2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656700摘要：80％的胰臟癌患者診斷時已因局部侵犯或轉移而無法手術，而肝是最常見的轉移器官。實驗性研究顯示CXCL12/SDF-1 與其受器CXCR4 在胰臟癌的增生、轉移扮演重要角色。CXCR4 之表現隨胰上皮內腫瘤(PanIN)之進展增加，而腫瘤基質細胞產生之CXCL12 可增加PanIN 及胰癌細胞株增生。在老鼠，胰臟癌肝轉移隨CXCR4 表現而增加並隨抑制CXCR4 而減少，而血漿CXCL12 濃度可以預測乳癌轉移及存活。然而CXCL12/CXCR4 是否確實與胰臟癌病患腫瘤轉移及存活有關，至今並無研究。CXCL12 其801 位置有GA 單核苷酸多型性，801A 者有較高表現量及攝護腺癌與乳癌風險，且801A 之乳癌病患存活較短。我們假設:（1）801 A 及高腫瘤CXCL12/CXCR4 表現者術後肝復發風險較高、存活較短（2）血漿CXCL12 濃度與801G/A 可預測胰臟癌預後（3）801 A 者胰臟癌風險較高。初步我們發現高腫瘤CXCR4表現者術後肝復發及死亡之危險比為2.24 及2.08，符合上述假設。我們計劃進行:（1）回溯性世代研究：以石蠟包埋檢體進行腫瘤CXCL12 及CXCR4免疫組織染色，另由非腫瘤部萃取DNA 分析801 G/A，評估基因型及CXCL12/CXCR4表現量對肝復發及存活之影響;（2）前瞻性世代研究: 由血液分析CXCL12 801G/A 基因型及測定CXCL12 濃度，分析此二者是否可預測預後; (3)病歷對照研究：探討801A之胰臟癌相對危險。若能證實以上假設，將有助於胰臟癌之篩檢、預後預測及治療決策。<br> Abstract: As tumor invasion and metastasis occurs early in pancreatic cancer (PC), more than 80%of the tumors are unresectable at diagnosis because of local invasion or distant metastasis.Liver is the most common metastasis site both at diagnosis and at recurrence after resectionwith a dismal prognosis. Therefore, identification of factors related to tumorprogression/invasion and liver metastasis is important. In vitro studies suggest thatinteraction between chemokine CXCL12 (stromal cell-derived factor-1, SDF-1) and itsreceptor CXCR4 is crucial in PC progression, invasion, and metastasis. While CXCR4 is notexpressed by normal pancreatic ductal cells, it is increasingly expressed during theprogression of pancreatic intraepithelial neoplasia (PanIN), the precursor of PC. CXCL12 isproduced by stromal cells in the tumor, and CXCL12/CXCR4 signaling can increase theproliferation of PanIN cells and PC cell lines. In mouse, CXCR4 expression of PC cellsincreases liver metastasis as CXCL12 is highly expressed in liver, and inhibition of CXCR4prevents liver metastasis. In breast cancer, plasma CXCL12 level is associated withmetastasis and survival and is a prognostic predictor. In spite of these supportingexperimental evidences, whether CXCL12/CXCR4 pathway promotes tumorprogression/metastasis and affects survival in PC patients has not been studied.A single nucleotide polymorphism exists at position 801 of CXCL12 (G to A), with the Aallele up-regulating CXCL12 expression. CXCL12 801A has been associated with increasedrisk of prostate and breast cancer and with poor survival in breast cancer. We hypothesizethat (1) CXCL12 801 A and higher tumor CXCL12/CXCR4 expression are associated with ahigher risk of liver recurrence/poor survival after resection; (2) plasma CXCL12 level andCXCL12 801 G/A are associated with survival and can be used as prognostic predictors; (3)CXCL12 801 A is associated with an increased risk of PC. Consistent with these hypotheses,in a pilot study we noted that higher CXCR4 expression in the resected tumors is anindependent risk factor of liver recurrence and poor survival, with an adjusted hazard ratioof 2.24 (p = 0.037) and 2.08 (p=0.031).To further test these hypotheses, three studies will be conducted: (1) retrospective cohortstudy: tumor CXCL12 and CXCR4 expression is evaluated by immunohistochemistry, andgenomic DNA is extracted from non-tumor part of paraffin-embedded tissue. CXCL12801G/A genotype is analyzed by PCR-RFLP, and the effects of genotype andCXCL12/CXCR4 expression on liver recurrence and overall survival are evaluated; (2)prospective cohort study: genomic DNA is extracted from buffy coat and genotyped, andplasma CXCL12 level is measured by ELISA. Correlation between plasma CXCL12 leveland CXCL12 801G/A genotype or tumor CXCL12/CXCR4 expression is analyzed, and thepotential usefulness of CXCL12 plasma level and 801G/A genotype as prognostic predictorsis evaluated; (3) case control study: cases and controls are genotyped to investigate potentialassociation between CXCL12 801G/A and risk of PC with adjustment for other risk factors.If the hypotheses are confirmed, the results may have important implications in screening,prognosis prediction, and treatment planning for PC.