探討幹細胞分子CD44及CD133在胃腸道基質瘤之表現及意義

The expression and significance of stem cell marker CD44 and CD133 in gastrointestinal stromal tumor

李泓儒(Hung-Ru Li)

指導教授 ： 蔡志仁

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2019年)

摘要

研究背景：
胃腸道基質瘤 (GIST)是胃腸道中最常見的間葉腫瘤。多數GIST腫瘤生成原因是因為表現細胞膜上的KIT或PDFGRA受體基因突變導致酪胺酸激酶(Receptor tyrosin kinase, RTK)的過度活化。GIST的侵犯性與復發率與腫瘤大小、細胞分裂數以及生長的位置有關。臨床上GIST的治療多數先以外科手術切除為主，部分high risk的GIST或是無法以手術切除的GIST則使用標靶藥物Imatinib 治療。然而，超過九成以上的GIST在使用Imatinib 24至36個月之後會產生腫瘤的抗藥性，研究指出抗藥性的產生和GIST受體基因產生第二位置的突變有關。腫瘤幹細胞(Tumor stem cell)被認為和腫瘤的轉移性或藥物抗性有相關。然而，tumor stem cell在GIST的表現與腫瘤侵襲性、抗藥性及病人的預後相關的研究資料並不多。CD133及CD44是較常被使用來代表腫瘤幹細胞的分子標記。本研究使用CD133及CD44這兩個分子標記在GIST腫瘤的表現，探討與GIST腫瘤侵襲性與抗藥性的關聯性。

方法：
我們使用免疫染色的方式去探討CD133及CD44在125位手術切除腫瘤的病人，並與臨床因子、病理型態及預後等資料作比對分析。

結果：在胃腸道基質瘤中，CD44傾向腫瘤異質性的染色，其CD44強陽性佔腫瘤的比例的高低，和腫瘤細胞型態、NIH risk、AJCC stage group、腫瘤復發及遠端轉移有統計上的顯著意義。另外，CD133傾向是腫瘤同質性的染色，其CD133強陽性佔腫瘤的比例的高低，和NIH risk、AJCC stage group、及腫瘤復發有統計上的顯著意義。存活分析中，CD44及CD133強陽性占腫瘤的比例的高低均與較差的病人整體存活率有統計上的顯著意義。

結論：
在胃腸道基質瘤中，幹細胞分子CD44及CD133在腫瘤的表現與較高的腫瘤復發及較差的預後有關。CD44的表現亦和較高的腫瘤遠端轉移機率有關。CD44或CD133分子的表現可以做為一個好的預測因子。未來，或許能針對CD44或CD133設計單株抗體作為胃腸道基質瘤的輔助標靶藥物治療。

關鍵字

胃腸道基質瘤 ； 幹細胞分子 ； CD133 ； CD44

並列摘要

Background：
Gastrointestinal stromal tumor(GIST) is the most common mesenchymal tumor in the gastrointestinal tract. Most GISTs have KIT or PDGFRA mutation that cause overexpression of tyrosine kinase receptor. Generally, the tumor aggressiveness and tumor recurrence rate are associated with tumor size, mitotic figures and tumor location. Most GISTs can be managed by radical surgical resection. In cases whose tumor is unresectable or the resected tumor bear high risk feature, Imatinib, one of drug targeting tyrosine kinase receptor, may be served as a neoadjuvant or adjuvant therapy after surgery. However, more than 90% cases develop drug resistancy after 24-36 months of imatinib treatment. Second hit mutation theory is postulated in these imatinib-resistance GIST. The concept of tumor stem cell is thought to be related to tumor distant metastasis and the ability to get drug resistance. However, there are few data reporting the relationship of stem cell features and the tumor aggressiveness, drug resistance and overall prognosis in GIST. CD133 and CD44 are commonly used to be served as stem cell features in other epithelial tumors. We study the expression of CD133 and CD44 in GIST and correlate these data with clinicopathological features and overall prognosis.

Method：
In this study, we studied the immunohistochemical expression and clinicopathological correlation of CD133 and CD44 in the specimen of 125 patients that received radical tumor resection.

Result ：
In gastrointestinal stromal tumor, the CD44 immunohistochemical stain revealed heterogenous expression in most GISTs. High percentage of strong CD44 expression (more than 50%) was significantly associated with histologic subtype(p=0.008), NIH risk (p<0.001), advanced disease stage (p<0.001), tumor recurrence (p<0.001) and distance metastasis(p=0.003). Otherwise, the CD133 immunohistochemical stain revealed more homogenous expression, and high percentage of strong CD133 expression (more than 50%) was also significantly associated with NIH risk (p<0.001), advanced disease stage(p<0.001) and tumor recurrence(p=0.003). In univariable analysis, patients with either high percentage of strong CD44 or CD133 expression was also identified with poor prognosis (p=0.035; p<0.001, separately).

Conclusions：
High percentage of strong CD44 or CD133 expression is associated with high NIH risk, advanced disease stage, tumor recurrence and poor prognosis. The CD44 expression is also associated with higher distant metastasis. Both CD44 and CD133 may serve as prognostic biomarker in therapeutic targeting in GIST in the future

並列關鍵字

Gastrointestinal stromal tumor ； stem cell marker ； CD133 ； CD44

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