| 摘要: | 研究目的
肺癌在世界上及國內均為癌症死因領先者，往往在早期即出現轉移，如淋巴系統、肝臟、骨骼、腦部及肺部轉移，這也是大多數肺癌患者死亡的原因。癌症轉移的過程包括癌細胞增生、遷移、附著、侵犯及血管新生等步驟，這些步驟的調控與癌細胞生存發展息息相關。化學激素(chemokine)為一群小分子蛋白質，與化學激素受體(chemokine receptor)結合後，在發炎反應中主要調控白血球之移行(trafficking)。由於癌細胞轉移行為與白血球移行相似，故化學激素與其受體也被發現與癌細胞轉移有關。目前已知化學激素受體CXCR7與乳癌及大腸癌等多種癌症之細胞增生、侵犯與轉移有關，而在肺癌、乳癌及攝護腺癌之組織中亦發現化學激素受體CXCR7有過度表現之現象。然而目前少有臨床研究探討化學激素受體CXCR7與肺癌轉移之關聯，且化學激素受體CXCR7與癌症轉移形成之作用機轉與媒介尚不清楚，故本研究之目的在於探討化學激素受體CXCR7與非小細胞肺癌轉移之關聯。
研究方法
我們選擇48位在中國醫藥大學附設醫院接受手術的非小細胞肺癌病人之病理標本，以化學激素受體CXCR7之免疫組織化學染色做臨床病理分析，探討化學激素受體CXCR7的表現與肺癌病患轉移及存活之關係。另以細胞培養方式，藉由基因轉染(transfection)方式調控肺癌細胞化學激素受體CXCR7之表現，觀察肺癌細胞的轉移，包括第九基質金屬蛋白酵素(matrix metalloproteinase-9; MMP-9)的活性及表現與細胞行為，包括遷移、侵犯與增生，來探討化學激素受體CXCR7與肺癌細胞轉移之關聯。
研究結果
在病患組織之免疫組織化學染色中發現，化學激素受體CXCR7以不同程度表現於肺癌細胞上；再以化學激素受體CXCR7之表現強度分析，發現具化學激素受體CXCR7高度表現之肺癌病患，較低度表現者有較高發生轉移的情形。另在細胞實驗中發現，以基因轉染方式調控化學激素抗體CXCR7之表現，可藉由改變第九基質金屬蛋白酵素的活性與表現，進而影響肺癌細胞的遷移、侵犯與増生。
研究結論
化學激素受體CXCR7藉由第九基質金屬蛋白酵素MMP-9為媒介，可促進非小細胞肺癌之轉移，其表現程度與臨床上肺癌病患之轉移有關，而藉由抑制化學激素受體CXCR7之表現，應可作為未來肺癌治療之方向。
Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related deaths in Western and Asian populations. Local invasion and distant metastasis usually develop at initial diagnosis. Certain chemokine receptors have been identified on tumor cells in several malignancies, including breast and lung cancers, and chemokine-induced signaling increases proliferation and pro-metastatic functions of cancer cells. CXCR7 is a new chemokine receptor that involves in several biological and pathological processes, including cell proliferation and adhesion. CXCR7 promotes breast and colon cancer growth through expression in malignant cells and may regulate carcinogenesis in a variety of common malignancies. Overexpression of CXCR7 has also been observed in various tumors, including breast, lung, prostate and pancreatic cancers. However, there is little information about the role of CXCR7 expression in clinical metastasis of human lung cancer and the mediation of action is still not clear.
Purpose:
To investigate the relationship between CXCR7 expression and the presence of metastasis in non-small cell lung cancer (NSCLC) patients and to evaluate the role of CXCR7 expression on the metastatic potential of NSCLC cells.
Experimental Designs:
CXCR7 expression in surgical specimens of 48 NSCLC patients was detected by immunohistochemistry and the relationship between CXCR7, clinical metastasis and survival was analyzed. In vitro, CXCR7 expression in two human lung adenocarcinoma cell lines (CL1-5 and CL1-0) was evaluated and modulated by transfection with the plasmid DNA containing CXCR7 coding gene or CXCR7 antisense nucleotide fragment. The effects of CXCR7 modulation on migration, invasion, proliferation, MMP-9 production and activity of lung cancer cells were measured.
Results:
Expression of CXCR7 was identified in 47 tumors, which were further divided into 32 high expression and 15 low expression tumors by their staining intensities. In comparison with low CXCR7-expression tumors, high CXCR7-expression tumors (19 of 32) were significantly prone to develop clinical metastasis. In vitro, modulation of CXCR7 expression significantly altered the metastatic potential, including migration, invasion, proliferation, MMP-9 production and activity, of lung cancer cells.
Conclusions:
Chemokine receptor CXCR7 is expressed and associated with the metastatic potential of human NSCLC by the mediation of MMP-9. CXCR7 expression might be one of the prognositc factors and therapeutic targets of NSCLC patients. |
