Serum lactate dehydrogenase levels and glycolysis significantly correlate with tumor VEGFA and VEGFR expression in metastatic CRC patients.
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.
Azuma
Mizutomo
M
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.
Shi
Michael
M
Danenberg
Kathleen D
KD
Gardner
Humphrey
H
Barrett
Carl
C
Jacques
Christian J
CJ
Sherod
Andrew
A
Iqbal
Syma
S
El-Khoueiry
Anthony
A
Yang
Dongyun
D
Zhang
Wu
W
Danenberg
Peter V
PV
Lenz
Heinz-Josef
HJ
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*
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