Abstract
This study applied a dual-agent, 13C-pyruvate and 13C-urea, hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) 1H 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 13C-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 13C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.
Highlights
A majority of newly diagnosed prostate cancer patients (164,690 men) will have indolent, non-life threatening disease, an estimated 29,430 men died of metastatic prostate cancer in the UnitedStates alone in 2018 [1]
This finding is consistent with prior publications suggesting that the Warburg effect does not become important in prostate cancer until late-stage/high-grade disease [33,34,35,36]. These publications argue that early-stage/low-grade prostate cancers rely on lipids and other biologic fuels for energy production [33,34,35,36], and that the glycolytic phenotype is only associated with the evolution of aggressive disease [37,38]. Another important finding of this study was the importance of the hypoxic tumor microenvironment in driving the elevated Warburg effect in high-grade prostate cancer
The fact that the incidence of metastases is not eliminated entirely in this study suggests either that knockdown of Ldha/lactate dehydrogenase (LDH)-5 activity was initiated in most animals after tumors had advanced to the state where cancer cell dissemination was occurring, or that certain tumors/tumor cells compensate for the loss of Ldha and, after a lag period, are capable of undertaking invasion and metastasis
Summary
A majority of newly diagnosed prostate cancer patients (164,690 men) will have indolent, non-life threatening disease, an estimated 29,430 men died of metastatic prostate cancer in the United. States alone in 2018 [1] While those with indolent tumors can be managed with active surveillance, approximately 30% of these patients will be reclassified as higher risk for disease progression, requiring definitive therapy [2,3]. There is an unmet clinical need for an accurate, non-invasive imaging method to detect aggressive, clinically significant cancer early in these patients so timely treatment of this potentially deadly disease can be initiated. It has been hypothesized that the Warburg effect, an up-regulation of aerobic glycolysis and production of lactate, the result of the lactate dehydrogenase (LDH) reaction, is an adaptation of cancer cells that aids in survival, growth, and metastasis [4]. Lactate dehydrogenase-A (LDHA), a protein subunit of the highly lactate-favoring LDH isoform muscle-type 5
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