Journal of Physiology & Pathology in Korean Medicine (동의생리병리학회지)

The Physiological Society of Korean Medicine and The Society of Pathology in Korean Medicine (대한동의생리학회·한의병리학회)
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Anti-migration Effects of the Daesiho-tang (Da Chai Hu-Tang) Water Extract in Cancer Cells by Regulating Macrophage Polarization

대식세포 분화 조절을 통한 대시호탕의 암세포 전이 억제 효과

  • Jae-Hoon Jeong (Department of Pathology, College of Korean Medicine, Dong-eui University) ;
  • Shin-Hyung Park (Department of Pathology, College of Korean Medicine, Dong-eui University)
  • 정재훈 (동의대학교 한의과대학 병리학교실) ;
  • 박신형 (동의대학교 한의과대학 병리학교실)
  • Received : 2023.12.18
  • Accepted : 2024.02.13
  • Published : 2024.02.25
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Abstract

The aim of this study was to investigate the role of Daesiho-tang (Da Chai Hu-Tang) water extract (DSTE) in regulating chronic stress-induced cancer progression, focusing on its activity in modulating tumor-associated macrophages (TAMs). Different stimuli can polarize TAMs into immune-stimulating M1 macrophages or immunosuppressive M2 macrophages. During cancer progression, M2 phenotype increases and supports tumor growth, angiogenesis and metastasis. Notably, chronic stress-induced catecholamines promote M2 macrophage polarization. In this study, we investigated whether DSTE regulates norepinephrine (NE)-induced M2 macrophage polarization in RAW 264.7 mouse macrophage cells. Even though NE itself did not increase the expression of M2 markers, the conditioned media of NE-treated 4T1 mouse breast cancer cells (NE CM) significantly up-regulated M2 markers in RAW 264.7 cells, suggesting that NE-regulated cancer cell secretome stimulated M2 polarization. However, such increase was abrogated by DSTE. NE CM also induced phosphorylation of signal transducer and activator of transcription 6 (STAT6) in RAW 264.7 cells, which was clearly reversed by pretreatment with DSTE, demonstrating that DSTE inhibited M2 polarization by inactivating STAT6. Finally, M2-polarized RAW264.7 cells by NE CM markedly increased the migration of 4T1 cells. However, such increase was completely reversed by co-treating RAW264.7 cells with NE CM and DSTE, indicating that DSTE attenuated cancer cell migration by blocking M2 polarization. Taken together, our results suggest a probable use of DSTE for cancer patients under chronic stress by regulating M2 macrophage polarization.

Keywords

Acknowledgement

본 연구는 한국연구재단의 우수신진연구의 사업비로 수행되었음(No. NRF-2021R1C1C100506211).

