DOI QR코드

DOI QR Code

Inhibitory Effects of Blood-activating and Stasis-dispelling Herbal Medicine Extracts on Colorectal Cancer Cell Migration and Invasion through Regulation of Platelet Activation

활혈거어제의 혈소판 활성화 조절을 통한 대장암 세포 이동 및 침윤 억제

  • Jae-Hoon Jeong (Department of Pathology, College of Korean Medicine, Dong-eui University) ;
  • Hyun-Ji Park (Department of Pathology, College of Korean Medicine, Dong-eui University) ;
  • Seon-Eun Park (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) ;
  • 박현지 (동의대학교 한의과대학 병리학교실) ;
  • 박선은 (동의대학교 한의과대학 병리학교실) ;
  • 박신형 (동의대학교 한의과대학 병리학교실)
  • Received : 2025.08.28
  • Accepted : 2025.10.27
  • Published : 2025.10.25

Abstract

Platelets play a pivotal role in cancer metastasis through diverse mechanisms, including the promotion of angiogenesis, induction of epithelial-mesenchymal transition, remodeling of the extracellular matrix, and the establishment of an immunosuppressive tumor microenvironment. In this study, we investigated the effects of blood-activating and stasis-dispelling herbal medicine (BASDH) extracts, traditionally used to enhance blood circulation, on platelet activation-mediated migration and invasion of colorectal cancer (CRC) cells. Extracts from 18 BASDHs were first screened for cytotoxicity in MC38 CRC cells and for platelet toxicity, and non-toxic concentrations were used for subsequent functional assays. All extracts significantly suppressed MC38 cell-induced platelet activation, as evidenced by reduced ATP release. Furthermore, co-culture with platelets markedly enhanced the migration and invasion of MC38 cells, indicating that CRC cell-induced platelet activation augments their metastatic potential. Among the 18 BASDH extracts, 15 inhibited platelet activation-driven migration, and 12 reduced invasion. Notably, Spatholobus suberectus extract exhibited the most potent inhibitory effects on both migration and invasion. Collectively, these findings suggest that BASDH extracts effectively attenuate the metastatic ability of CRC cells by inhibiting platelet activation, supporting their potential as promising adjunctive agents for preventing CRC metastasis.

Keywords

Acknowledgement

본 연구는 보건복지부의 재원으로 한국보건산업진흥원의 보건의료기술연구개발사업 지원에 의하여 이루어진 것임(과제고유번호 RS-2025-02215233).

