Lactate MRSI and DCE MRI as surrogate markers of prostate tumor aggressiveness
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.NMR in Biomedicine (Impact Factor: 3.04). 01/2012; 25(1):113-22. DOI: 10.1002/nbm.1723
Longitudinal studies of lactate MRSI and dynamic contrast-enhanced MRI were performed at 4.7 T in two prostate tumor models grown in rats, Dunning R3327-AT (AT) and Dunning R3327-H (H), to determine the potential of lactate and the perfusion/permeability parameter Ak(ep) as markers of tumor aggressiveness. Subcutaneous AT (n = 12) and H (n = 6) tumors were studied at different volumes between 100 and 2900 mm(3) (Groups 1-5). Lactate concentration was determined using selective multiple quantum coherence MRSI with the phantom substitution method. Tumor enhancement after the administration of gadolinium diethylenetriaminepenta-acetic acid was analyzed using the Brix-Hoffmann model and the Ak(ep) parameter was used as a measure of tumor perfusion/permeability. Lactate was not detected in the smallest AT tumors (Group 1; 100-270 mm(3) ). In larger AT tumors, the lactate concentration increased from 2.8 ± 1.0 mm (Group 2; 290-700 mm(3)) to 8.4 ± 2.9 mm (Group 3; 1000-1340 mm(3)) and 8.2 ± 2.2 mm (Group 4; 1380-1750 mm(3) ), and then decreased to 5.0 ± 1.7 mm (Group 5; 1900-2500 mm(3)), and was consistently higher in the tumor core than in the rim. Lactate was not detected in any of the H tumors. The mean tumor Ak(ep) values decreased with increasing volume in both tumor types, but were significantly higher in H tumors. In AT tumors, the Ak(ep) values were significantly higher in the rim than in the core. Histological hypoxic and necrotic fractions in AT tumors increased with volume from 0% in Group 1 to about 20% and 30%, respectively, in Group 5. Minimal amounts of hypoxia and necrosis were found in H tumors of all sizes. Thus, the presence of lactate and heterogeneous perfusion/permeability are signatures of aggressive, metabolically deprived tumors.
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ABSTRACT: Oxygen deprivation leading to hypoxia is a common feature of solid tumours. Under these conditions a signalling pathway involving a key oxygen-response regulator termed the hypoxia-inducible factor (HIF) is switched on. HIF is a transcription factor that, in hypoxia, drives the induction or repression of a myriad of genes controlling multiple cell functions such as angiogenesis, metabolism, invasion/metastasis and apoptosis/survival. Thus, the level of oxygen in a cell dictates the molecular response of cells through modulation of gene expression. Here we review the central role of HIF in cancer progression through the tumour response to hypoxia. Within this context the following aspects will be discussed: i) the mechanism by which oxygen deprivation inhibits two oxygen-sensor hydroxylases, thereby releasing the alpha subunit of HIF from programmed destruction by the ubiquitin-proteasome system and from a lock on its transcriptional activity; ii) the way in which the bi-transcriptional activity of HIF-alpha, which is regulated by the interplay between an oxygen-sensor attenuator and co-activators, determines the repertoire of gene expression; and iii) the role that HIF plays in tumour metabolism, in particular in glycolysis, and consequent acidification of the microenvironment, which influences both cell survival and cell death. Finally, the direct link of HIF to tumourigenesis and metastasis will be investigated and approaches for fighting tumour progression through a better understanding of HIF-mediated modulation of tumour metabolism and cell death will be considered.
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ABSTRACT: We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. LDH-A expression, lactate concentration, glucose utilization, and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels [measured by magnetic resonance spectroscopic imaging (MRSI)] and tumor glucose utilization [measured by [(18)F]2-deoxy-2-fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET)] was assessed in orthotopic breast tumors derived from these cell lines. We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate 10-fold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less-intense hypoxia staining was observed in the larger 67NR tumors and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Lactate-MRSI has a greater dynamic range than [(18)F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors.Clinical Cancer Research 08/2011; 17(19):6250-61. DOI:10.1158/1078-0432.CCR-11-0397 · 8.72 Impact Factor
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ABSTRACT: High-resolution magic-angle spinning (HR-MAS) proton NMR spectroscopy is used to explore the metabolic signatures of head and neck squamous cell carcinoma (HNSCC) which included matched normal adjacent tissue (NAT) and tumor originating from tongue, lip, larynx and oral cavity, and associated lymph-node metastatic (LN-Met) tissues. A total of 43 tissues (18 NAT, 18 Tumor and 7 LN-Met) from 22 HNSCC patients were analyzed. Principal Component Analysis of NMR data showed a clear classification between NAT and tumor tissues, however, LN-Met tissues were classified among tumor. A partial least-squares discriminant analysis model generated from NMR metabolic profiles was used to differentiate normal from tumor samples (Q(2) > 0.80, Receiver Operator Characteristic area under the curve >0.86, using 7-fold cross validation). HNSCC and LN-Met tissues showed elevated levels of lactate, amino acids including leucine, isoleucine, valine, alanine, glutamine, glutamate, aspartate, glycine, phenylalanine and tyrosine, choline containing compounds, creatine, taurine, glutathione, and decreased levels of triglycerides. These elevated metabolites were associated with highly active glycolysis, increased amino acids influx (anaplerosis) into the TCA cycle, altered energy metabolism, membrane choline phospholipid metabolism, and oxidative and osmotic defense mechanisms. Moreover, decreased levels of triglycerides may indicate lipolysis followed by β-oxidation of fatty acids that may exist to deliver bioenergy for rapid tumor cell proliferation and growth.Journal of Proteome Research 10/2011; 10(11):5232-41. DOI:10.1021/pr200800w · 4.25 Impact Factor
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