scholarly journals The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized 13C MRSI

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 257 ◽  
Author(s):  
Robert Bok ◽  
Jessie Lee ◽  
Renuka Sriram ◽  
Kayvan Keshari ◽  
Subramaniam Sukumar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
Magnetic Resonance ◽  
Tumor Microenvironment ◽  
Warburg Effect ◽  
Low Grade ◽  
High Grade ◽  
Lactate Metabolism ◽  
Hyperpolarized 13C ◽  
Ldh Activity

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.

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 ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Magnetic Resonance ◽  
Gleason Score ◽  
Prostate Tissue ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
High Grade ◽  
Metabolic Alterations ◽  
Ldh Activity ◽  
Benign Prostate

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.

The genomic relationship among matched prostate cancer foci.

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 ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Node ◽  
Gleason Score ◽  
Somatic Mutations ◽  
Local Therapy ◽  
Low Grade ◽  
High Grade ◽  
Genomic Relationship ◽  
High Confidence ◽  
Cancer Management

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.

Multiparametric Magnetic Resonance Imaging for Discriminating Low-Grade From High-Grade Prostate Cancer

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 ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Prostate Cancer ◽  
Magnetic Resonance ◽  
Low Grade ◽  
High Grade ◽  
Resonance Imaging ◽  
Multiparametric Magnetic Resonance Imaging

scholarly journals Clinical use of the SelectMDx urinary-biomarker test with or without mpMRI in prostate cancer diagnosis: a prospective, multicenter study in biopsy-naïve men

2021 ◽  
Author(s):  
Rianne J. Hendriks ◽  
Marloes M. G. van der Leest ◽  
Bas Israël ◽  
Gerjon Hannink ◽  
Anglita YantiSetiasti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Stratification ◽  
Specific Antigen ◽  
Low Grade ◽  
Diagnostic Study ◽  
High Grade ◽  
Net Benefit ◽  
Conditional Strategy ◽  
Detection Rates ◽  
Guided Biopsy

Abstract Background Risk stratification in men with suspicion of prostate cancer (PCa) requires reliable diagnostic tests, not only to identify high-grade PCa, also to minimize the overdetection of low-grade PCa, and reduction of “unnecessary” prostate MRIs and biopsies. This study aimed to evaluate the SelectMDx test to detect high-grade PCa in biopsy-naïve men. Subsequently, to assess combinations of SelectMDx test and multi-parametric (mp) MRI and its potential impact on patient selection for prostate biopsy. Methods This prospective multicenter diagnostic study included 599 biopsy-naïve patients with prostate-specific antigen level ≥3 ng/ml. All patients underwent a SelectMDx test and mpMRI before systematic transrectal ultrasound-guided biopsy (TRUSGB). Patients with a suspicious mpMRI also had an in-bore MR-guided biopsy (MRGB). Histopathologic outcome of TRUSGB and MRGB was used as reference standard. High-grade PCa was defined as ISUP Grade Group (GG) ≥ 2. The primary outcome was the detection rates of low- and high-grade PCa and number of biopsies avoided in four strategies, i.e., (1) SelectMDx test-only, (2) mpMRI-only, (3) SelectMDx test followed by mpMRI when SelectMDx test was positive (conditional strategy), and (4) SelectMDx test and mpMRI in all (joint strategy). A positive SelectMDx test outcome was a risk score of ≥−2.8. Decision curve analysis (DCA) was performed to assess clinical utility. Results Prevalence of high-grade PCa was 31% (183/599). Thirty-eight percent (227/599) of patients had negative SelectMDx test in whom biopsy could be avoided. Low-grade PCa was not detected in 35% (48/138) with missing 10% (18/183) high-grade PCa. Yet, mpMRI-only could avoid 49% of biopsies, not detecting 4.9% (9/183) of high-grade PCa. The conditional strategy reduces the number of mpMRIs by 38% (227/599), avoiding biopsy in 60% (357/599) and missing 13% (24/183) high-grade PCa. Low-grade PCa was not detected in 58% (80/138). DCA showed the highest net benefit for the mpMRI-only strategy, followed by the conditional strategy at-risk thresholds >10%. Conclusions SelectMDx test as a risk stratification tool for biopsy-naïve men avoids unnecessary biopsies in 38%, minimizes low-grade PCa detection, and misses only 10% high-grade PCa. Yet, using mpMRI in all patients had the highest net benefit, avoiding biopsy in 49% and missing 4.9% of high-risk PCa. However, if mpMRI availability is limited or expensive, using mpMRI-only in SelectMDx test positive patients is a good alternative strategy.

