Huandong Luo, Bin He, Keith W Kelley, Quentin Liu.
      Circadian clocks orchestrate daily rhythms in many organisms and are essential for optimal health. Circadian rhythm disrupting events, such as jet-lag, shift-work, night-light exposure and clock gene alterations, give rise to pathologic conditions that include cancer and clinical depression. This review systemically describes the fundamental mechanisms of circadian clocks and the interacting relationships among a broken circadian clock, cancer and depression. We propose that this broken clock is an emerging link that connects depression and cancer development. Importantly, broken circadian clocks, cancer and depression form a vicious feedback loop that threatens systemic fitness. Arresting this harmful loop by restoring normal circadian rhythms is a potential therapeutic strategy for treating both cancer and depression.
    Keywords:  Cancer; Circadian clock; Depression; Immunity; Neuro-endocrine
    DOI:  https://doi.org/10.1016/j.bbih.2022.100533
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