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024;74(3):229-63. doi:10.3322/caac.21834.
  2. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, Vignat J, Ferlay J, Murphy N, Bray F. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72(2):338-44. doi:10.1136/gutjnl-2022-327736.
  3. National Cancer Information Center. https://www.cancer.go.kr/
  4. The Lancet Gastroenterology Hepatology. The rise in early-onset colorectal cancer: now a global issue. Lancet Gastroenterol. Hepatol. 2025;10(2):95. doi:10.1016/S2468-1253(24)00441-2.
  5. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J. Clin. 2023;73(1):17-48.
  6. Fabregas JC, Ramnaraign B, George TJ. Clinical Updates for Colon Cancer Care in 2022. Clin. Colorectal Cancer. 2022;21(3):198-203. https://doi.org/10.1016/j.clcc.2022.05.006
  7. Haemmerle M, Stone RL, Menter DG, Afshar-Kharghan V, Sood AK. The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell. 2018;33(6):965-83. https://doi.org/10.1016/j.ccell.2018.03.002
  8. Braun A, Anders HJ, Gudermann T, Mammadova-Bach E. Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues. Front. Oncol. 2021;11:665534.
  9. Abdol Razak NB, Jones G, Bhandari M, Berndt MC, Metharom P. Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment. Cancers (Basel). 2018;10(10):380. doi:10.3390/cancers10100380.
  10. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576-90. https://doi.org/10.1016/j.ccr.2011.09.009
  11. Lou XL, Sun J, Gong SQ, Yu XF, Gong R, Deng H. Interaction between circulating cancer cells and platelets: clinical implication. Chin. J. Cancer Res. 2015;27(5):450-60. doi:10.3978/j.issn.1000-9604.2015.04.10.
  12. Gresele P, Falcinelli E, Momi S, Petito E, Sebastiano M. Platelets and Matrix Metalloproteinases: A Bidirectional Interaction with Multiple Pathophysiologic Implications. Hamostaseologie. 2021;41(2):136-45. doi:10.1055/a-1393-8339.
  13. Gil-Bernabé AM, Ferjancic S, Tlalka M, Zhao L, Allen PD, Im JH, Watson K, Hill SA, Amirkhosravi A, Francis JL, Pollard JW, Ruf W, Muschel RJ. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood. 2012;119(13):3164-75. https://doi.org/10.1182/blood-2011-08-376426
  14. Battinelli EM, Markens BA, Italiano JE Jr. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood. 2011;118(5):1359-69. doi:10.1182/blood-2011-02-334524.
  15. Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past? Cancer Metastasis Rev. 2017;36(2):305-29. https://doi.org/10.1007/s10555-017-9683-z
  16. Tao DL, Tassi Yunga S, Williams CD, McCarty OJT. Aspirin and antiplatelet treatments in cancer. Blood. 2021;137(23):3201-11. https://doi.org/10.1182/blood.2019003977
  17. Editorial Committee of Korean Medicine Pathology Textbook. Pathology of Korean Medicine. Seoul: Hani Munhwasa; 2019.
  18. Zhang T. The TCM constitution analysis of colorectal cancer and the distribution of cancer toxin [Master's thesis]. Nanjing University of Chinese Medicine; 2020.
  19. Zhang ZL. A study on the correlation between preoperative types of TCM syndromes and clinicopathological factors in stage I–III colorectal cancer [Master's thesis]. Nanjing University of Chinese Medicine; 2020.
  20. Fotakis G, Timbrell JA. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol. Lett. 2006;160(2):171-7. doi:10.1016/j.toxlet.2005.07.001.
  21. Kim EJ, Lim KM, Kim KY, Bae ON, Noh JY, Chung SM, Shin S, Yun YP, Chung JH. Doxorubicin-induced platelet cytotoxicity: a new contributory factor for doxorubicin-mediated thrombocytopenia. J. Thromb. Haemost. 2009;7(7):1172-83. doi:10.1111/j.1538-7836.2009.03477.x.
  22. Tan D, Fu Y, Su Q, Wang H. Prognostic role of platelet-lymphocyte ratio in colorectal cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2016;95(24):e3837. doi:10.1097/MD.0000000000003837.
  23. You J, Zhang H, Shen Y, Chen C, Liu W, Zheng M, Van Poucke S, Guo G, Huang Z. Impact of platelet to lymphocyte ratio and metabolic syndrome on the prognosis of colorectal cancer patients. Onco Targets Ther. 2017;10:2199-208. doi:10.2147/OTT.S132621.
