Differential Expression of Metabolic Genes in Tumor and Stromal Components of Primary and Metastatic Loci in Pancreatic Adenocarcinoma

BackgroundPancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a five-year survival rate of 6%. It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions. However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and, hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma. Methods and FindingsWe analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism) expression profiles of primary and metastatic lesions from pancreatic cancer patients by gene expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC) analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites. ConclusionsHere, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer.

背景
胰腺癌是美国第四大癌症相关死亡病因，五年生存率仅为6%。该疾病以极具侵袭性的肿瘤生长速率与极高的转移发生率为典型特征。动物与人类癌细胞最常见且显著的生化表型之一，是即便在有氧条件下也能以高速率代谢葡萄糖。然而，肿瘤细胞与周围微环境细胞间的代谢互作对癌症进展的贡献尚未得到充分阐明。我们针对胰腺腺癌患者的原发肿瘤与转移灶，评估了代谢基因的差异表达情况，并进一步分析了相关代谢通路的差异。
方法与结果
我们通过基因表达芯片（gene expression arrays），分析了胰腺癌患者原发与转移病灶的代谢基因（参与糖酵解（glycolysis）、三羧酸循环（tri-carboxylic acid pathway）、磷酸戊糖途径（pentose-phosphate pathway）及脂肪酸代谢的基因）表达谱。本研究得到两项核心结果：一是在原发灶及多数转移灶中均上调的基因；二是仅以位点特异性方式在特定转移灶中上调的基因。对多种代谢基因产物的免疫组织化学（Immunohistochemical, IHC）分析在蛋白水平验证了基因表达模式；该分析还揭示了代谢酶在肿瘤与间质中的差异表达模式，且该模式与转移位点存在相关性。
结论
本研究为首项全面分析，明确了胰腺腺癌中肿瘤与间质组分的代谢状态差异，以及有氧糖酵解（aerobic glycolysis）相关基因的表达上调现象。