title: Serum lactate dehydrogenase levels and glycolysis significantly correlate with tumor VEGFA and VEGFR expression in metastatic CRC patients.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Mizutomo
authors: M
authors: Azuma
authors: Michael
authors: M
authors: Shi
authors: Kathleen D
authors: KD
authors: Danenberg
authors: Humphrey
authors: H
authors: Gardner
authors: Carl
authors: C
authors: Barrett
authors: Christian J
authors: CJ
authors: Jacques
authors: Andrew
authors: A
authors: Sherod
authors: Syma
authors: S
authors: Iqbal
authors: Anthony
authors: A
authors: El-Khoueiry
authors: Dongyun
authors: D
authors: Yang
authors: Wu
authors: W
authors: Zhang
authors: Peter V
authors: PV
authors: Danenberg
authors: Heinz-Josef
authors: HJ
authors: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D007770:L-Lactate Dehydrogenase; D040262:Receptors, Vascular Endothelial Growth Factor