| 摘要: | 近年來，大量的研究顯示腫瘤的微環境與其生長及侵襲作用息息相關。這些微環境，包括免疫細胞、纖維母細胞、血管及細胞外基質，與癌細胞間形成一種合作模式，在癌症發生的每個階段給予幫助，幫助癌細胞的發展。ADAMTS1 (A disintegrin and metalloproteinase with thrombospondin type 1 motif, 1) 是一種金屬蛋白分解?，在個體生長發育、泌尿生殖器官形態改變、炎症、腫瘤生長及轉移、動脈粥樣硬化等生理和病理過程中均扮演重要的角色。先前本實驗室研究發現將乳癌細胞與纖維母細胞共同培養四代後，會使纖維母細胞表現高量的 ADAMTS1，進而促進癌細胞的侵襲能力。ADAMTS1 被研究指出會被前列腺素 (prostaglandin) 的 PGE2 和 PGF2 誘導產生，而 COX-2 可調節 prostaglandin 的合成。 因此，本研究試圖了解乳癌細胞是否透過 COX-2/prostaglandin 的機制，誘導纖維母細胞表現高量的 ADAMTS1，進而促進癌細胞的侵襲能力。結果顯示，COX-2 抑制劑可顯著地抑制共同培養之乳癌細胞誘導纖維母細胞所產生的 ADAMTS1。進一步的實驗顯示，PGE2 和 PGF2 的拮抗劑各展現 50% 的最大抑制效果，然而兩種拮抗劑聯合使用並無法提高其抑制率，顯示可能有其他 COX-2 調節的下游反應路徑亦會調控 ADAMTS1 的表現，而 PGE2 和 PGF2 間可能有互相連結的關係存在。本研究的成果顯示，抗發炎藥 ─ COX-2 抑制劑可抑制乳癌細胞誘導纖維母細胞產生 ADAMTS1。此結果有助於了解微環境促進腫瘤發展的作用機制，進而提供一個對抗癌症的新契機，將來可研究並運用於結合目前的抗癌藥物，特別是對一些有抗藥性的癌細胞，予以較有效的治療。
In recent years, a large number of studies have shown that the tumor microenvironment is closely related to its role in the growth and invasion of cancer cells. The microenvironment, which includes immune cells, fibroblasts, vasculature and extracellular matrix, appear to cooperate with malignant cells to assist in cancer development. ADAMTS1 (A disintegrin and metalloproteinase with thrombospondin type 1 motif, 1), a protease, has been reported to play a role in growth and development of the individual, urogenital morphological changes, inflammation, tumor growth and metastasis, atherosclerosis, as well as other physiological and pathological processes. We found that fibroblasts co-cultured with breast cancer cells for four generations expressed high levels of ADAMTS1, which increased the invasive ability of cancer cells. The expression of ADAMTS1 has been shown to be regulated by prostaglandin PGE2 and PGF2 respectively. COX-2 catalyzed the synthesis of prostaglandin. Based on these finding, I tested the hypothesis that COX-2/prostaglandin regulated the process that breast cancer cells induced the ADAMTS1 expression in fibroblasts by using a co-culture system. The results showed that a COX- inhibitor repressed the ADAMTS1 expression in fibroblasts induced by co-cultured breast cancer cells. A PGE2 antagonist and a PGF2 antagonist exhibited 50% of inhibitory effect on breast cancer cell-induced ADAMTS1 expression in fibroblasts respectively. However, the combination of PGE2 and PGF2 antagonists did not enhance the inhibitory efficiency. The results indicated that there are some other COX-2-regulated downstream signaling pathways participating in the induction of ADAMTS1 in fibroblasts. And, there is connection and conversion between PGE2 and PGF2. The results showed that the ADAMTS1 expression in fibroblasts induced by breast cancer cells was repressed by the inhibition of COX-2 activity. It may help to understand the mechanism of tumor microenvironment and provide a new opportunity to fight against cancer. COX-2 inhibitors or other anti-inflammatory drugs are then expected to combine anticancer drugs together in treatment of cancer, especially for some resistant cancer cells. |
