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.

在鼠胰腺导管腺癌中异常表达的蛋白也在人类胰腺癌的早期表达。西雅图Fred Hutchinson癌症研究中心的高级作者Dr. Samir M. Hanash和其同事认为：“发现肿瘤血浆标记物具有十分重要的意义，它们可以早期发现肿瘤，帮助分类从而指导治疗，还能监测癌症的进展、退化以及复发。抽取由基因工程得来的早期、晚期胰腺癌模型小鼠和对照组小鼠的血浆成分，应用高级蛋白质组学技术对比其差异，他们发现胰腺癌模型血浆中有165种蛋白的表达上调。Dr. Hanash和同事挑选了一些在早期肿瘤模型中高表达的蛋白，检测他们在30位新近诊断胰腺癌患者、20个正常人和15位慢性胰腺炎患者血浆中的表达。五种在肿瘤患者中明显上调的蛋白分别是：在胰腺癌MRNA水平上调的LCN2胰岛细胞大量分泌的REG1A胰岛细胞分泌的REG3参与肿瘤进展和胞外基质降解的TIMP1和肿瘤生长有关的IGFBP4研究对象来自一个有血样库存的大型研究名册，从中挑出在胰腺癌诊断前10留取了血样的13个患者，对照组也设为13例。研究发现，此组5个蛋白在receiver operating特征曲线下的面积达到0.817 (p = 0.005). 当加入第六个蛋白 CA19.9后，AUC下面积达到0.911。据此，作者认为，组织/循环标志物在鼠和人胰腺癌中的高一致性非常明显。在这些结果之上，研究者还准备应用高通量检测手段进一步研究该组队方法在监测高危胰腺癌患者早期发病中的意义。