Neuro-Tumor Relationships and Their Clinical and Physiological Significance

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

The key stages of carcinogenesis – initiation, promotion, and progression – are influenced by external and endogenous tumor growth factors. Even small tumors by 1–2 mm3 in diameter secret angiogenic factors because malignant tumor needs vascularization and trophic compounds. However, not only angiogenesis but also tumor innervation plays a role in tumor growth. The purpose of this review is to summarize the available data on neuro-tumor relationships and their physiological significance. A search was performed for sources in the databases PubMed, Web of Science, CyberLeninka, NIH and ClinicalTrials among the works from 2015 to 2025. There are many relevant studies indicating a close relationship between innervation and tumor growth. It is known that the degree of malignancy of a tumor increases with an increase in the number of nerve fibers innervating it. It can be unequivocally stated that the sympathetic innervation of the tumor enhances its growth and invasiveness. The role of parasympathetic and sensory innervation in oncogenesis is ambiguous, and various studies indicate both pro-oncogenic and anti-oncogenic effects depending on the type of tumor and other factors. Various studies have also revealed many neurogenic factors affecting neoplasms and altering their growth. The data presented in this paper highlights the mechanisms of neuro-tumor interaction and determines directions to nerve-oriented diagnostic and treatment methods.

About the authors

I. A Krupatkin

NPP “Lazma”

Email: krupatkin.sci@gmail.com
ORCID iD: 0009-0006-9256-3426
Medical Researcher Moscow, Russian Federation

V. V Sidorov

NPP “Lazma”; Priorov National Research Medical Center of Traumatology and Orthopedics of the Ministry of Health of the Russian Federation

Email: victor.v.sidorov@mail.ru
ORCID iD: 0000-0002-0594-1534
Ph.D., General Director Moscow, Russian Federation; Moscow, Russian Federation

