過去的研究發現分布於腫瘤微環境中的基質細胞對於腫瘤的生長和癌症的進程扮演著很重要的角色。腫瘤間的基質主要是由腫瘤相關纖維母細胞所組成。腫瘤相關纖維母細胞能幫助營造促腫瘤生長的微環境，進而幫助腫瘤細胞的血管生成、侵襲以及轉移等等。Fas ligand (FasL)屬於腫瘤壞死因子家族的一員 (tumor necrosis factor, TNF family)，表現於多種癌細胞。FasL能透過結合標的細胞膜上的Fas受體而誘發計畫性的的細胞凋亡(program cell death, apoptosis)，藉此可調節免疫系統的平衡，甚至能促進癌細胞的發展進程。過去的研究發現FasL的表現量和癌細胞之惡性程度與轉移能力有相關性。在我們實驗室過去的研究中發現抑制FasL的表現量能促使腫瘤的形成且被包覆於類似纖維母細胞之細胞。因此，我們推測腫瘤的FasL表現可能會影響腫瘤生成結構進而導致腫瘤侵襲與轉移或躲避免疫系統的攻擊。為了探討FasL與癌細胞惡性程度的相關性，我們將各種不同惡性程度的癌細胞株與人類纖維母細胞共培養，結果發現良性的腫瘤細胞能被纖維母細胞所包圍住而形成壁壘分明的腫瘤細胞區塊，然而越惡性的細胞則較不被纖維母細胞包圍住反能穿越跨過纖維母細胞。接著我們利用FasL專一的核酶抑制FasL表現的U118與B16F10細胞，我們實驗結果顯示FasL低表現會使癌細胞較易被纖維母細胞包圍，而FasL高表現則會使癌細胞較易跨越纖維母細胞。另一方面，FasL高表現之癌細胞其培養液能吸引更多的纖維母細胞，且能誘導其活化。綜合以上結果，我們認為FasL能促進癌細胞的侵襲行為進而使得腫瘤細胞不被纖維母細胞包覆住並能影響腫瘤與纖維母細胞間的相互作用。

Stromal cells in the tumor microenvironment play an important role in cancer development. Cancer associated fibroblasts make up the bulk of cancer stroma and contribute to create a tumor-promoting microenvironment for cancer initiation, angiogenesis, invasion, and metastasis. Fas ligand (FasL), the conventional ligand of Fas, is widely expressed in a variety of cancers. Fas/FasL interaction induces signal for program cell death that not only regulates the homeostasis of immune system, but also participates in the progression of cancer. It was reported FasL expression correlates with malignancy and metastasis. Our previous studies showed that tumor nodules were encapsulated by fibroblast-like cells when FasL was knocked down. We hypothesize that the level of FasL expression in tumor cells can affect tumor nodule architecture and the interaction between tumor cells and fibroblasts leading to metastasis or immune evasion. To determine the correlation of FasL and tumor encapsulation by fibroblasts, we co-cultured various tumor cell lines with human primary fibroblasts. Tumor cells with low expression level of FasL could be well-encapsulated by fibroblasts while those with high expression level of FasL could not but cross over fibroblasts. To investigate the role of FasL in tumor-fibroblasts interaction, we down-regulated the FasL of U118 and B16F10 cell by FasL-ribozyme (FasL-RZ). Down-regulation of FasL had increased the percentage of tumor cells encircled by fibroblasts. We further performed invasion assay by using µ-dish culture-insert. We observed that FasL enhanced tumor cell invasion into a culture of fibroblasts. On the other hand, conditioned medium from FasLhigh tumor cells could attract more fibroblasts and induced fibroblasts activation. Collectively, FasL can induce tumor invasion, inhibit tumor encapsulated by fibroblasts, and avtivate fibroblasts.

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