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  • 學位論文

褐藻醣對於三陰性乳癌的抑癌作用與抗血管新生之機制探討

Investigation of inhibitory mechanism of Fucoidan on antitumor and anti-angiogenesis in triple-negative breast cancer

指導教授 : 林政緯

摘要


褐藻醣(Fucoidan)是一種自褐藻分離出且結構中富含岩藻糖(Fucose)的硫酸化多醣體,其因為具有多樣化的生物活性,包括許多的抗腫瘤活性而廣受關注。然而,褐藻醣對於三陰性乳癌的作用以及相關的潛在機制尚未清楚被了解,因此在本研究中,我們探討了源自昆布(Laminaria japonica)之褐藻醣的抗腫瘤能力。本論文發現透過褐藻醣的處理能夠顯著地降低三陰性乳癌細胞MDA-MB-231與HCC1806的侵犯性。於分子機轉上,本研究發現褐藻醣能夠抑制三陰性乳癌細胞中MAPK及PI3K訊息傳遞路徑的活化,進而抑制了AP-1與NF-κB的訊號通路。另外,以褐藻醣處理三陰性乳癌細胞MDA-MB-231及HCC1806會降低其促血管生成因子的表現,並且經褐藻醣處理的TNBC細胞條件培養基,可以抑制由腫瘤誘導的血管生成作用,本研究亦證實了褐藻醣能有效地阻斷腫瘤細胞向血管內皮細胞的貼附與侵犯。另一方面,本研究發現在低濃度褐藻醣的處理下,血管內皮細胞的血管生成能力即可有效地被抑制。此外,為了更進一步探討褐藻醣在活體中的作用,本論文利用斑馬魚動物模型進行驗證。我們發現褐藻醣顯著地抑制斑馬魚體內的血管生成與發育,並且也明顯地降低了TNBC腫瘤細胞的微轉移;同時,在過程中並沒有伴隨著毒性副作用。綜合上述,本篇研究證實了源自於Laminaria japonica的褐藻醣能夠透過抑制三陰性乳癌細胞的侵犯性以及降低其促血管生成能力而表現出有效的抗腫瘤作用,未來或許可成為治療三陰性乳癌策略中一項極具潛力的輔助劑。

並列摘要


Fucoidan is a fucose-rich sulfated polysaccharide isolated from brown alga that has garnered great attention for its high and strongly diversified biological activities, including various antitumor properties. However, the effects and underlying mechanism of fucoidan on triple-negative breast cancer (TNBC) are still unknown. In the present study, we investigated the anticancer potential of fucoidan from Laminaria japonica. The experiment results showed that treatments with fucoidan exhibited effective antiproliferative activity against TNBC MDA-MB-231 and HCC1806 cells by significantly reducing their migratory and invasive capacities. Mechanistically, fucoidan was found to suppress activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathway followed by inhibition of activator protein (AP)-1 and nuclear factor (NF)-κB signaling in TNBC. Furthermore, treatments with fucoidan downregulated expressions of proangiogenic factors in TNBC cells, and conditioned medium from fucoidan-treated TNBC substantially inhibited tumor-elicited tube formation of vascular endothelial cells. Fucoidan was found to effectively block tumor cells adhesion and invasion towards vascular endothelial cells. Additionally, fucoidan robustly suppressed tube formation of vascular endothelial cells at low concentrations. Moreover, to further examine in vivo effects of fucoidan, we conducted in vivo experiments in a zebrafish model. The experiment results showed that fucoidan significantly inhibited in vivo angiogenesis and micrometastasis without toxic side-effects in a zebrafish model. Taken together, fucoidan from Laminaria japonica exhibits potent antitumor effects by its attenuation of invasiveness and proangiogenesis in TNBC, and therefore, fucoidan from Laminaria japonica may be a potentially effective adjuvant for treatments on TNBC in the future.

參考文獻


[1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019, CA: A Cancer Journal for Clinicians, 69 (2019) 7-34.
[2] K. Polyak, Heterogeneity in breast cancer, Journal of Clinical Investigation, 121 (2011) 3786-3788.
[3] Y.-Z. Jiang, D. Ma, C. Suo, J. Shi, M. Xue, X. Hu, Y. Xiao, K.-D. Yu, Y.-R. Liu, Y. Yu, Y. Zheng, X. Li, C. Zhang, P. Hu, J. Zhang, Q. Hua, J. Zhang, W. Hou, L. Ren, D. Bao, B. Li, J. Yang, L. Yao, W.-J. Zuo, S. Zhao, Y. Gong, Y.-X. Ren, Y.-X. Zhao, Y.-S. Yang, Z. Niu, Z.-G. Cao, D.G. Stover, C. Verschraegen, V. Kaklamani, A. Daemen, J.R. Benson, K. Takabe, F. Bai, D.-Q. Li, P. Wang, L. Shi, W. Huang, Z.-M. Shao, Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies, Cancer Cell, 35 (2019) 428-440.
[4] R. Rouzier, C.M. Perou, W.F. Symmans, N. Ibrahim, M. Cristofanilli, K. Anderson, K.R. Hess, J. Stec, M. Ayers, P. Wagner, P. Morandi, C. Fan, I. Rabiul, J.S. Ross, G.N. Hortobagyi, L. Pusztai, Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy, Clinical Cancer Research, 11 (2005) 5678-5685.
[5] D. Zardavas, A. Irrthum, C. Swanton, M. Piccart, Clinical management of breast cancer heterogeneity, Nature Reviews Clinical Oncology, 12 (2015) 381-394.

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