Satoru Mihara*

Nishinippori 2-10-12, Arakawa-ku, Tokyo, Japan

*Corresponding Author: Satoru Mihara, Nishinippori 2-10-12, Arakawa-ku, Tokyo, Japan.

Received: May 18, 2023; Published: May 31, 2023

Abstract

Transplantations of β-endorphin neurons into the hypothalamus in rats suppress the growth and progression of cancers in various tissues and prevent the metastasis of tumors via the suppression of the sympathetic nervous system and the activation of the parasympathetic nervous system. A fragrant environment containing a low concentration of α-pinene induces a significant increase in the parasympathetic nervous activity in young adult females, and long-term exposure to that suppresses melanoma growth in mice. Long-term exposure to low concentrations of a homologous series of aliphatic alcohols, phenols, ketones, and their derivatives generally enhance the hypothalamic β-endorphin levels in rats. The enriched environment induces suppression of the sympathetic nervous system and/or activation of the parasympathetic nervous system through decreased leptin expression and secretion as well as releasing β-endorphin and show a suppression of tumor growth in mice.

Moderate-intensity physical activity results in tumor suppression, at least in part through the actions of hypothalamic β-endorphin, which is responsible for a physical effect known as a runner's high.

 Keywords: Tumor; Cancer; Enriched Environment; Odor; Autonomic; β-endorphin; Physical Activity

