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Lactate AND Pimonidazole

Saurabh S Gorad, Christine Ellingsen, Tone F Bathen, Berit S Mathiesen, Siver A Moestue, Einar K Rofstad
Tumors develop an abnormal microenvironment during growth, and similar to the metastatic phenotype, the metabolic phenotype of cancer cells is tightly linked to characteristics of the tumor microenvironment (TME). In this study, we explored relationships between metabolic profile, metastatic propensity, and hypoxia in experimental tumors in an attempt to identify metastasis-associated metabolic profiles. Two human melanoma xenograft lines (A-07, R-18) showing different TMEs were used as cancer models. Metabolic profile was assessed by proton high resolution magic angle spinning magnetic resonance spectroscopy ((1)H-HR-MAS-MRS)...
October 2015: Neoplasia: An International Journal for Oncology Research
Amanda F Baker, Scott W Malm, Ritu Pandey, Cindy Laughren, Haiyan Cui, Denise Roe, Setsuko K Chambers
A panel of nine hypoxia regulated genes, selected from a previously published fifty gene panel, was investigated for its ability to predict hypoxic ovarian cancer phenotypes. All nine genes including vascular endothelial growth factor A, glucose transporter 1, phosphoglycerate mutase 1, lactate dehydrogenase A, prolyl 4-hydroxylase, alpha-polypeptide 1, adrenomedullin, N-myc downstream regulated 1, aldolase A, and carbonic anhydrase 9 were upregulated in the HEY and OVCAR-3 human ovarian cell lines cultured in vitro under hypoxic compared to normoxic conditions as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR)...
April 2015: Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society
Ramona-Cosmina Adochite, Anna Moshnikova, Sean D Carlin, Renato A Guerrieri, Oleg A Andreev, Jason S Lewis, Yana K Reshetnyak
Extracellular acidity is associated with tumor progression. Elevated glycolysis and acidosis promote the appearance of aggressive malignant cells with enhanced multidrug resistance. Thus, targeting of tumor acidity can open new avenues in diagnosis and treatment of aggressive tumors and targeting metastatic cancers cells within a tumor. pH (low) insertion peptides (pHLIPs) belong to the class of pH-sensitive agents capable of delivering imaging and/or therapeutic agents to cancer cells within tumors. Here, we investigated targeting of highly metastatic 4T1 mammary tumors and spontaneous breast tumors in FVB/N-Tg (MMTV-PyMT)634Mul transgenic mice with three fluorescently labeled pHLIP variants including well-characterized WT-pHLIP and, recently introduced, Var3- and Var7-pHLIPs...
August 4, 2014: Molecular Pharmaceutics
Yong Shao, Theresa L Wellman, Karen M Lounsbury, Feng-Qi Zhao
Glucose is a major substrate for milk synthesis and is taken up from the blood by mammary epithelial cells (MECs) through facilitative glucose transporters (GLUTs). The expression levels of GLUT1 and GLUT8 are upregulated dramatically in the mammary gland from late pregnancy through early lactation stages. This study aimed to test the hypothesis that this increase in GLUT1 and GLUT8 expression involves hypoxia signaling through hypoxia inducible factor-1α (HIF-1α) in MECs. Mouse mammary glands showed significantly more hypoxia in midpregnancy through early lactation stages compared with in the virgin stage, as stained by the hypoxia marker pimonidazole HCl...
August 1, 2014: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Yong Shao, Feng-Qi Zhao
Hypoxia is a physiological or pathological condition of a deficiency of oxygen supply in the body as a whole or within a tissue. During hypoxia, tissues undergo a series of physiological responses to defend themselves against a low oxygen supply, including increased angiogenesis, erythropoiesis, and glucose uptake. The effects of hypoxia are mainly mediated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimeric transcription factor consisting of α and β subunits. HIF-1β is constantly expressed, whereas HIF-1α is degraded under normal oxygen conditions...
2014: Journal of Animal Science and Biotechnology
Christine Ellingsen, Stefan Walenta, Tord Hompland, Wolfgang Mueller-Klieser, Einar K Rofstad
Poor disease-free and overall survival rates in locally advanced cervical cancer are associated with a tumor micro-environment characterized by extensive hypoxia, interstitial hypertension, and high lactate concentrations. The potential of gadolinium diethylenetriamine pentaacetic acid-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the microenvironment and microenvironment-associated aggressiveness of cervical carcinomas was investigated in this preclinical study. CK-160 and TS-415 cervical carcinoma xenografts were used as tumor models...
2013: Translational Oncology
Sinyoung Kang, Dongchul Lee, Brett E Theusch, Christopher J Arpey, Timothy J Brennan
Our previous studies using rat models of incisional pain have shown that tissue lactate levels increase and pH decreases for several days after incision, suggesting the presence of an ischemic-like condition. The purpose of this study was to evaluate the time course and the extent of tissue hypoxia that develops in incised muscle and skin. We directly measured oxygen tension at several time points after incisions of the gastrocnemius muscle, the paraspinal skin, and the plantar hindpaw in anesthetized rats using an oxygen-sensitive microelectrode...
September 2013: Wound Repair and Regeneration
Inna Serganova, Asif Rizwan, Xiaohui Ni, Sunitha B Thakur, Jelena Vider, James Russell, Ronald Blasberg, Jason A Koutcher
PURPOSE: 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. EXPERIMENTAL DESIGN: 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...
