NEW YORK (Reuters Health) Jun 18 - Proteins differentially expressed in a mouse model of pancreatic ductal adenocarcinoma are also present in early-stage disease in humans, scientists report in the June issue of PLoS Medicine.
"There is a compelling need to develop blood-based markers that allow early cancer detection, classify tumors to direct therapy, and monitor disease progression, regression, or recurrence," senior author Dr. Samir M. Hanash, at the Fred Hutchinson Cancer Research Center in Seattle, and his colleagues write.
The researchers compared plasma samples from genetically engineered mice with early-stage or advanced-stage pancreatic tumor development and from control mice. Using advanced proteomic techniques, they identified 165 proteins upregulated in cancer samples compared to controls.
Dr. Hanash and co-investigators selected a subset of proteins over-expressed in mice with early-stage tumors and tested for their presence in human sera from 30 patients newly diagnosed with pancreatic cancer, 20 matched healthy individuals and 15 patients with chronic pancreatitis.
Five proteins were significantly elevated in cancer patients compared with both control groups:
--Neutrophil gelatinase-associated lipocalin (LCN2), which is overexpressed in pancreatic cancer at the mRA level
--Lithostathine 1 (REG1A), highly secreted by pancreatic islet cells
--Regenerating islet-derived protein 3 (REG3), also secreted by pancreatic islet cells
--Tissue inhibitor of metalloproteinase 1 (TIMP1), involved in tumor progression and extracellular matrix degradation
--Insulin-like growth factor binding protein 4 (IGFBP4), associated with tumor growth.
The researchers tested this panel in a cohort of patients drawn from a large trial registry for which blood had been kept in storage. Included were 13 subjects who had been diagnosed with pancreatic cancer approximately 10 months after blood was drawn and 13 controls.
As a panel, the five proteins achieved an area under the receiver operating characteristic curve (AUC) of 0.817 (p = 0.005). When they added a sixth protein previously identified as a biomarker of pancreatic cancer, CA19.9, an AUC of 0.911 was achieved.
"The strong concordance between mouse and human pancreatic cancer in both tissue and circulating markers is striking," the authors write.
Based on these findings, the investigators now plan to develop high-throughput assays to distinguish between pancreatitis and pancreatic cancer, "and to further assess the utility of a panel approach for detecting pancreatic cancer early among individuals at increased risk of developing the disease."
PLoS Medicine 2008;5:e123.
在鼠胰腺導管腺癌中異常表達的蛋白也在人類胰腺癌的早期表達。
西雅圖Fred Hutchinson癌症研究中心的高級作者Dr. Samir M. Hanash和其同事認爲：“發現腫瘤血漿標記物具有十分重要的意義，它們可以早期發現腫瘤，幫助分類從而指導治療，還能監測癌症的進展、退化以及復發。
抽取由基因工程得來的早期、晚期胰腺癌模型小鼠和對照組小鼠的血漿成分，應用高級蛋白質組學技術對比其差異，他們發現胰腺癌模型血漿中有165種蛋白的表達上調。
Dr. Hanash和同事挑選了一些在早期腫瘤模型中高表達的蛋白，檢測他們在30位新近診斷胰腺癌患者、20個正常人和15位慢性胰腺炎患者血漿中的表達。五種在腫瘤患者中明顯上調的蛋白分別是：
在胰腺癌MRNA水平上調的LCN2
胰島細胞大量分泌的REG1A
胰島細胞分泌的REG3
參與腫瘤進展和胞外基質降解的TIMP1
和腫瘤生長有關的IGFBP4研究對象來自一個有血樣庫存的大型研究名冊，從中挑出在胰腺癌診斷前10留取了血樣的13個患者，對照組也設爲13例。
研究發現，此組5個蛋白在receiver operating特徵曲線下的面積達到0.817 (p = 0.005). 當加入第六個蛋白 CA19.9後，AUC下面積達到0.911。
據此，作者認爲，組織/循環標誌物在鼠和人胰腺癌中的高一致性非常明顯。
在這些結果之上，研究者還準備應用高通量檢測手段進一步研究該組隊方法在監測高危胰腺癌患者早期發病中的意義。