Azuma Mizutomo, Shi Michael, Danenberg Kathleen D, Gardner Humphrey, Barrett Carl, Jacques Christian J, Sherod Andrew, Iqbal Syma, El-Khoueiry Anthony, Yang Dongyun, Zhang Wu, Danenberg Peter V, Lenz Heinz-Josef
University of Southern California/Norris Comprehensive Cancer Center, Division of Medical Oncology, The Sharon Carpenter Laboratory, Keck School of Medicine, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA 90033, USA.
Pharmacogenomics. 2007 Dec;8(12):1705-13. doi: 10.2217/14622416.8.12.1705.
In an attempt to elucidate the relationship between biomarkers of tumor hypoxia, glycolysis and angiogenesis, we tested the hypothesis that intratumoral gene expression of the hypoxia response (hypoxia inducible factor [HIF1 alpha and 2 alpha]), glycolysis (lactate dehydrogenase A [LDHA]), glucose metabolism (glucose transporter-1 [Glut-1]) and genes involved in angiogenesis (i.e., VEGFA, VEGFR1-3, and neuropilin [NRP]1) are upregulated in metastatic colorectal cancer (mCRC) patients with high serum lactate dehydrogenase (LDH).
78 formalin-fixed, paraffin-embedded (FFPE) tumor samples were collected from 36 patients with mCRC. Tumor gene expression was correlated with serum LDH levels from the same group of patients. FFPE tissues were dissected using laser-captured microdissection and analyzed for gene expression using a quantitative real-time RT-PCR method.
Intratumoral gene expression of VEGFA and VEGFR1 showed a statistically significant correlation with serum LDH levels (p = 0.006, r = 0.45 and p = 0.004, r = 0.50, respectively). Intratumoral expression of LDHA gene showed a significant correlation with Glut-1, VEGF, HIF1 alpha, HIF2 alpha and VEGFR1 (p = 0.007, r = 0.44; p < 0.001, r = 0.57; p = 0.013, r = 0.41; p = 0.044, r = 0.34; p = 0.026, r = 0.40). Serum LDH levels also correlated with microvessel density analyzed by immunohistochemical analysis.
The results demonstrated a significant correlation between the intratumoral gene expression of LDHA, HIF1 alpha, HIF2 alpha, Glut-1, NRP1, VEGFA and VEGFR1. Patients with high serum LDH have increased intratumoral gene expression of VEGFA and VEGFR1. The results also support the hypothesis that serum LDH levels may serve as a surrogate marker for activation of the HIF-related genes in the tumor.
为了阐明肿瘤缺氧、糖酵解和血管生成的生物标志物之间的关系，我们检验了以下假设：在血清乳酸脱氢酶（LDH）水平较高的转移性结直肠癌（mCRC）患者中，肿瘤内缺氧反应（缺氧诱导因子 [HIF1α 和 2α]）、糖酵解（乳酸脱氢酶 A [LDHA]）、葡萄糖代谢（葡萄糖转运蛋白 -1 [Glut-1]）以及参与血管生成的基因（即血管内皮生长因子 A [VEGFA]、血管内皮生长因子受体 1 - 3 [VEGFR1 - 3] 和神经纤毛蛋白 [NRP]1）的基因表达上调。
从 36 例 mCRC 患者中收集了 78 份福尔马林固定、石蜡包埋（FFPE）的肿瘤样本。将肿瘤基因表达与同一组患者的血清 LDH 水平进行关联分析。使用激光捕获显微切割技术解剖 FFPE 组织，并采用定量实时 RT-PCR 方法分析基因表达。
VEGFA 和 VEGFR1 的肿瘤内基因表达与血清 LDH 水平呈统计学显著相关性（分别为 p = 0.006，r = 0.45 和 p = 0.004，r = 0.50）。LDHA 基因的肿瘤内表达与 Glut-1、VEGF、HIF1α、HIF2α 和 VEGFR1 呈显著相关性（p = 0.007，r = 0.44；p < 0.001，r = 0.57；p = 0.013，r = 0.41；p = 0.044，r = 0.34；p = 0.026，r = 0.40）。血清 LDH 水平也与通过免疫组织化学分析的微血管密度相关。
结果表明 LDHA、HIF1α、HIF2α、Glut-1、NRP1、VEGFA 和 VEGFR1 的肿瘤内基因表达之间存在显著相关性。血清 LDH 水平较高的患者，其肿瘤内 VEGFA 和 VEGFR1 的基因表达增加。结果还支持血清 LDH 水平可能作为肿瘤中 HIF 相关基因激活的替代标志物这一假设。