  24. Gronostaj K, Richter P, Nowak W, Undas A. Determinants of hypofibrinolysis in patients with digestive tract cancer. Prz. Gastroenterol. 2016;11(2):104-10. doi:10.5114/pg.2016.57619.
  25. Bonfitto PHL, Rodrigues BAG, Siqueira NSN, Genaro LM, Rodrigues BL, Oliveira PSP, Martinez CAR, Ayrizono MLS, Leal RF. Involvement of platelet signaling pathways in colorectal cancer and new therapeutic targets. Am. J. Cancer Res. 2024;14(11):5133-53. doi:10.62347/PJNU8987.
  26. Mitrugno A, Tassi Yunga S, Sylman JL, Zilberman-Rudenko J, Shirai T, Hebert JF, Kayton R, Zhang Y, Nan X, Shatzel JJ, Esener S, Duvernay MT, Hamm HE, Gruber A, Williams CD, Takata Y, Armstrong R, Morgan TK, McCarty OJT. The role of coagulation and platelets in colon cancer-associated thrombosis. Am. J. Physiol. Cell Physiol. 2019;316(2):C264-C273. doi:10.1152/ajpcell.00367.2018.
  27. Zhang F, Qiao S. Research Progress on the Relationship Between Inflammation and Colorectal Cancer. Ann. Gastroenterol. Surg. 2021;6(2):204-11. doi:10.1002/ags3.12517.
  28. Catalano T, Selvaggi F, Cotellese R, Aceto GM. The Role of Reactive Oxygen Species in Colorectal Cancer Initiation and Progression: Perspectives on Theranostic Approaches. Cancers (Basel). 2025;17(5):752. doi:10.3390/cancers17050752.
  29. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, Li Y. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target Ther. 2021;6(1):263. doi:10.1038/s41392-021-00658-5.
  30. Tajima H, Ohta T, Miyashita T, Nakanuma S, Matoba M, Miyata T, Sakai S, Okamoto K, Makino I, Kinoshita J, Hayashi H, Nakamura K, Oyama K, Inokuchi M, Nakagawara H, Takamura H, Kitagawa H, Fushida S, Ikeda H. Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver. Mol. Clin. Oncol. 2015;3(3):555-8. doi:10.3892/mco.2015.512.
  31. Kumar J, Bhargava M, Aggarwal S. Bevacizumabinduced reversible thrombocytopenia in a patient with adenocarcinoma of colon: rare adverse effect of bevacizumab. Case Rep. Oncol. Med. 2012;2012:695430. doi:10.1155/2012/695430.
  32. Liu F, Xu Y, Yang G, Guo Y, Nian J. Portal vein thrombosis after cetuximab and 5-fluorouracil therapy in a patient with advanced colon cancer and decompensated cirrhosis: a case report and review of the literature. World J. Surg. Oncol. 2023;21(1):302. doi:10.1186/s12957-023-03175-7.
  33. Susan M, Macasoi I, Pinzaru I, Dehelean C, Ilia I, Susan R, Ionita I. In Vitro Assessment of the Synergistic Effect of Aspirin and 5-Fluorouracil in Colorectal Adenocarcinoma Cells. Curr. Oncol. 2023;30(7):6197-219. https://doi.org/10.3390/curroncol30070460
  34. Fu J, Xu Y, Yang Y, Liu Y, Ma L, Zhang Y. Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation. Sci. Rep. 2019;9(1):16937. https://doi.org/10.1038/s41598-019-53276-1
  35. Wu S, Sun Z, Guo Z, Li P, Mao Q, Tang Y, Chen H, Peng H, Wang S, Cao Y. The effectiveness of blood-activating and stasis-transforming traditional Chinese medicines (BAST) in lung cancer progression-a comprehensive review. J Ethnopharmacol. 2023;314:116565. https://doi.org/10.1016/j.jep.2023.116565
  36. Lu X, Li B. Exploration of the effect and mechanism of activating blood circulation and stasis-removing therapy on tumor metastasis. Chin J Integr Med. 2009;15(5):395-400. https://doi.org/10.1007/s11655-009-0395-2
  37. Wu LS, Wang XW, He W, Ma XT, Wang HY, Han M, Li BH. TRAIL inhibits platelet-induced colorectal cancer cell invasion. J. Int. Med. Res. 2019;47(2):962-72. doi:10.1177/0300060518820785.
  38. Sun L, Li Q, Guo Y, Yang Q, Yin J, Ran Q, Liu L, Zhao Z, Wang Y, Li Y, Chen Y, Weng X, Cai W, Zhu X. Extract of Caulis Spatholobi, a novel platelet inhibitor, efficiently suppresses metastasis of colorectal cancer by targeting tumor cell-induced platelet aggregation. Biomed. Pharmacother. 2020;123:109718. doi:10.1016/j.biopha.2019.109718.
  39. Chen X, Li Q, Kan XX, Wang YJ, Li YJ, Yang Q, Xiao HB, Chen Y, Weng XG, Cai WY, Zhu XX. Extract of Caulis Spatholobi, a novel blocker targeting tumor cell-induced platelet aggregation, inhibits breast cancer metastasis. Oncol. Rep. 2016;36(6):3215-24. doi:10.3892/or.2016.5184.