References

  1. Онкология: Национальное руководство. Краткое издание / Под ред. Чиссова В.И., Давыдова М.И. М.: ГЭОТАР-Медиа, 2017. 576 с.
  2. Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation // Cell. 2011. V. 144. № 5. P. 646.
  3. Lempesis I.G., Georgakopoulou V.E., Papalexis P. et al. Role of stress in the pathogenesis of cancer // Int. J. Oncol. 2023. V. 63. № 5. P. 124.
  4. Глушков А.Н. Общебиологические закономерности и механизмы канцерогенеза // Медицина в Кузбассе. 2004. Т. 3. № 1. C. 3.
  5. Levine A.J. p53: 800 million years of evolution and 40 years of discovery // Nat. Rev. Cancer. 2020. V. 20. № 8. P. 471.
  6. Pan C., Winkler F. Insights and opportunities at the crossroads of cancer and neuroscience // Nat. Cell Biol. 2022. V. 24. № 10. P. 1454.
  7. Mancusi R., Monje M. The neuroscience of cancer // Nature. 2023. V. 618. № 7965. P. 467.
  8. Куликов Е.П., Судаков А.И., Каминский Ю.Д. и др. Основные прогностические факторы, влияющие на качество жизни пациентов, получавших лечение рака прямой кишки // Паллиативная медицина и реабилитация. 2020. № 3. C. 5.
  9. Zhang Z., Gang Lv Z., Lu M. et al. Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications // Biochim. Biophys. Acta Rev. Cancer. 2024. V. 1879. № 4. P. 189121.
  10. Jiang S.-H., Hu L.-P., Wang H. et al. Neurotransmitters: Emerging targets in cancer // Oncogene. 2020. V. 39. № 3. P. 503.
  11. Mravec B. Neurobiology of cancer: Definition, hysterical overview, and clinical implications // Cancer Med. 2022. V. 11. № 4. P. 903.
  12. Faulkner S., Jobling P., March B. et al. Tumor neurobiology and the war of nerves in cancer // Cancer Discov. 2019. V. 9. № 6. P. 702.
  13. Ayala G. Neuroepithelial interactions in cancer // Annu. Rev. Pathol. 2023. V. 18. P. 493.
  14. Silverman D.A., Martinez V.K., Dougherty P.M. et al. Cancer-associated neurogenesis and nerve-cancer cross-talk // Cancer Res. 2021. V. 81. № 6. P. 1431.
  15. Magnon C., Hall S.J., Lin J. et al. Autonomic nerve development contributes to prostate cancer progression // Science. 2013. V. 341. № 6142. P. 1236361.
  16. Chen H., Liu D., Guo L. et al. Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre-metastatic niche through activating beta-adrenergic signaling // J. Patol. 2018. V. 244. № 1. P. 49.
  17. Mravec B., Tibensky M. Increased cancer incidence in “cold” countries: An (un)sympathetic connection? // J. Therm. Biol. 2020. V. 89. P. 102538.
  18. Park H., Lee C.H. The contribution of the nervous system in the cancer progression // BMB Rep. 2024. V. 57. № 4. P. 167.
  19. Konishi M., Hayakawa Y., Koike K. Role of muscarinic acetylcholine signaling in gastrointestinal cancers // Biomedicines. 2019. V. 7. № 3. P. 58.
  20. Kamiya A., Hiyama T., Fujimura A., Yoshikawa S. Sympathetic and parasympathetic innervation in cancer: Therapeutic implications // Clin. Auton. Res. 2021. V. 31. № 2. P. 165.
  21. Zhao C.M., Hayakawa Y., Kodama Y. et al. Denervation suppresses gastric tumorigenesis // Sci. Transl. Med. 2014. V. 6. № 250. P. 250a115.
  22. Renz B.W., Tanaka T., Sunagawa M. et al. Cholinergic signaling via muscarinic receptors directly and indirectly suppresses pancreatic tumorigenesis and cancer stemness // Cancer Discov. 2018. V. 8. № 11. P. 1458.
  23. Zhang L., Guo L., Tao M. et al. Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma // Chin. J. Cancer Res. 2016. V. 28. № 2. P. 180.
  24. Cui Q., Jiang D., Zhang Y., Chen C. The tumor-nerve circuit in breast cancer // Cancer Metastasis Rev. 2023. V. 42. № 2. P. 543.
  25. Saloman J.L., Albers K.M., Hartman D.J. et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer // Proc. Natl. Acad. Sci. U.S.A. 2016. V. 113. № 11. P. 3078.
  26. Sinha S., Fu Y.-Y., Grimont A. et al. PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk // Cancer Res. 2017. V. 77. № 8. P. 1868.
  27. Peterson S.C., Eberl M., Vagnozzi A.N. et al. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches // Cell Stem Cell. 2015. V. 16. № 4. P. 400.
  28. Yoneda T., Hiasa M., Okui T. Crosstalk between sensory nerves and cancer in bone // Curr. Osteoporos. Rep. 2018. V. 16. № 6. P. 648.
  29. Erin N., Shurin G.V., Baraldi J.H., Shurin M.R. Regulation of carcinogenesis by sensory neurons and neuromediators // Cancers (Basel). 2022. V. 14. № 9. P. 2333.
  30. Жукова Г.В., Шихарова А.Н., Протасова Т.П. и др. Влияние хронической боли различной этиологии на опухолевой процесс в эксперименте // Современные проблемы науки и образования. 2020. № 2. С. 143.
  31. Ayala G.E., Dai H., Powell M. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer // Clin. Cancer Res. 2008. V. 14. № 23. P. 7593.
  32. Magnon C., Hondermarek H. The neural addiction of cancer // Nat. Rev. Cancer. 2023. V. 23. № 5. P. 317.
  33. Szpunar M.J., Burke K.A., Dawes R.P. et al. The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure // Cancer Prev. Res. (Phila). 2013. V. 6. № 12. P. 1262.
  34. Dlamini Z., Khanyile R., Molefi T. Genomic interplay between neoneurogenesis and neoangiogenesis in carcinogenesis: Therapeutic interventions // Cancers (Basel). 2023. V. 15. № 6. P. 1805.
  35. Zahalka A.H., Arnal-Estapé A., Maryanovich M. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer // Science. 2017. V. 358. № 6361. P. 321.
  36. Walker A.K., Martelli D., Ziegler A.I. et al. Circulating epinephrine is not required for chrono stress to enhance metastasis // Psychoneuroendocrinology. 2019. V. 99. P. 191.
  37. Vasudev N.S., Reynolds A.R. Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions // Angiogenesis. 2014. V. 17. № 3. P. 471.
  38. Bucsek M.J., Qiao G., MacDonald C.R. Beta-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy // Cancer Res. 2017. V. 77. № 20. P. 5639.
  39. Ding Y., Lee M., Gao Y. et al. Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance // Prostate. 2021. V. 81. № 1. P. 58.
  40. Munoz M., Coveñas R. Neurokinin-1 receptor: A new promising target in the treatment of cancer // Discov. Med. 2010. V. 10. № 53. P. 305.
  41. Fischer A., Rennert H.S., Rennert G. Selective serotonin reuptake inhibitors associated with increased mortality risk in breast cancer patients in northern Israel // Int. J. Epidemiol. 2022. V. 51. № 3. P. 807.
  42. Liu Q., Sun H., Liu Y. et al. HTR1A inhibits the progression of triple-negative breast cancer via TGF-β canonical and noncanonical pathways // Adv. Sci (Weinh). 2022. V. 9. № 12. P. e2105672.
  43. McCallum G.A., Shiralkar J., Suciu D. et al. Chronic neural activity recorded within breast tumors // Sci. Rep. 2020. V. 10. № 1. P. 14824.
  44. Sloan E.K., Priceman S.J., Cox B.F. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer // Cancer Res. 2010. V. 70. № 18. P. 7042.
  45. Dubeykovskaya Z., Si Y., Chen X. et al. Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer // Nat. Commun. 2016. V. 7. P. 10517.
  46. Mohammadpour H., MacDonald C.R., Qiao G. et al. β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells // J. Clin. Invest. 2019. V. 129. № 12. P. 5537.
  47. Schmid L.B., Perez-Pacheco C., De Silva N.J. Nerve density in cancer: Less is better // FACEB Bioadv. 2021. V. 3. № 10. P. 773.
  48. Kloter E., Barruejo K., Klein S.D. et al. Heart rate variability as a prognostic factor for cancer survival – a systematic review // Front. Physiol. 2018. V. 9. P. 623.
  49. Tibensky M., Mravec B. Role of parasympathetic nervous system in cancer initiation and progression // Clin. Translat. Oncol. 2021. V. 23. № 4. P. 669.
  50. Mitsou J.D., Tseveleki V., Dimitrakopoulos F.-I. et al. Radical tumor denervation activates potent local and global cancer treatment // Cancers (Basel). 2023. V. 15. № 15. P. 3758.
  51. Coarfa C., Florentin D., Putluri N. et al. Influence of the neural microenvironment on prostate cancer // Prostate. 2018. V. 78. № 2. P. 128.
  52. Xie M., Guo F., Song L. et al. Noninvasive neuromodulation protects against doxorubicin-induced cardiotoxicity and inhibits tumor growth // iScience. 2024. V. 27. № 3. P. 109163.
  53. Griffin N., Faulkner S., Jobbling P. et al. Targeting neurotrophin signaling in cancer: The renaissance // Pharmacol. Res. 2018. V. 135. P. 12.

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2025 Russian Academy of Sciences

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).