尿路上皮癌(UC)是指腫瘤發生在泌尿系統的癌症，在臨床上大於90%的膀胱癌是
屬於尿路上皮癌。根據2022 年的統計，UC 的發生率為男性第4 名，而死亡率為
男性第8 名。化學療法可用於治療高度分化的UC，gemcitabine 和cisplatin 為常
見用於治療UC 的化療藥物。化學治療在臨床上的前期反應良好，能有效殺死癌
細胞。可是治療後復發機率高，容易產生抗藥性。近年來，有更多研究證實腫瘤
微環境(TME)與癌症發展和抗藥性有關。當中腫瘤相關巨噬細胞(TAM)為TME 中
主要一員。TAM 可分為與促進發炎和抗腫瘤生成的M1 型巨噬細胞；以及與抗發
炎和促進腫瘤生成的M2 型巨噬細胞。在我們近期的研究發現， CDCP1 的表現
量與UC 臨床分期及gemcitabine 抗藥性有相關性。也有文獻指出癌症組織會表現
較多M2 巨噬細胞，因此我們想要進一步探討CDCP1 與TAM 的關係。利用細胞
實驗我們驗證CDCP1 在T24 細胞高度表現時會促進單核球聚集和促進巨噬細胞
的分化作用，所分化的巨噬細胞也會增加抗發炎因子IL-1Ra 與CCL17 的表現量。
相反，當CDCP1 於T24 細胞剔除後，與其條件培養後M2 巨噬細胞的分化程度下
降並會增強促發炎因子IL-6 和CCL5 的表現量。此外，我們在CDCP1 過度表現
的細胞培養基中發現有高量的PAI-1。過往有相關研究指出PAI-1 會促進肺癌中單
核球聚集及巨噬細胞的分化作用。為了探討PAI-1 與巨噬細胞間的相互作用，我
們利用knockdown 的方式在T24-CDCP1 細胞中減少PAI-1 的表現，再與巨噬細
胞共同培養，結果發現M2 巨噬細胞、抗發炎因子IL-1Ra 和CCL17 的表現量有
所下降。此外促發炎因子IL-6 和CCL5 的表現量有所上升。綜合以上結果，我們
推測CDCP1 與PAI-1 在TME 及UC 癌症進展中參與非常重要的角色。並且在未
來會以更多實驗證實CDCP1/PAI-1 分化巨噬細胞對UC 癌症進展的貢獻。希望能
夠找出於臨床上治療UC 及解決化療藥物產生抗藥性的策略。

Urothelial carcinoma (UC) has been reported as the 4th and 8th in incident and mortality rate respectively. Chemotherapy, such as cisplatin and gemcitabine treatment, was used for the UC patient with advanced stage. Although the efficiency of chemotherapy is responsive, but there is high recurrence rate in patient after therapy. Recently, tumor microenvironment (TME) has been indicated to be an important role in cancer progression and chemoresistance. Macrophage is one of the critic factor in TME and worth noting it. The M1 macrophages participate in pro-inflammatory and anti-cancer response, however, the M2 macrophages possess anti-inflammation and pro-cancer development properties. Previously, we demonstrated that CUB domain binding protein1 (CDCP1) had high correlation with clinical stage and gemcitabine-resistance of UC. Also, more evidence indicated that M2 macrophages showed a high expression in cancer tissue. Thus, we further proceeded to elucidate the relationship between CDCP1 and tumor-associated macrophages (TAMs) in TME. Our in vitro experiments suggested that CDCP1-overexpressed T24 cells promoted macrophages recruitment and differentiation to TAMs. To elucidate whether TAMs affect UC progression, higher expression of anti-inflammatory cytokines IL-1Ra and CCL17 expression were found in CDCP1-CM differentiated macrophages. Conversely, pro-inflammatory cytokines IL-6 and CCL5 expression were found in CDKO-CM differentiated macrophages. In addition, the plasminogen activator inhibitor-1 (PAI-1) was detected in CDCP-1 overexpression cell’s CM. It has been reported that PAI-1 could promote recruitment and differentiation to macrophages in lung cancer. In order to investigate the crosstalk between PAI-1 and macrophages, PAI-1-silencing cells were generated and cultured with macrophages. The result suggested that PAI-1 silencing in UC cells may down-regulated M2 macrophage differentiation and anti-inflammatory cytokines IL-1Ra and CCL17 expression. As noted above, we speculate CDCP1/PAI-1 has a critical role in TME and cancer progression of UC. In the future, more functional experiments to verify the interaction between CDCP1/PAI-1 and TAMs as well as the modulation of chemoresistant in UC will be further investigated.

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