References

1. Zahalka AH., et al. “Adrenergic nerves activate an angio-metabolic switch in prostate cancer”. Science6361 (2017): 321-326. 
2. Cui Q., et al. “The tumor-nerve circuit in breast cancer”. Cancer and Metastasis Reviews (2023).
3. Horvathova L., et al. “Sympathectomized tumor-bearing mice survive longer but develop bigger melanomas”. Endocrine Regulations4 (2016) : 207-214.
4. Silverman DA., et al. “Cancer-associated neurogenesis and nerve-cancer crosstalk”. Cancer Research6 (2021): 1431-1440.
5. Tibensky M and Mravec B. “Role of the parasympathetic nervous system in cancer initiation and progression”. Clinical and Translational Oncology23 (2021): 669-681.
6. Yin QQ., et al. “Muscarinic acetylcholine receptor M1 mediates prostate cancer cell migration and invasion through hedgehog signaling”. Asian Journal of Andrology6 (2018): 608-614.
7. Hayakawa Y., et al. “Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling”. Cancer Cell1 (2017): 21-34.
8. Zhou H., et al. “Expression and significance of autonomic nerves and alpha9 nicotinic acetylcholine receptor in colorectal cancer”. Molecular Medicine Reports6 (2018): 8423-8431.
9. Renz BW., et al. “Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness”. Cancer Discovery11 (2018): 1458-1473.
10. Sarkar DK., et al. “Cyclic adenosine monophosphate differentiated β-endorphin neurons promote immune function and prevent prostate cancer growth”. Proceedings of the National Academy of Sciences of the United States of America 26 (2008): 9105-9110.
11. Sarkar DK., et al. “Transplantation of β-endorphin neurons into the hypothalamus promotes immune function and restricts the growth and metastasis of mammary carcinoma”. Cancer Research19 (2011): 6282-6291.
12. Sarkar DK. and Zhang C. “β-endorphin neuron regulates stress response and innate immunity to prevent breast cancer growth and progression”. Vitamins and Hormones 93 (2013): 263-276.
13. Murugan S., et al. “Hypothalamic β-endorphin neurons suppress preneoplastic and neoplastic lesions development in 1,2-dimethylhydrazine induced rat colon cancer model”. Journal of Cancer16 (2017): 3105-3113.
14. Sengottuvelan M. “Protective effects of hypothalamic β-endorphin neurons against alcohol-induced liver injuries and liver cancer in rat animal models”. Alcoholism: Clinical and Experimental Research12 (2014): 2988-2997.
15. Kusuhara M., et al. “A Fragrant Environment Containing α-Pinene Suppresses Tumor Growth in Mice by Modulating the Hypothalamus/Sympathetic Nerve/Leptin Axis and Immune System”. Integrative Cancer Therapies18 (2019): 1534735419845139.
16. Ikei, et al. “Effects of olfactory stimulation by α-pinene on autonomic nervous activity”. Journal of Wood Science 62 (2016): 568-572.
17. Liu X., et al. “Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice”. Molecular Therapy7 (2014): 1275-1284.
18. Cao, et al. “Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition”. Cell. 142.1 (2010): 52-64.
19. Xiao R., et al. “Environmental and genetic activation of hypothalamic BDNF modulates T-cell immunity to exert an anticancer phenotype”. Cancer Immunology Research 6 (2016): 488-497.
20. Song Y., et al. “Enriching the housing environment for mice enhances their NK cell antitumor immunity via sympathetic nerve-dependent regulation of NKG2D and CCR5”. Cancer Research7 (2017): 1611-1622.
21. Li G., et al. “Enriched environment inhibits mouse pancreatic cancer growth and downregulates the expression of mitochondria-related genes in cancer cells”. Scientific Reports 5 (2015): 7856.
22. Garofalo S., et al. “Enriched environment reduces glioma growth through immune and nonimmune mechanisms in mice”. Nature Communications 6 (2015): 6623.
23. Bautista M and Krishnan A. “The Autonomic Regulation of Tumor Growth and the Missing Links”. Frontiers in Oncology 10 (2020): 744.
24. Godinho-Silva C., et al. “Neuro-Immune Cell Units: A New Paradigm in Physiology”. Annual Review of Immunology 37 (2019): 19-46.
25. Zhang C. and Sarkar DK. “β-endorphin neuron transplantation”. OncoImmunology4 (2012): 552-554.
26. Sarkar DK., et al. “Regulation of Cancer Progression by β-Endorphin Neuron”. Cancer Research4 (2012): 836-840.
27. Zhang C., et al. “β-endorphin cell therapy for cancer prevention”. Cancer Prevention Research1 (2015): 56-67.
28. Kusuhara M., et al. “Fragrant environment with α-pinene decreases tumor growth in mice”. Biomedical Research1 (2012): 57-61.
29. Cawley NX., et al. “Biosynthesis, Trafficking and Secretion of Pro-opiomelanocortin-derived peptides”. Journal of Molecular Endocrinology4 (2016): T77-T97.
30. Hassan QN., et al. “Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis”. Translational Cancer Research 9 (2020): 5687-5699. 
