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論文名稱(外文):The Role of Stromal Cell-derived Factor 1 in Tumor Microenvironment Contributes to the Promotion of Colorectal Cancer
外文關鍵詞:Colorectal cancerTumor microenvironmentFibroblastsSDF1
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大腸直腸癌的發生率及死亡率在全球一直都排名在前,多因於手術後復發並且轉移至其他器官,導致預後往往不佳,終至病人死亡。過去對於癌症的研究不在話下,但效果始終因為癌症幹細胞的產生,造成侵襲力提升、抗藥特性等而打折扣,然而近十幾年來,大家陸陸續續把焦點拉出針對癌細胞本身,而開始著手研究腫瘤周遭的微環境(Microenvironment),發現腫瘤微環境在多種癌症中做為引導腫瘤發展或惡化轉移的調控者。大腸直腸癌微環境中,癌相關纖維母細胞(Carcinoma associated fibroblast, CAF) 為主要的組成成員,其在癌變的進展過程中扮演著重要角色,主要基於CAFs為主要分泌趨化因子的來源細胞之一。第一基質衍生因子(stromal cell-derived factor 1, SDF-1),亦稱CXCL12,是一種趨化因子(chemokine),目前已有許多研究指出在乳癌及肺癌中 SDF-1主要由纖維母細胞所分泌,並與促進癌細胞生長及血管新生有關。然而SDF-1在大腸直腸癌細胞中的角色以及其分子機制都尚未被釐清。

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The prognosis of CRC is usually poor because of its propensity for extensive invasion, local recurrence and frequent regional lymph node metastasis. Researches have shown Carcinoma-associated fibroblasts (CAFs), a major type of tumor-surrounding stromal cell, generate mediators, such as Stromal Cell-Derived factor 1 (SDF-1), through which they interact with tumors and contribute to the progression and increase of stemness of cancer. The orchestration between CAFs and CRC cells is complex. Despite recent studies demonstrating the paracrine effect of stromal cells in the tumor microenvironment on initiation and progression of colorectal cancer cells, the major mediator related to CAFs and its underlying mechanism still remain unknown.
Based on our present study, we found that the expression of SDF-1 and its receptor C-X-C chemo receptor type 4 (CXCR4) are stronger when co-cultured with CAFs than with NFs. In addition, ELISA assay also validates the presence of SDF-1 that is responsible for the crosstalk between fibroblasts and CRC cells via the paracrine effect. Furthermore, the mediator SDF-1 not only triggers epithelial-mesenchymal-transition (EMT), showing upregulation of EMT markers in RNA and proteins levels, but also improves the capabilities of migration and invasion. CRC cells treated with recombinant SDF-1, mimics the CAFs-CRC paracrine route, increased capabilities of sphere formation in ten days. To simulate SDF-1-induced autocrine signaling, we established stable clones of SDF-1-overexpressing CRC cells. Stable clone CRC cells exhibited the epithelial-mesenchymal-transition, increased mobility and upregulation of drug-resistant genes. In vivo study reconfirmed the functional role of SDF-1 in tumor initiation. Immunohistochemistry of tumor dissected from mouse confirmed that autocrined-SDF-1 enhances CSCs properties through different pathways than paracrine. Besides the paracrine signaling, we clearly verified that CAFs-induced SDF-1 reciprocally triggered cancer cells to produce SDF-1 in an autocrine manner, which resulted in the binding to CXCR4 and cancer progression. Further studies include evaluations of the mechanism of autocrine signaling. Meanwhile, validates in clinical patients.
Our results verify that CAFs promote cancer invasiveness via paracrine and autocrine effects on microenvironmental SDF-1 signaling, and suggest that SDF-1 is a potentially biomarker which contributes to the expression of CSC properties, and may provide as a therapeutic option for improving prognosis in patients with CRC.

謝誌 i
目錄 iii
圖次目錄 iv
表次目錄 v
英文縮寫 vi
中文摘要 vii
Abstract ix
壹‧序論 1
貳‧研究方向與目的 6
參‧材料與方法 8
肆‧實驗結果 24
伍‧討論 33
陸‧結論 38
柒‧參考文獻 41
捌‧附圖 45
玖‧附表 62
拾‧附錄 65

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