scholarly journals Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 537 ◽  
Author(s):  
Renuka Sriram ◽  
Mark Van Criekinge ◽  
Justin DeLos Santos ◽  
Fayyaz Ahamed ◽  
Hecong Qin ◽  
...  

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR.

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 257 ◽  
Author(s):  
Robert Bok ◽  
Jessie Lee ◽  
Renuka Sriram ◽  
Kayvan Keshari ◽  
Subramaniam Sukumar ◽  
...  

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.


2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 20-20
Author(s):  
Glenn Bauman ◽  
Rohann Correa ◽  
Erfan Aref-Eshghi ◽  
Ryan Alfano ◽  
Bekim Sadikovic ◽  
...  

20 Background: Multi-focality and heterogeneity in prostate cancer can confound the selection of appropriate clinical management. Our study aimed to explore radio-genomic correlations using multiparametric magnetic resonance imaging (mpMRI) against a histopathologic reference standard. Methods: Eight men with prostate cancer who underwent mpMRI followed by prostatectomy were selected for this pilot. Whole-mount histopathology was digitized and co-registered to corresponding MRI slices using a validated high-fidelity methodology.(1) Foci, including central/transitional and peripheral zone lesions were identified by a pathologist, and contoured on digitized histopathology specimens and these digitized maps were used to guide macrodissection of the individual foci for genomic copy-number aberration (CNA) analysis. Correlation of radiomics signatures with the histologic findings and genomic analysis was performed. Results: We found a broad range of CNAs revealing inter-patient and intra-prostatic heterogeneity. Recurrently-altered loci ( e.g., 8p21) containing genes of known significance ( e.g., NKX3-1) were observed. Only radiomic features derived from apparent diffusion coefficient (ADC) independently correlated with both Gleason grade (Rho=-0.62, p=0.003) and median CNA burden (Rho=-0.68, p<0.001). While greater CNA burden expectedly correlated with higher grade, intermediate-grade (Gleason score 3+4 or 4+3) lesions appeared more like either high-grade (Gleason scores ≥4+4) or low-grade (Gleason score 3+3) disease when clustered based on CNA and ADC metrics. Conclusions: These findings suggest ADC derived radiomic metrics may be a useful imaging biomarker across both central and peripheral zone lesion and could aid in further characterization of intra-prostatic biologic heterogeneity. These proof-of-principle data reveal novel radio-genomic correlations that could supplement histologic grading and conventional imaging, thus warranting expanded study and validation. 1) Int J Rad Oncol Biol Phys. 2016; 96(1):188-96.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5028-5028
Author(s):  
David James VanderWeele ◽  
Christopher D. Brown ◽  
Robert L. Grossman ◽  
Jerome B. Taxy ◽  
Walter Michael Stadler ◽  
...  

5028 Background: Cancer management is influenced by how one views progression and how one calculates the risk of metastases and death. For prostate cancer, this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. Despite recommendations supporting active surveillance for Gleason 6 prostate cancer, the vast majority of American patients receive aggressive local therapy, in part based on a presumption that low grade cancer progresses to high grade, lethal disease. Methods: To assess the genomic relationship between low and high grade disease, laser capture microdissection was used to isolate concurrent cancer foci from prostates with multifocal disease, and somatic mutations were identified using exome sequencing. The relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects, and a lymph node metastasis was examined for two of those subjects. Results: We obtained an average of 41-fold median coverage of the exome, with an average high confidence mutation rate of 0.8/Mb. Seventy of 79 (0.886) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 15 of 80 (0.188) high confidence somatic mutations in the high grade focus were private. Seven of the 80 (0.088) were shared with low grade foci, and 65 (0.813) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations is consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.


2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 96-96
Author(s):  
Daniel Hovelson ◽  
Simpa Samuel Salami ◽  
Jeremy B Kaplan ◽  
Romain Mathieu ◽  
Aaron Udager ◽  
...  

96 Background: Tissue based biomarkers are increasingly utilized in men diagnosed with low grade prostate cancer (PCa) to guide definitive management vs. active surveillance. PCa is uniquely multifocal, suggesting ideal prognostic biomarkers should be robust to both undersampling of a high grade component of a mixed-grade tumor focus, as well as unsampled multifocal high grade tumor foci. Methods: To assess the robustness of prognostic biomarkers to multifocality, we designed a comprehensive multiplexed targeted RNA sequencing assay (mxRNAseq) capable of assessing multiple classes of transcriptional alterations and deriving available prognostic signature scores (e.g. Prolaris CCP and OncotypeDX GPS). We applied this assay to a retrospective cohort of 176 FFPE tissue samples representing the range of PCa progression. Single candidate biomarkers and derived prognostic signatures were analyzed in multifocal cases with only low-grade disease as well as those with extreme grade differences across tumor foci. Results: Our mxRNAseq assay robustly detected known coding gene/lncRNA expression, gene fusions, splice variants, and expressed somatic and germline mutations. Supervised clustering of target gene expression confirmed expected transcriptional module deregulation and derived prognostic signatures across PCa progression. Prognostic biomarkers (including derived signatures) showed no significant expression differences between low grade foci from prostates with and without high grade disease foci and were uniformly higher in high vs. low grade foci from the same case. In four cases of extreme multifocality (Gleason score 6 vs. ≥ 8 foci), prognostic signatures were significantly lower in low vs. high grade foci. In a clinical prostatectomy cohort of 1,418 men with diagnostic biopsy Gleason score 3+3 = 6 or 3+4 = 7, 21 (1.5%) had Gleason score ≥ 4+4 = 8, suggesting the initial biopsy missed or undersampled the most clinically relevant focus. Conclusions: Using a novel comprehensive mxRNAseq assay, our results challenge the robustness of prognostic biomarkers between multifocal low and high grade PCa foci, critically important in the context of un/under-sampled aggressive tumor foci.


2015 ◽  
Vol 50 (8) ◽  
pp. 490-497 ◽  
Author(s):  
Eline K. Vos ◽  
Thiele Kobus ◽  
Geert J.S. Litjens ◽  
Thomas Hambrock ◽  
Christina A. Hulsbergen-van de Kaa ◽  
...  

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