Metabolic Phenotypes in Pancreatic Cancer

IntroductionThe aim of present study was to profile the glucose-dependent and glutamine- dependent metabolism in pancreatic cancer.MethodsWe performed Immunohistochemical staining of GLUT1, CAIX, BNIP3, p62, LC3, GLUD1, and GOT1. Based on the expression of metabolism-related proteins, the metabolic phenotypes of tumors were classified into two categories, including glucose- and glutamine-dependent metabolism. There were Warburg type, reverse Warburg type, mixed type, and null type in glucose-dependent metabolism, and canonical type, non-canonical type, mixed type, null type in glutamine-dependent metabolism.ResultsLonger overall survival was associated with high expression of BNIP3 in tumor (p = 0.010). Shorter overall survival was associated with high expression of GLUT1 in tumor (P = 0.002) and GOT1 in tumor (p = 0.030). Warburg type of glucose-dependent metabolism had a highest percentage of tumors with nerve infiltration (P = 0.0003), UICC stage (P = 0.0004), and activated autophagic status in tumor (P = 0.0167). Mixed type of glucose-dependent metabolism comprised the highest percentage of tumors with positive marginal status (PConclusionWarburg type, non-canonical type and mixed types of glucose- and glutamine-dependent metabolism comprised of more metabolically active, biologically aggressive and poor prognostic tumors. Moreover, the increasing subtypes and categories of the metabolism in each tumor significantly associated with poor prognosis.

引言
本研究旨在解析胰腺癌中葡萄糖依赖型与谷氨酰胺依赖型代谢特征。

方法
本研究对葡萄糖转运蛋白1（GLUT1）、碳酸酐酶IX（CAIX）、Bcl-2/腺病毒E1B 19kDa相互作用蛋白3（BNIP3）、p62、微管相关蛋白1轻链3（LC3）、谷氨酸脱氢酶1（GLUD1）以及天冬氨酸转氨酶1（GOT1）进行了免疫组化染色。基于代谢相关蛋白的表达水平，将肿瘤代谢表型分为两类：葡萄糖依赖型代谢与谷氨酰胺依赖型代谢。其中葡萄糖依赖型代谢可分为瓦伯格型（Warburg type）、逆转瓦伯格型（reverse Warburg type）、混合型（mixed type）与空白型（null type）；谷氨酰胺依赖型代谢则分为经典型（canonical type）、非经典型（non-canonical type）、混合型与空白型。

结果
肿瘤中BNIP3高表达与更长的总生存期相关（p=0.010）。肿瘤中GLUT1（P=0.002）与GOT1（p=0.030）高表达则与更短的总生存期相关。葡萄糖依赖型代谢的瓦伯格型肿瘤，伴神经浸润、国际抗癌联盟（Union for International Cancer Control，UICC）分期较高以及肿瘤自噬激活状态的占比均为最高（分别对应P=0.0003、P=0.0004、P=0.0167）。葡萄糖依赖型代谢的混合型肿瘤，伴切缘阳性的占比最高（P）。

结论
葡萄糖依赖型与谷氨酰胺依赖型代谢的瓦伯格型、非经典型及混合型肿瘤，均为代谢活性更高、生物学侵袭性更强且预后较差的肿瘤。此外，单例肿瘤所包含的代谢亚型与分类越多，其预后越差，二者存在显著关联。