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74.  https://doi.org/10.1016/j.cell.2011.02.013
  2. Wang J, Li D, Cang H, Guo B. Crosstalk between cancer and immune cells: Role of tumor-associated macrophages in the tumor microenvironment. Cancer Med. 2019; 8:4709-1. 
  3. Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front. Immunol. 2020;11:583084. 
  4. Ovais M, Guo MY, Chen CY. Tailoring Nanomaterials for Targeting Tumor-Associated Macrophages. Adv Mater. 2019;31(19):e1808303. 
  5. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 2012;122:787-95.  https://doi.org/10.1172/JCI59643
  6. Batty GD, Russ TC, Stamatakis E, Kivimaki M. Psychological distress in relation to site specific cancer mortality: Pooling of unpublished data from 16 prospective cohort studies. BMJ 2017;356:j108. 
  7. Cui B, Peng F, Lu J, He B, Su Q, Luo H, et al. Cancer and stress: NextGen strategies. Brain Behav. Immun. 2021;93:368-83.  https://doi.org/10.1016/j.bbi.2020.11.005
  8. Cole SW, Sood AK. Molecular pathways: Beta-adrenergic signaling in cancer. Clin. Cancer Res. 2012;18:1201-6.  https://doi.org/10.1158/1078-0432.CCR-11-0641
  9. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F. et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 2011;29:2645-52.  https://doi.org/10.1200/JCO.2010.33.4441
  10. Parada-Huerta E, Alvarez-Dominguez T, Uribe-Escamilla R, Rodriguez-Joya J, Ponce-Medrano JD, Padron-Lucio S, et al. Metastasis Risk Reduction Related with Beta-Blocker Treatment in MexicanWomen with Breast Cancer. Asian Pac. J. Cancer Prev. 2016;17:2953-7. 
  11. Udumyan R, Montgomery S, Fang F, Almroth H, Valdimarsdottir U, Ekbom A, et al. Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma. Cancer Res. 2017;77:3700-7. 
  12. Freire BM, de Melo FM, Basso AS. Adrenergic signaling regulation of macrophage function: do we understand it yet? Immunother. Adv. 2022;2(1):ltac010. 
  13. Grailer JJ, Haggadone MD, Sarma JV, Zetoune FS, Ward PA. Induction of M2 regulatory macrophages through the β2-adrenergic receptor with protection during endotoxemia and acute lung injury. J. Innate. Immun. 2014;6(5):607-18. 
  14. Qin JF, Jin FJ, Li N, Guan HT, Lan L, Ni H, et al. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep. 2015;48(5):295-300.  https://doi.org/10.5483/BMBRep.2015.48.5.008
  15. Kim SC, Kim SH, Noh SH, Park SD, Kim SK, Seo BI, et al. Formulas of Oriental Medicine. Seoul: Younglim press; 2003. 
  16. Kim HH, Yeo WH, Cho HJ. Effects of DaeSiHo-Tang extract on Hypertension and Arterial Contraction. Korean J. Ori. Med. Physiol. Pathol. 2005;19(6):1573-9. 
  17. Park SD, Yoon BK. Effects of Daesihotang and its component groups on diabetes, free radical and antioxidative defense system in alloxan induced diabetic rats. Korean J. Orient. Med. Prescription 2001;9(1):289-317. 
  18. Kim CH, Kweon YM, Lee YT, Park SD. The preventive effect of Daeshiho-tang on liver damage induced by acetaminophen in the rats. Korean J. Orient. Med. Prescription 2004;12(2):139-54. 
  19. Song MY, Kim EK, Kong JC, Lee JH, Ryu DG, Kwon KB, et al. Inhibitory Effect of Daesiho-tang(Dachaihu-tang) Extracts on High-fat Diet-induced Obesity. J. Korean Med. Rehabil. 2008;18(3):41-9. 
  20. Hussain A, Yadav MK, Bose S, Wang JH, Lim D, Song YK, et al. Daesiho-Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota. PLoS One 2016;11(11):e0165483. 
  21. Lim DW. The Effect of Daeshiho-tang(DS) on Hepatocellular Carcinogenesis Induced by Diethylnitrosamine(DENA) in Rats. Doctoral Thesis at Dongshin University. 2011. 
  22. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 2013;229:176-85.  https://doi.org/10.1002/path.4133
  23. Tugal D, Liao X, Jain MK. Transcriptional control of macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 2013;33(6):1135-44.  https://doi.org/10.1161/ATVBAHA.113.301453
  24. The Textbook Compilation Committee of Pathology of Korean Medicine. Pathology of Korean Medicine. Seoul: Hanimunhwasa; 2019. 
  25. Roszer T. Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators Inflamm. 2015;2015:816460. 
  26. Xia T, Zhang M, Lei W, Yang R, Fu S, Fan Z, et al. Advances in the role of STAT3 in macrophage polarization. Front. Immunol. 2023;14:1160719. 
  27. Duan LF, Xu XF, Zhu LJ, Liu F, Zhang XQ, Wu N, et al. Dachaihu decoction ameliorates pancreatic fibrosis by inhibiting macrophage infiltration in chronic pancreatitis. World J. Gastroenterol. 2017;23(40):7242-52.  https://doi.org/10.3748/wjg.v23.i40.7242
  28. Xu X, Cui L, Zhang L, Yang L, Zhuo Y, Li C. Saikosaponin d modulates the polarization of tumor-associated macrophages by deactivating the PI3K/AKT/mTOR pathway in murine models of pancreatic cancer. Int. Immunopharmacol. 2023;122:110579. 
  29. Park SH. The Tuber Extract of Pinellia ternata (Thunb.) Brei Suppresses Cancer Cell Migration by Regulating Tumor-associated Macrophages. Korean J. Ori. Med. Physiol. Pathol. 2022;36(1):1-6.