Effect of Statins on the Risk of Different Stages of Prostate Cancer: A Meta-Analysis

2021 ◽  
pp. 1-9
Author(s):  
Yun Li ◽  
Xuan Cheng ◽  
Jia-lian Zhu ◽  
Wen-wen Luo ◽  
Huai-rong Xiang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lower Risk ◽  
Advanced Prostate Cancer ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Low Grade ◽  
High Grade ◽  
The Cochrane Library ◽  
The Relationship ◽  
Comprehensive Literature Search

<b><i>Introduction:</i></b> The aim of this article was to investigate the relationship between statins and the risk of different stages or grades of prostate cancer. <b><i>Methods:</i></b> A comprehensive literature search was performed for articles published until December 18, 2020, on the PubMed, Embase, and the Cochrane Library databases. The pooled relative risk (RR) and 95% confidence interval (CI) were then analyzed using the STATA.16.0 software. <b><i>Results:</i></b> A total of 588,055 patients from 14 studies were included in the analysis. We found that the use of statins expressed a significant correlation with a lower risk of advanced prostate cancer (RR = 0.81, 95% CI: 0.73–0.91; RR = 0.86, 95% CI: 0.75–0.99, respectively). However, no evidence suggested that the use of statins was beneficial for the prevention of localized prostate cancer incidence. Similarly, the pooled results also revealed no association between the use of statins and the risk of high-grade and low-grade prostate cancer. <b><i>Conclusion:</i></b> It has been found that the use of statins is associated with a lower risk of advanced prostate cancer but was not related to the risk of localized, low-grade, or high-grade prostate cancer.

scholarly journals Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

2021 ◽  
Author(s):  
Sakthi Rajendran ◽  
Clayton Peterson ◽  
Alessandro Canella ◽  
Yang Hu ◽  
Amy Gross ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Malignant Progression ◽  
Low Grade ◽  
Cell Trafficking ◽  
High Grade ◽  
Single Cell Rna Sequencing

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

scholarly journals The expression of YAP1 is increased in high-grade prostatic adenocarcinoma but is reduced in neuroendocrine prostate cancer

2019 ◽  
Author(s):  
Siyuan Cheng ◽  
Nestor Prieto-Dominguez ◽  
Shu Yang ◽  
Zachary M. Connelly ◽  
Samantha StPierre ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Hippo Pathway ◽  
Luciferase Reporter ◽  
Low Grade ◽  
Beta Catenin ◽  
High Grade ◽  
Protein Levels ◽  
Neuroendocrine Prostate Cancer ◽  
Functional Involvement

ABSTRACTBACKGROUNDAfter long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed.METHODSImmunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling.RESULTSYAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development.CONCLUSIONSThe expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.

Role of magnetic resonance imaging in prediction of chondrosarcoma of bone grade

2021 ◽  
pp. 21-24
Author(s):  
A. V. Fedorova ◽  
N. V. Kochergina ◽  
A. B. Bludov ◽  
I. V. Boulycheva ◽  
E. A. Sushentsov ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Diagnostic Value ◽  
Low Grade ◽  
High Grade ◽  
Resonance Imaging ◽  
Accurate Definition ◽  
Definition Of ◽  
Decisive Rule

Purpose. Determining the diagnostic value of magnetic resonance imaging in the accurate definition of chondrosarcoma of bone grade at the pre-surgery examination. Material and methods. We analyzed examination data (magnetic resonance imaging with no contrast enhancement) of 70 patients with chondrosarcoma (35 patients with low-grade chondrosarcoma and 35 patients with high grade chondrosarcoma). Informative weighted coefficients were determined separately for ‘learning’ and ‘examination’ samples. On the basis of weighted coefficients, the decisive rule was created for differentiation between low-grade and high-grade chondrosarcoma. Results. The sensitivity of the method was 87.0%, specificity was 95.6%, total correct classification was 91.03%. Conclusion. Magnetic resonance imaging is a highly informative method for prediction of chondrosarcoma grade at the pre-surgery examination.

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