2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657255摘要：肝細胞癌（簡稱肝癌）是全世界常見的癌之一，自從1984 至今，肝癌就高居台灣十大癌症死因的首位，每年大約有8000 國人死於肝癌，以超音波及甲種胎兒蛋白定期追蹤檢查，可以早期篩檢出肝癌，5 年的存活率可以達到50%以上。可是對於無法手術切除或局部治療的肝癌，肝癌的治療仍不十分的理想。預後不良的原因，除了發現太晚之外，肝癌復發也是一個很重要的原因。雖然肝癌的危險因子(B 型肝炎及C 型肝炎等)已早為所知，可是對於肝癌的治癌機轉，目前所知仍然有限。有越來越多的研究顯示出腫瘤的微環境對於腫瘤的生成與腫瘤的生物學影響很大。在腫瘤微環境中，非癌細胞及基質對於原發性癌症的生長、侵襲和轉移扮演著重要的角色。將具有轉移性的黑色素細胞癌與胚胎幹細胞共同培養來改變腫瘤的微環境，可以使這個具有轉移性的黑色素細胞癌表現出成熟黑色素細胞的型態，同時減低腫瘤生成及侵襲性特徵，這更加的告訴我們腫瘤的微環境對於腫瘤的生長是非常重要。因此對於一個癌症的研究來講，我們的重點將不能只限於癌細胞本身，更要將注意力轉移到腫瘤的微環境。對於肝癌的研究，在腫瘤微環境方面的研究事實上並不多。在零星的研究報告裡面指出，肝癌細胞與基質的互相對話，與腫瘤相關的免疫細胞發炎性腫瘤的微環境，以及肝臟的星型細胞，這幾項因素都被報導和肝癌的發生及肝癌進展有相關。不過在肝癌細胞與腫瘤微環境之間的交互作用仍有很多未知，因此我們計畫進行這個兩年的研究計畫。在第一年計畫中，我們將使用四氯化碳(CCL4)來誘導小鼠的肝纖維化，來探討肝癌細胞在正常的肝及纖維化的肝，它們的生長速度有何不同。我們也將研究肝纖維化對肝癌細胞生長的影響，是屬於局部作用還是系統性作用，及此作用是只侷限於肝癌細胞還是也適用於所有的腫瘤細胞。在第二年的研究，我們將會探討，如果肝癌細胞在正常的肝臟與纖維化的肝臟生長速度有所不同的話，此生長不同的原因是否因為肝臟的星型細胞所導致。我們也將用蛋白質體學方式，嘗試找出因為腫瘤微環境的改變導致肝癌細胞有不同表現量的蛋白質。相信經由這個研究計畫我們可以更加了解肝癌細胞與肝臟腫瘤微環境之間的交互作用及影響，也期待能夠找到與這些影響有相關的蛋白質，相信在肝癌未來的治療當中，除了針對癌細胞本身之外，對於腫瘤微環境的標靶治療也將是未來的一條路。<br> Abstract: Hepatocellular carcinoma (HCC) is one the most common malignancies in the world.About 8000 people died of this cancer every year in Taiwan. The risk factors of HCCs arewell characterized; however, the exact hepatocarcinogenesis is still unknown because ofmultiple risk factors involved in its initiation, promotion, conversion, and progression.Despite the many treatment options, the prognosis of HCC remains dismal. A majority (70%to 85%) of patients present with advanced or unresectable disease. In contrast, small HCCscan be cured with an appreciable frequency. Five-year disease-free survival exceeding 50%has been reported for both resection and liver transplantation.Accumulating evidences demonstrate that the tumor microenvironment (TME) is a keyfactor in the tumorigenesis and tumor biology. The non-tumor cells and stroma in the TMEnot only influence growth of the primary cancer but also its metastasis. The importance ofTME is further strengthened by the observation that the microenvironment of humanembryonic stem cells can epigenetically reprogram multipotent metastatic melanoma cells toassume a melanocyte-like phenotype with invasive and tumorigenic ability. The stroma andnon-tumor cells in TME are not just innocent bystanders for the tumors. Therefore, it is veryimportant to investigate the role of TME in cancer researches.Limited studies have explored the influences of TME on HCC. Crosstalk between tumorand stroma via the inhibition of the production of connective tissue growth factor,tumor-associated immune cells, inflammatory tumor microenvironment, and hepatic stellatecells have been reported to be associated with HCC development and progression. However,many aspects of the interactions between HCC cells and the hepatic microenvironments arestill unknown. Thus, we initiate this 2-year project.In the first year, we will use CCL4 to induce hepatic fibrosis in the murine liver. We willinvestigate whether the growth rate of tumor cells in fibrotic liver is different from that innormal liver. We will also study that the influence of hepatic fibrosis on the growth rate ofcancer cells is local or systemic and whether the influence is tumor-specific. In the 2nd year,we will investigate whether the difference in the tumor growth is due to myofibroblasts andwe will identify the proteins with different expressions between parent HCC cell line andHCC cell line co-cultured with myofibroblasts.Through this project, we expect to understand the influence of microenvironment on thegrowth HCC cells. We expect to identify the proteins with different expression induced by themicroenvironments. If there is difference in the growth of HCC in the normal and fibroticliver, targeting fibrotic liver might be equally important as targeting cancer cells for HCCtreatment.