轉移是在癌症進程中最重要的階段，也造成癌症患者預後不良的主要原因。癌細胞貼附血管內皮細胞在癌症的滲透和外滲過程中扮演決定性的步驟，在我們過去的研究當中，發現表皮生長因子增強了頭頸癌細胞與內皮細胞的貼附，然而其中參與的機制為何還不清楚。在本篇研究中，我們發現表皮生長因子增強了頭頸癌FaDu細胞與內皮細胞的貼附，而不會與FaDu細胞本身貼附，並且在頭頸癌FaDu細胞中處理了RGD胜肽來阻斷整聯蛋白受體的訊息傳遞，發現明顯抑制表皮生長因子所誘導細胞的貼附。另一方面，我們致弱了纖連蛋白，也發現抑制了表皮生長因子所誘導細胞的貼附。除此之外，我們使用了模擬血液循環的系統來更進一步了解癌細胞與內皮細胞的貼附，依然發現在模擬血液循環的系統中表皮生長因子增強了癌細胞與內皮細胞的貼附。根據這些結果，了解了纖連蛋白-整聯蛋白的訊息傳遞在表皮生長因子所誘導的癌細胞與內皮細胞的貼附中，扮演了重要的角色。另外，我們透過生物資訊學的搜索，以表皮生長因子受體和纖連蛋白為目標，找到了血小板反應素也可能參與在表皮生長因子受體和纖連蛋白誘導的癌細胞與內皮細胞貼附當中。在癌症從原位轉移至遠端器官過程中，抗失巢凋亡是癌症必要的能力，在我們的研究中，癌細胞擁有抗失巢凋亡的能力增強了與內皮細胞的貼附，並且透過RGD胜肽抑制了細胞貼附，說明了整聯蛋白訊息傳遞的參與。未來，我們會更進一步的探討纖連蛋白-整聯蛋白的訊息傳遞和血小板反應素在表皮生長因子誘導的癌細胞與內皮細胞貼附的角色。

Metastasis is the most important stage in cancer progression and the major cause for poor outcome of cancer patients. During metastasis, the attachment of tumor cells to endothelial cells is the initial step for intravasation and extravasation. Our previous studies showed that epidermal growth factor (EGF) enhanced the interaction between head and neck squamous cell carcinomas (HNSCC) and endothelial cells. However, the mechanism involved in the regulation of tumor and endothelial cell interaction is still unclear. In this study, we found that EGF enhanced FaDu and endothelial cells but not tumor/tumor cell interaction. In addition, we pretreated FaDu cells with RGD peptide, which blocks integrin signaling also inhibited EGF-enhanced cancer cells and endothelial cells interaction. On the other hand, knockdown of fibronectin in tumor cells decreased the interaction with endothelial cells. We further study cell-cell interaction by using dynamic flow circulation which mimics blood circulatory system. We also confirmed that EGF enhanced FaDu and endothelial cells interaction in the flow circulation. These results suggest that fibronectin-integrins signaling pathway may play an important role in EGF-enhanced tumor and endothelial cell interaction. Besides that, we surveyed bioinformatics of EGFR and fibronectin from websites and found that Thrombospondin 1 (THBS1) might be a potential molecule in EGF/fibronectin-regulated tumor cells and endothelial cells interaction. In tumor metastasis, anoikis resistance is essential for cancer dissemination to distal organs. In our results, tumor cells with the ability of anoikis resistance had more ability to interact with endothelial cells that was also blocked by RGD. These results suggested the involvement of integrin signaling in anoikis-resistance tumor cells and endothelial cells interaction. In the future, we will further study the roles of fibronectin-integrins signaling pathway and THBS1 in tumor cells and endothelial cells interaction.

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