31. Pilozzi A., et al. “Roles of β-Endorphin in Stress, Behavior, Neuroinflammation, and Brain Energy Metabolism”. International Journal of Molecular Sciences1 (2020): 338.
32. Smyth DG. “60 years of pomc: Lipotropin and β-endorphin: A perspective”. Journal of Molecular Endocrinology4 (2016): T13-T25.
33. Haynes WG., et al. “Receptor-mediated regional sympathetic nerve activation by leptin”. The Journal of Clinical Investigation 2 (1997): 270-278.
34. Wada , et al. “Leptin and its receptors”. Journal of Chemical Neuroanatomy 61-62 (2014): 191-199.
35. Shi Z., et al. “Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus”. eLife 9 (2020): e55357.
36. Bouret SG., et al. “Distinct Roles for Specific Leptin Receptor Signals in the Development of Hypothalamic Feeding Circuits”. Journal of Neuroscience4 (2012): 1244-1252.
37. Liu S., et al. “NK cell-based cancer immunotherapy: from basic biology to clinical development”. Journal of Hematology and Oncology 1 (2021): 7.
38. Yoon S., et al. “Understanding of molecular mechanisms in natural killer cell therapy”. Experimental and Molecular Medicine 2 (2015): e141.
39. Ambrose AR., et al. “Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles”. Proceedings of the National Academy of Sciences of the United States of America 38 (2020): 23717-23720.
40. Wang L., et al. “Functional crosstalk and regulation of natural killer cells in tumor microenvironment: Significance and potential therapeutic strategies”. Genes and Diseases (2022).
41. Raskov H., et al. “Cytotoxic CD8⁺T cells in cancer and cancer immunotherapy”. British Journal of Cancer 124 (2021): 359-367.
42. Farhood B., et al. “CD8⁺ cytotoxic T lymphocytes in cancer immunotherapy: A review”. Journal of Cellular Physiology 6 (2019): 8509-8521.
43. Kobayakawa K. “Innate versus learned odour processing in the mouse olfactory bulb”. Nature7169 (2007): 503-508.
44. Oka Y., et al. “Odorant Receptor Map in the Mouse Olfactory Bulb: In Vivo Sensitivity and Specificity of Receptor-Defined Glomeruli”. Neuron5 (2006): 857-869.
45. de Castro F. “Wiring olfaction: the cellular and molecular mechanisms that guide the development of synaptic connections from the nose to the cortex”. Frontiers in Neuroscience 3 (2009): 52.
46. Sakano H. “Neural map formation in the mouse olfactory system”. Neuron4 (2010): 530-542.
47. Mori K and Sakano H. “How is the olfactory map formed and interpreted in the mammalian brain?” Annual Review of Neuroscience34 (2011): 467-499.
48. Takeuchi H and Sakano H. “Neural map formation in the mouse olfactory system”. Cellular and Molecular Life Sciences 71 (2014): 3049-3057.
49. Sakano H. “Developmental regulation of olfactory circuit formation in mice”. Development Growth and Differentiation 62 (2020): 199-213.
50. Imamura F., et al. “Subpopulations of Projection Neurons in the Olfactory Bulb”. Frontiers in Neural Circuits 14 (2020): 561822.
51. Mori K., et al. “Maps of Odorant Molecular Features in the Mammalian Olfactory Bulb”. Physiological Reviews2 (2006): 409-433.
52. Uchida N., et al. “Odor maps in the mammalian olfactory bulb: domain organization and odorant structural features”. Nature Neuroscience3 (2000): 1035-1043.
53. Imamura F., et al. “Timing of neurogenesis is a determinant of olfactory circuitry”. Nature Neuroscience 3 (2011): 331-337.
54. Root CM., et al. “The participation of cortical amygdala in innate, odour-driven behaviour”. Nature7526 (2014): 269-273.
55. Asano K., et al. “Influence of odor stimulation on β-endorphin levels in rat hypothalamus”. Journal of Japanese Society of Aromatherapy 1 (2009): 17-22.
56. Mihara S., et al. “Effects of olfactory stimulation with phenols on β-endorphin levels in rat hypothalamus”. The Japanese Journal of Taste and Smell research 18 (2011): 525-528.
57. Igarashi KM., et al. “Parallel mitral and tufted cell pathways route distinct odor information to different targets in the olfactory cortex”. The Journal of Neuroscience23 (2012): 7970 -7985.
58. Huilgol D and Tole S. “Cell migration in the developing rodent olfactory system”. Cellular and Molecular Life Sciences 73 (2016): 2467-2490.
59. Doty RL. “Sense of smell”. In: Ramachandran VS. (Ed). Encyclopedia of Human Behavior, 2^nd Elsevier 3 (2012): 366-372.
60. Granados-Fuentes D., et al. “A Circadian Clock in the Olfactory Bulb Controls Olfactory Responsivity”. The Journal of Neuroscience 47 (2006): 12219-12225.
61. Mori K., et al. “Olfactory consciousness and gamma oscillation couplings across the olfactory bulb, olfactory cortex, and orbitofrontal cortex”. Frontiers in Psychology 4 (2013): 743.
