創新抑制劑：治療乳癌之新方向

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題名:	創新抑制劑：治療乳癌之新方向 Novel Inhibitors: New Directions In The Treatment Of Breast Cancer
作者:	蘇智銘 Su, Chih-Ming
貢獻者:	吳志維
關鍵詞:	乳癌;抑制劑 breast cancer;inhibitors
日期:	2015-07-03
上傳時間:	2020-08-11 15:39:14 (UTC+8)
摘要:	乳癌是女性癌症發生率第一名，每年造成很多生命的喪失。早期乳癌治癒率是很高的，但如果乳癌細胞轉移，其治癒率就差很多，因此找出乳癌細胞轉移之機制並進而抑制其轉移是一重要的課題。我們在此利用氨基酸及一種存在水果中的化合物紫檀芪（pterostilbene）來進行研究。發現他們無論在細胞株或動物實驗上可抑制癌細胞轉移能力或細胞轉型，是乳癌治療的一個新方向。我們先前發現如果啟動VEGF-C/VEGFR-3這個系統，會增加癌細胞的轉移能力，這代表抑制VEGFR-3將是治療癌症轉移一個很好的治療目標。我們篩減出了八種氨基酸，其中有兩種強烈抑制VEGFR-3的活性併減低VEGF-C所造成癌細胞侵犯的能力。我們展示出了這些以VEGFR-3為目標的氨基酸的治療潛力。百分之九十五的乳癌均源自上皮細胞，而細胞從上皮細胞轉型成間質細胞(細胞轉，EMT)已經並證實是乳癌產生轉移的初始步驟，因此抑制細胞轉型是一個發展治療癌症新藥物的最佳目標。我們利用一種存在水果中的化合物紫檀芪（pterostilbene）來進行研究，發現其會抑制乳癌細胞的細胞轉型，是一個治療乳癌，尤其是三陰性乳癌，很有潛力的新藥物。 Breast cancer is the leading cause of cancer-related deaths among females in economically developing countries. The treatment outcome was excellent for early breast cancer and was poor for advanced breast cancer. Therefore, to study the mechanism of breast cancer cell metastasis is critical for treatment od breast cancer. Here, we examine some peptides and the anti-metastatic potential of pterostilbene both in vitro and in vivo. We found that they are new directions in the treatment of breast cancer. Vascular endothelial growth factor 3 (VEGFR-3) supports tumor lymphangiogenesis. It was originally identified as a lymphagiogentic factor expressed in lymphatic endothelial cells. VEGFR-3 was detected in advanced human malignancies and correlated with poor prognosis. Our previous studies show that activation of the VEGF-C/VEGFR-3 axis promotes cancer metastasis indicating that VEGFR-3 is a potential target of cancer therapy. We developed eight peptides targeting VEGFR-3. Two peptides strongly inhibited the kinase activity of VEGFR-3 and suppressed VEGF-C-mediated invasion of cancer cells. Moreover, these peptides abolished VEGF-C-induced drug resistance and tumor initiating cell formation. We demonstrated the therapeutic potential of VEGFR-3-targeting peptides. Greater than 95% of breast malignancies are of epithelial origin; the induction of epithelial-to-mesenchymal transition (EMT) has been shown to initiate the metastatic process in breast carcinoma and remains the key target for drug development. Here, we examine the anti-metastatic potential of pterostilbene in modulating EMT process in breast cancer cells both in vitro and in vivo. The differential invasive ability among MCF7, Hs578t and MDA-MB-231 breast cancer cell lines were closely correlated with the expression of EMT markers. Pterostilbene inhibited the migratory and invasive potential of triple-negative MDA-MB-231 and Hs578t cells, accompanied by the up-regulation of E-cadherin and down-regulation of Snail, Slug, vimentin and ZEB1. Mechanistic investigations revealed a significant up-regulation of miR-205, which resulted in the reduction of Src expression in pterostilbene-treated breast cancer cells. Importantly, pterostilbene suppressed tumor growth and metastasis in MDA-MB-231-bearing NOD/SCID mice by reducing Src/Fak signaling; this observation was consistent with the negative correlations between miR-205 and Src expression in both normal and malignant breast tissues. Our findings provide supports for the usage of pterostilbene as an inhibitor of EMT process and potential candidate for adjuvant therapy.
描述:	博士指導教授:吳志雄委員:蘇振良委員:趙祖怡委員:陳建志
資料類型:	thesis
顯示於類別:	[臨床醫學研究所] 博碩士論文

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