The nerve cells in gastrointestinal cancers: from molecular mechanisms to clinical intervention

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Abstract

Gastrointestinal (GI) cancer is a formidable malignancy with significant morbidity and mortality rates. Recent studies have shed light on the complex interplay between the nervous system and the GI system, influencing various aspects of GI tumorigenesis, such as the malignance of cancer cells, the conformation of tumor microenvironment (TME), and the resistance to chemotherapies. The discussion in this review first focused on exploring the intricate details of the biological function of the nervous system in the development of the GI tract and the progression of tumors within it. Meanwhile, the cancer cell-originated feedback regulation on the nervous system is revealed to play a crucial role in the growth and development of nerve cells within tumor tissues. This interaction is vital for understanding the complex relationship between the nervous system and GI oncogenesis. Additionally, the study identified various components within the TME that possess a significant influence on the occurrence and progression of GI cancer, including microbiota, immune cells, and fibroblasts. Moreover, we highlighted the transformation relationship between non-neuronal cells and neuronal cells during GI cancer progression, inspiring the development of strategies for nervous system-guided anti-tumor drugs. By further elucidating the deep mechanism of various neuroregulatory signals and neuronal intervention, we underlined the potential of these targeted drugs translating into effective therapies for GI cancer treatment. In summary, this review provides an overview of the mechanisms of neuromodulation and explores potential therapeutic opportunities, providing insights into the understanding and management of GI cancers.

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Cancer statistics, 2023

Rebecca L Siegel, Kimberly D Miller, Nikita Sandeep Wagle … (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

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The Microbiota-Gut-Brain Axis

John F. Cryan, Kenneth J. O'Riordan, Caitlin S M Cowan … (2019)

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

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Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

Hong. Wang, Man Yu, Mahendar Ochani … (2003)

Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.

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Author and article information

Contributors

Wei Kang:

ORCID: http://orcid.org/0000-0002-4651-677X

weikang@cuhk.edu.hk

Journal

Journal ID (nlm-ta): Oncogene

Journal ID (iso-abbrev): Oncogene

Title: Oncogene

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date (Electronic): 11 December 2023

Publication date PMC-release: 11 December 2023

Publication date (Print): 2024

Volume: 43

Issue: 2

Pages: 77-91

Affiliations

[1 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, , The Chinese University of Hong Kong, ; Hong Kong, China

[2 ]Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, ( https://ror.org/00t33hh48) Hong Kong, China

[3 ]CUHK-Shenzhen Research Institute, ( https://ror.org/00sz56h79) Shenzhen, China

[4 ]Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, ( https://ror.org/00rfd5b88) Shenzhen, China

[5 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Pediatrics, , The Chinese University of Hong Kong, ; Hong Kong, China

[6 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Medicine and Therapeutics, , The Chinese University of Hong Kong, ; Hong Kong, China

Author information

Yulong He http://orcid.org/0000-0002-1902-0963

Kam Tong Leung http://orcid.org/0000-0002-7695-2513

Gary M. K. Tse http://orcid.org/0000-0002-9405-9665

Jun Yu http://orcid.org/0000-0001-5008-2153

Ka Fai To http://orcid.org/0000-0003-4919-3707

Wei Kang http://orcid.org/0000-0002-4651-677X

Article

Publisher ID: 2909

DOI: 10.1038/s41388-023-02909-x

PMC ID: 10774121

PubMed ID: 38081962

SO-VID: 2da27cb4-d3a4-4cc0-819b-9d8480e49366

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 October 2023

Date revision received : 22 November 2023

Date accepted : 24 November 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82272990

Award Recipient : Wei Kang

Funded by: FundRef https://doi.org/10.13039/501100005847, Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (HMRF);

Award ID: 08190586

Award Recipient : Gary M. K. Tse

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: gastrointestinal cancer,cancer microenvironment

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: gastrointestinal cancer, cancer microenvironment

The nerve cells in gastrointestinal cancers: from molecular mechanisms to clinical intervention

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Abstract

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Karger: Oncology

Most cited references 165

Cancer statistics, 2023

The Microbiota-Gut-Brain Axis

Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

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