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Cancers
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The Tumor Neuroenvironment
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The Tumor Neuroenvironment

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 14026

Special Issue Editors

Prof. Dr. Michael Shurin

E-Mail Website
Guest Editor
Division of Clinical Immunopathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
Interests: immune regulators; neuroimmunology; tumor innervation; tumor immunoenvironment
Prof. Dr. Nuray Erin

E-Mail Website
Guest Editor
1. Department of Medical Pharmacology, Faculty of Medicine, Akdeniz University, 07070 Antalya, Turkey
2. Immunopharmacology and Immunooncology Unit, 07070 Antalya, Turkey
Interests: cancer immunology; neurobiology; neuroimmunology; neuropeptides; sensory nerves; pharmacology

Special Issue Information

Dear Colleagues,

Tumor development and progression largely depend on the malignant cell interaction with the microenvironmental components. The role of cancer-associated fibroblasts, endothelial cells, tumor-infiltrating immune cells and other stromal elements in controlling tumor growth and spreading is intensively investigated. Nerve endings are also often identified within solid tumors, but their impact on tumor growth and progression is not entirely understood. Emerging data suggests that the CNS may affect cancer development via the HPA axis. The role of the PNS in tumorigenesis is less clear, although the involvement of the efferent innervation in controlling tumor growth and spreading has been reported. However, the contribution of the afferent neurons in tumor growth is less clear, while the engagement of the PNS neuroglial cells in the regulation of tumor growth and in cancer-associated neurodegenerative processes has been only hypothesized. Understanding the crosstalk between the neuronal and ‘classical’ players involved in pathophysiological regulations in the tumor milieu and development of the general concept of the tumor neuroenvironment is highly justified and necessary for designing innovative cancer therapeutic and preventing approaches. Focused topics of this Special Issue are: Role of efferent and sensory tumor innervation, including neuroglia and neuropeptides, in cancer progression,  perineural invasion, paraneoplastic syndrome, psychoneuroimmunology and neurodegeneration in cancer, as well as therapeutic and psychosocial aspects of tumor innervation.

Prof. Dr. Michael Shurin
Prof. Dr. Nuray Erin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor innervation
  • neuropeptides
  • neuroglia
  • neuro-immune axis
  • metastases

Published Papers (5 papers)

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Research

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22 pages, 8521 KiB  
Article
A Novel Therapeutic Target for Small-Cell Lung Cancer: Tumor-Associated Repair-like Schwann Cells
by Shuhui Cao, Yue Wang, Yan Zhou, Yao Zhang, Xuxinyi Ling, Lincheng Zhang, Jingwen Li, Yu Yang, Weimin Wang, Michael R. Shurin and Hua Zhong
Cancers 2022, 14(24), 6132; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246132 - 12 Dec 2022
Cited by 2 | Viewed by 1859
Abstract
Small-cell lung cancer (SCLC), representing 15–20% of all lung cancers, is an aggressive malignancy with a distinct natural history, poor prognosis, and limited treatment options. We have previously identified Schwann cells (SCs), the main glial cells of the peripheral nervous system, in tumor [...] Read more.
Small-cell lung cancer (SCLC), representing 15–20% of all lung cancers, is an aggressive malignancy with a distinct natural history, poor prognosis, and limited treatment options. We have previously identified Schwann cells (SCs), the main glial cells of the peripheral nervous system, in tumor tissues and demonstrated that they may support tumor spreading and metastasis formation in the in vitro and in vivo models. However, the role of SCs in the progression of SCLC has not been investigated. To clarify this issue, the cell proliferation assay, the annexin V apoptosis assay, and the transwell migration and invasion assay were conducted to elucidate the roles in SCLC of tumor-associated SCs (TA-SCs) in the proliferation, apoptosis, migration, and invasion of SCLC cells in vitro, compared to control group. In addition, the animal models to assess SC action’s effects on SCLC in vivo were also developed. The result confirmed that TA-SCs have a well-established and significant role in facilitating SCLC cell cancer migration and invasion of SCLC in vitro, and we also observed that SC promotes tumor growth of SCLC in vivo and that TA-SCs exhibited an advantage and show a repair-like phenotype, which allowed defining them as tumor-associated repair SCs (TAR-SCs). Potential molecular mechanisms of pro-tumorigenic activity of TAR-SCs were investigated by the screening of differentially expressed genes and constructing networks of messenger-, micro-, and long- non-coding RNA (mRNA-miRNA-lncRNA) using DMS114 cells, a human SCLC, stimulated with media from DMS114-activated SCs, non-stimulated SCs, and appropriate controls. This study improves our understanding of how SCs, especially tumor-activated SCs, may promote SCLC progression. Our results highlight a new functional phenotype of SCs in cancer and bring new insights into the characterization of the nervous system-tumor crosstalk. Full article
(This article belongs to the Special Issue The Tumor Neuroenvironment)
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20 pages, 2966 KiB  
Article
Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis
by Daniela M. Sousa, Veronica Fernandes, Catarina Lourenço, Carina Carvalho-Maia, Helena Estevão-Pereira, João Lobo, Mariana Cantante, Marina Couto, Francisco Conceição, Carmen Jerónimo, Luisa Pereira and Meriem Lamghari
Cancers 2022, 14(22), 5518; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225518 - 10 Nov 2022
Cited by 4 | Viewed by 1592
Abstract
Epidemiological studies and preclinical models suggest that chronic stress might accelerate breast cancer (BC) growth and the development of metastasis via sympathetic neural mechanisms. Nevertheless, the role of each adrenergic pathway (α1, α2, and β) in human samples remains poorly depicted. Herein, we [...] Read more.
Epidemiological studies and preclinical models suggest that chronic stress might accelerate breast cancer (BC) growth and the development of metastasis via sympathetic neural mechanisms. Nevertheless, the role of each adrenergic pathway (α1, α2, and β) in human samples remains poorly depicted. Herein, we propose to characterize the profile of the sympathetic system (e.g., release of catecholamines, expression of catecholamine metabolic enzymes and adrenoreceptors) in BC patients, and ascertain its relevance in the development of distant metastasis. Our results demonstrated that BC patients exhibited increased plasma levels of catecholamines when compared with healthy donors, and this increase was more evident in BC patients with distant metastasis. Our analysis using the BC-TCGA database revealed that the genes coding the most expressed adrenoreceptors in breast tissues (ADRA2A, ADRA2C, and ADRB2, by order of expression) as well as the catecholamine synthesizing (PNMT) and degrading enzyme (MAO-A and MAO-B) genes were downregulated in BC tissues. Importantly, the expression of ADRA2A, ADRA2C, and ADRB2 was correlated with metastatic BC and BC subtypes, and thus the prognosis of the disease. Overall, we gathered evidence that under stressful conditions, both the α2- and β2-signaling pathways might work on a synergetic matter, thus paving the way for the development of new therapeutic approaches. Full article
(This article belongs to the Special Issue The Tumor Neuroenvironment)
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Review