62. Murata K., et al. “Mapping of Learned Odor-Induced Motivated Behaviors in the Mouse Olfactory Tubercle”. Journal of Neuroscience29 (2015): 10581-10599.
63. Höferl M., et al. “Chirality influences the effects of linalool on physiological parameters of stress”. Planta Medica13 (2006): 1188-1192.
64. Fushiki T. “Interaction of flavor with taste in the palatability for dried bonito broth”. The Japanese Journal of Taste and Smell Research 2 (2009): 185-188.
65. Kawasaki H., et al. “Preference for Dried Bonito Broth in Olfactory-Blocked or Taste Nerve-Sectioned Mice in the Two-Bottle Choice Test”. Bioscience, Biotechnology, and Biochemistry 11 (2008): 2840-2846.
66. Sakakibara H., et al. “Volatile Flavor Compounds of Some Kinds of Dried and Smoked Fish”. Agricultural and Biological Chemistry1 (1990): 9-16.
67. Kjällstrand J. and Petersson G. “Phenolic antioxidants in alder smoke during industrial meat curing”. Food Chemistry1 (2001): 85-89.
68. Kawasaki H., et al. “Effect of Early Flavor Experience of a Bonito Bouillon-flavored Diet on the Flavor Preference of Adult Mice”. Journal of Cookery Science of Japan2 (2003): 116-122.
69. Tsigos C. and Chrousos GP. “Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress”. Journal of Psychosomatic Research4 (2002): 865-871.
70. Fujiwara Y and Ito M. “Synergistic Effect of Fragrant Herbs in Japanese Scent Sachets”. Planta medica3 (2015): 193-199.
71. Foglesong GD., et al. “Enriched environment inhibits breast cancer progression in obese models with intact leptin signaling”. Endocrine-Related Cancer5 (2019): 483-495.
72. Xiao R., et al. “Enhancing Effects of Environmental Enrichment on the Functions of Natural Killer Cells in Mice”. Frontiers in Immunology12 (2021): 695859.
73. Takemoto H., et al. “Effects of Sesame Oil Aroma on Mice after Exposure to Water Immersion Stress: Analysis of Behavior and Gene Expression in the Brain”. Molecules 24 (2020): 5915.
74. Lizarraga-Valderrama LR. “Effects of essential oils on central nervous system: Focus on mental health”. Phytotherapy Research2 (2020): 657-679.
75. Smith SM and Vale WW. “The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress”. Dialogues in Clinical Neuroscience4 (2006): 383-395.
76. Bergin SM., et al. “Environmental activation of a hypothalamic BDNF-adipocyte IL-15 axis regulates adipose-natural killer cells”. Brain, Behavior, and Immunity95 (2021): 477-488.
77. Gurfein BT., et al. “Enriched environment and stress exposure influence splenic B lymphocyte composition”. PLOS ONE. 12.7 (2017): e0180771.
78. García-Estevez L., et al. “The Leptin Axis and Its Association With the Adaptive Immune System in Breast Cancer”. Frontiers in Immunology12 (2021): 784823. 
79. Spiliopoulou P., et al. “Exercise-Induced Changes in Tumor Growth via Tumor Immunity”. Sports4 (2021): 46.
80. Eschke RCKR. et al. “Impact of physical exercise on growth and progression of cancer in rodents—A systematic review and meta-analysis”. Frontiers in Oncology. 9 (2019): 35.
81. Asahina S., et al. “Enhancement of β-endorphin levels in rat hypothalamus by exercise”. Japanese Journal of Physical Fitness and Sports Medicine 2 (2003): 159-166.
82. Daniela M., et al. “Effects of Exercise Training on the Autonomic Nervous System with a Focus on Anti-Inflammatory and Antioxidants Effects”. Antioxidants2 (2022): 350.
83. Zimmer P., et al. “Exercise-induced natural killer cell activation is driven by epigenetic modifications”. International Journal of Sports Medicine 6 (2015): 510-515.
84. Lin DC. “Exercise impacts the epigenome of cancer”. Prostate Cancer and Prostatic Diseases 25 (2022): 379-380.
85. Dufresne S., et al. “Exercise training as a modulator of epigenetic events in prostate tumors”. Prostate Cancer and Prostatic Diseases 1 (2022): 119-122.
86. Almeida PW., et al. “Swim training suppresses tumor growth in mice”. Journal of Applied Physiology 107 (2009): 261-265.
87. Li J., et al. “Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway”. Open Life Sciences1 (2022): 121-130.
88. Asahina S., et al. “The Influence of Exercise Intensity, Frequency and Duration on β-Endorphin Production in Rat Hypothalamus”. Journal of the Showa Medical Association 5 (2007): 414-421.
89. Schoenfeld TJ and Swanson C. “A Runner's High for New Neurons? Potential Role for Endorphins in Exercise Effects on Adult Neurogenesis”. Biomolecules8 (2021): 1077.

Citation

Citation: Satoru Mihara. “The Effects of β-Endorphin, the Autonomic Nervous System and the Environment on Suppressing the Growth and Progression of Malignant Tumors (Cancers)" Acta Scientific Cancer Biology 7.4 (2023): 25-35.

Copyright

Copyright: © 2023 Satoru Mihara. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.