The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI
This study applied a dual-agent, <sup>13</sup>C-pyruvate and <sup>13</sup>C-urea, hyperpolarized <sup>13</sup>C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) <sup>1</sup>H magnetic resonance imaging (MRI) approach in the tra...
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doaj-7d3f4736cfa64d73bdb4ee3d15107dea2020-11-24T21:21:34ZengMDPI AGCancers2072-66942019-02-0111225710.3390/cancers11020257cancers11020257The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSIRobert Bok0Jessie Lee1Renuka Sriram2Kayvan Keshari3Subramaniam Sukumar4Saeed Daneshmandi5David E. Korenchan6Robert R. Flavell7Daniel B. Vigneron8John Kurhanewicz9Pankaj Seth10Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10065, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Medicine, Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Beth Israel Cancer Center, Harvard Medical School, Boston, MA 02215, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Medicine, Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Beth Israel Cancer Center, Harvard Medical School, Boston, MA 02215, USAThis study applied a dual-agent, <sup>13</sup>C-pyruvate and <sup>13</sup>C-urea, hyperpolarized <sup>13</sup>C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) <sup>1</sup>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 <i>Ldha</i> 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 <sup>13</sup>C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased <i>Hif1α</i> and then <i>Ldha</i> expression. Increased lactate induced <i>Mct4</i> 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 <i>Ldha</i> 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 <i>Ldha</i> 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 <sup>13</sup>C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response.https://www.mdpi.com/2072-6694/11/2/257hyperpolarized <sup>13</sup>Cprostate cancerlactatemagnetic resonance imaginglactate dehydrogenase |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Robert Bok Jessie Lee Renuka Sriram Kayvan Keshari Subramaniam Sukumar Saeed Daneshmandi David E. Korenchan Robert R. Flavell Daniel B. Vigneron John Kurhanewicz Pankaj Seth |
spellingShingle |
Robert Bok Jessie Lee Renuka Sriram Kayvan Keshari Subramaniam Sukumar Saeed Daneshmandi David E. Korenchan Robert R. Flavell Daniel B. Vigneron John Kurhanewicz Pankaj Seth The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI Cancers hyperpolarized <sup>13</sup>C prostate cancer lactate magnetic resonance imaging lactate dehydrogenase |
author_facet |
Robert Bok Jessie Lee Renuka Sriram Kayvan Keshari Subramaniam Sukumar Saeed Daneshmandi David E. Korenchan Robert R. Flavell Daniel B. Vigneron John Kurhanewicz Pankaj Seth |
author_sort |
Robert Bok |
title |
The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI |
title_short |
The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI |
title_full |
The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI |
title_fullStr |
The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI |
title_full_unstemmed |
The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized <sup>13</sup>C MRSI |
title_sort |
role of lactate metabolism in prostate cancer progression and metastases revealed by dual-agent hyperpolarized <sup>13</sup>c mrsi |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-02-01 |
description |
This study applied a dual-agent, <sup>13</sup>C-pyruvate and <sup>13</sup>C-urea, hyperpolarized <sup>13</sup>C magnetic resonance spectroscopic imaging (MRSI) and multi-parametric (mp) <sup>1</sup>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 <i>Ldha</i> 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 <sup>13</sup>C-urea perfusion and increased PIM staining, played a key role in increasing lactate production through increased <i>Hif1α</i> and then <i>Ldha</i> expression. Increased lactate induced <i>Mct4</i> 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 <i>Ldha</i> 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 <i>Ldha</i> 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 <sup>13</sup>C MRSI to detect aggressive disease at diagnosis and predict early therapeutic response. |
topic |
hyperpolarized <sup>13</sup>C prostate cancer lactate magnetic resonance imaging lactate dehydrogenase |
url |
https://www.mdpi.com/2072-6694/11/2/257 |
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