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24 pages, 1110 KiB  
Review
Regulation of Carcinogenesis by Sensory Neurons and Neuromediators
by Nuray Erin, Galina V. Shurin, James H. Baraldi and Michael R. Shurin
Cancers 2022, 14(9), 2333; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092333 - 09 May 2022
Cited by 12 | Viewed by 3866
Abstract
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of [...] Read more.
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread. Full article
(This article belongs to the Special Issue The Tumor Neuroenvironment)
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18 pages, 1026 KiB  
Review
Tumor Innervation: History, Methodologies, and Significance
by James H. Baraldi, German V. Martyn, Galina V. Shurin and Michael R. Shurin
Cancers 2022, 14(8), 1979; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081979 - 14 Apr 2022
Cited by 7 | Viewed by 2899
Abstract
The role of the nervous system in cancer development and progression has been under experimental and clinical investigation since nineteenth-century observations in solid tumor anatomy and histology. For the first half of the twentieth century, methodological limitations and opaque mechanistic concepts resulted in [...] Read more.
The role of the nervous system in cancer development and progression has been under experimental and clinical investigation since nineteenth-century observations in solid tumor anatomy and histology. For the first half of the twentieth century, methodological limitations and opaque mechanistic concepts resulted in ambiguous evidence of tumor innervation. Differential spatial distribution of viable or disintegrated nerve tissue colocalized with neoplastic tissue led investigators to conclude that solid tumors either are or are not innervated. Subsequent work in electrophysiology, immunohistochemistry, pathway enrichment analysis, neuroimmunology, and neuroimmunooncology have bolstered the conclusion that solid tumors are innervated. Regulatory mechanisms for cancer-related neurogenesis, as well as specific operational definitions of perineural invasion and axonogenesis, have helped to explain the consensus observation of nerves at the periphery of the tumor signifying a functional role of nerves, neurons, neurites, and glia in tumor development. Full article
(This article belongs to the Special Issue The Tumor Neuroenvironment)
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16 pages, 692 KiB  
Review
Stress in Metastatic Breast Cancer: To the Bone and Beyond
by Catarina Lourenço, Francisco Conceição, Carmen Jerónimo, Meriem Lamghari and Daniela M. Sousa
Cancers 2022, 14(8), 1881; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081881 - 08 Apr 2022
Cited by 9 | Viewed by 3000
Abstract
Breast cancer (BRCA) remains as one the most prevalent cancers diagnosed in industrialised countries. Although the overall survival rate is high, the dissemination of BRCA cells to distant organs correlates with a significantly poor prognosis. This is due to the fact that there [...] Read more.
Breast cancer (BRCA) remains as one the most prevalent cancers diagnosed in industrialised countries. Although the overall survival rate is high, the dissemination of BRCA cells to distant organs correlates with a significantly poor prognosis. This is due to the fact that there are no efficient therapeutic strategies designed to overcome the progression of the metastasis. Over the past decade, critical associations between stress and the prevalence of BRCA metastases were uncovered. Chronic stress and the concomitant sympathetic hyperactivation have been shown to accelerate the progression of the disease and the metastases incidence, specifically to the bone. In this review, we provide a summary of the sympathetic profile on BRCA. Additionally, the current knowledge regarding the sympathetic hyperactivity, and the underlying adrenergic signalling pathways, involved on the development of BRCA metastasis to distant organs (i.e., bone, lung, liver and brain) will be revealed. Since bone is a preferential target site for BRCA metastases, greater emphasis will be given to the contribution of α2- and β-adrenergic signalling in BRCA bone tropism and the occurrence of osteolytic lesions. Full article
(This article belongs to the Special Issue The Tumor Neuroenvironment)
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