The role of lactate metabolism in prostate cancer progression and metastases revealed by dual-agent hyperpolarized (13)C MRSI Journal Article


Authors: Bok, R.; Lee, J.; Sriram, R.; Keshari, K.; Sukumar, S.; Daneshmandi, S.; Korenchan, D. E.; Flavell, R. R.; Vigneron, D. B.; Kurhanewicz, J.; Seth, P.
Article Title: The role of lactate metabolism in prostate cancer progression and metastases revealed by dual-agent hyperpolarized (13)C MRSI
Abstract: This study applied a dual-agent, 13 C-pyruvate and 13 C-urea, hyperpolarized 13 C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) 1 H magnetic resonance imaging (MRI) approach in the transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate changes in tumor perfusion and lactate metabolism during prostate cancer development, progression and metastases, and after lactate dehydrogenase-A (LDHA) knock-out. An increased Warburg effect, as measured by an elevated hyperpolarized (HP) Lactate/Pyruvate (Lac/Pyr) ratio, and associated Ldha expression and LDH activity were significantly higher in high-versus low-grade TRAMP tumors and normal prostates. The hypoxic tumor microenvironment in high-grade tumors, as measured by significantly decreased HP 13 C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased Hif1α and then Ldha expression. Increased lactate induced Mct4 expression and an acidic tumor microenvironment that provided a potential mechanism for the observed high rate of lymph node (86%) and liver (33%) metastases. The Ldha knockdown in the triple-transgenic mouse model of prostate cancer resulted in a significant reduction in HP Lac/Pyr, which preceded a reduction in tumor volume or apparent water diffusion coefficient (ADC). The Ldha gene knockdown significantly reduced primary tumor growth and reduced lymph node and visceral metastases. These data suggested a metabolic transformation from low-to high-grade prostate cancer including an increased Warburg effect, decreased perfusion, and increased metastatic potential. Moreover, these data suggested that LDH activity and lactate are required for tumor progression. The lactate metabolism changes during prostate cancer provided the motivation for applying hyperpolarized 13 C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords: controlled study; protein expression; treatment response; unclassified drug; cancer growth; nonhuman; magnetic resonance imaging; lymph node metastasis; mouse; metabolism; animal tissue; gene expression; tumor volume; animal experiment; animal model; enzyme activity; carcinogenesis; prostate cancer; cancer inhibition; liver metastasis; diagnostic agent; visceral metastasis; lactate dehydrogenase; prostate adenocarcinoma; metastasis potential; malignant transformation; hypoxia inducible factor 1alpha; proton nuclear magnetic resonance; carbon nuclear magnetic resonance; lactic acid; tumor microenvironment; pyruvic acid; metastasis inhibition; apparent diffusion coefficient; lactate; pyruvic acid c 13; hyperpolarization; multiparametric magnetic resonance imaging; male; article; monocarboxylate transporter 4; gene knockout; hyperpolarized 13 c; urea c 13; ldha gene
Journal Title: Cancers
Volume: 11
Issue: 2
ISSN: 2072-6694
Publisher: MDPI  
Date Published: 2019-02-01
Start Page: 257
Language: English
DOI: 10.3390/cancers11020257
PROVIDER: scopus
PMCID: PMC6406929
PUBMED: 30813322
DOI/URL:
Notes: Article -- Export Date: 1 May 2019 -- Source: Scopus
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