October 1, 2011: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Morten Busk, Stefan Walenta, Wolfgang Mueller-Klieser, Torben Steiniche, Steen Jakobsen, Michael Robert Horsman, Jens Overgaard
BACKGROUND AND PURPOSE: Tumor cells are recognized as being highly glycolytic. However, recently it was suggested that lactate produced in hypoxic tumor areas may be taken up by the monocarboxylate transporter MCT1 and oxidized in well-oxygenated tumor parts. Furthermore, it was shown that inhibition of lactate oxidation using the MCT1 inhibitor α-cyano-hydroxycinnamate (CHC) can radio-sensitize tumors possibly by forcing a switch from lactate oxidization to glycolysis in oxygenated cells, which in turn improves tumor oxygenation and indirectly kills radio-resistant hypoxic tumor cells from glucose starvation...
June 2011: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Saskia E Rademakers, Jasper Lok, Albert J van der Kogel, Johan Bussink, Johannes H A M Kaanders
BACKGROUND: The cellular response of malignant tumors to hypoxia is diverse. Several important endogenous metabolic markers are upregulated under hypoxic conditions. We examined the staining patterns and co-expression of HIF-1α, CAIX, LDH-5, GLUT-1, MCT1 and MCT4 with the exogenous hypoxic cell marker pimonidazole and the association of marker expression with clinicopathological characteristics. METHODS: 20 biopsies of advanced head and neck carcinomas were immunohistochemically stained and analyzed...
May 12, 2011: BMC Cancer
Philipp Mörchel, Gerd Melkus, Ala Yaromina, Daniel Zips, Michael Baumann, Peter M Jakob, Michael Flentje
PURPOSE: To correlate non-invasively acquired radiobiologically relevant magnetic resonance (MR) parameters with functional histology and tumor control doses (TCD(50)). MATERIALS AND METHODS: The MR parameters relative perfusion, re-oxygenation and lactate (Lac) concentration from eight human xenograft squamous tumor lines were compared with the histologically acquired pimonidazole hypoxic fraction, the perfused vessel area and TCD(50). RESULTS: Good spatial correlation in the parameter maps could be observed between the pimonidazole staining and tumor regions, which can be reoxygenated when breathing carbogen...
July 2010: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Ala Yaromina, Verena Quennet, Daniel Zips, Sandra Meyer, Georgy Shakirin, Stefan Walenta, Wolfgang Mueller-Klieser, Michael Baumann
PURPOSE: To examine relationships between tumour hypoxia, perfusion and metabolic microenvironment at the microregional level in three different human squamous cell carcinomas (hSCC). MATERIALS AND METHODS: Nude mice bearing FaDu, UT-SCC-15, and UT-SCC-5 hSCC were injected with pimonidazole hypoxia and Hoechst perfusion markers. Bioluminescence imaging was used to determine spatial distribution of glucose and lactate content in serial tumour sections. Metabolite levels were grouped in 10 concentration ranges...
November 2009: International Journal of Radiation Biology
Naomi Hosogai, Atsunori Fukuhara, Kazuya Oshima, Yugo Miyata, Sachiyo Tanaka, Katsumori Segawa, Shigetada Furukawa, Yoshihiro Tochino, Ryutaro Komuro, Morihiro Matsuda, Iichiro Shimomura
Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker...
April 2007: Diabetes
Ming Yin, Zhi Zhong, Henry D Connor, Hartwig Bunzendahl, William F Finn, Ivan Rusyn, Xiangli Li, James A Raleigh, Ronald P Mason, Ronald G Thurman
Although glycine prevents renal tubular cell injury in vitro, its effect in vivo is not clear. The purpose of this study was to investigate whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward would reduce renal injury caused by ischemia-reperfusion. Female Sprague-Dawley rats received a semisynthetic powdered diet containing 5% glycine and 15% casein (glycine group) or 20% casein (control group). Two days later, renal ischemia was produced by cross-clamping the left renal vessels for 15 min, followed by reperfusion...
March 2002: American Journal of Physiology. Renal Physiology
G E Arteel, R G Thurman, J A Raleigh
2-Nitroimidazoles, such as pimonidazole, are reduced in cells with low oxygen tension and are, therefore, used as hypoxia markers. However, the effect of the pyridine nucleotide redox state on pimonidazole reduction is not known. Therefore, livers from fed or fasted rats were perfused with oxygen-saturated buffer containing pimonidazole (400 microM) in the presence and absence of an inhibitor of the mitochondrial respiratory chain, potassium cyanide; these treatments were used to modulate the mitochondrial and cytosolic pyridine nucleotide redox states...
May 1, 1998: European Journal of Biochemistry
P Tamulevicius, C Streffer
The levels and distribution of ATP, glucose and lactate in human tumour xenografts following either single or combined treatment with hyperthermia (43 degrees C for 30 min) and/or pimonidazole (1 mg/g b.w) were determined by bioluminescence and compared with the mean 'global' levels obtained from the same tumours using conventional biochemical analysis. In general, the levels of ATP, glucose and lactate measured with both methods were in good agreement although the latter was consistently lower after bioluminescence determination...
March 1997: International Journal of Hyperthermia
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