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Xiaoming Xie - One of the best experts on this subject based on the ideXlab platform.

  • PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a
    Journal of Experimental & Clinical Cancer Research, 2017
    Co-Authors: Xiaojia Huang, Hai Lin Tang, Xiangsheng Xiao, Xiaofang Guo, Zhi Tian, Xinhua Xie, Lu Yang, Lijuan Zhang, Hua Wang, Xiaoming Xie
    Abstract:

    BackgroudThe purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a.MethodsWestern blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC.ResultsWe found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC.ConclusionsThis study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

  • PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a.
    Journal of experimental & clinical cancer research : CR, 2017
    Co-Authors: Xiaojia Huang, Hai Lin Tang, Xiangsheng Xiao, Xiaofang Guo, Zhi Tian, Xinhua Xie, Lu Yang, Lijuan Zhang, Hua Wang, Xiaoming Xie
    Abstract:

    The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a. Western blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC. We found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC. This study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

  • High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer
    Breast (Edinburgh Scotland), 2016
    Co-Authors: Xiaojia Huang, Hai Lin Tang, Xinhua Xie, Bo Chen, Cailu Song, Xiaoming Xie
    Abstract:

    Abstract Objectives The purpose of this study was to investigate the potential correlation between lactate dehydrogenase A (LDHA) and AMP-activated protein kinase (AMPK) and their clinicopathologic significance in breast cancer. Materials and Methods Western blot and qRT-PCR were used to detect the expression levels of LDHA and AMPK in eight breast cancer lines and eight breast cancer tissues. In addition, LDHA and AMPK were detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs) of 112 patients. The association between LDHA and AMPK expression levels was statistically analyzed. So were the prognostic roles and clinicopathologic significances in breast cancer. Results The expression levels of LDHA and AMPK were relatively higher in triple-negative breast cancer (TNBC) cell lines than in non-triple-negative breast cancer (NTNBC) cell lines. LDHA and AMPK were also further up-regulated in TNBC tissues than in NTNBC tissues. Correlation analysis showed a positive correlation between LDHA and AMPK expression levels. Expression of LDHA and AMPK were significantly correlated with TNM stage, distant metastasis, Ki67 status and survival outcomes of patients. Patients with both positive expression of LDHA and AMPK showed shorter overall survival (OS) and disease-free survival (DFS). Conclusions These findings improve our understanding of the expression pattern of LDHA and AMPK in breast cancer and clarify the role of LDHA and AMPK as promising prognostic biomarkers for breast cancer.

  • The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer
    Scientific reports, 2016
    Co-Authors: Xiangsheng Xiao, Hai Lin Tang, Xiaojia Huang, Bo Chen, Cailu Song, Jiahuai Wen, Zhijie Zhang, Guopei Zheng, Xiaoming Xie
    Abstract:

    Lactate dehydrogenase A (LDHA) is involved in a variety of cancers. The purpose of this study was to investigate the expression, prognostic roles and function of LDHA in breast cancer. We found that LDHA was upregulated in both breast cancer cell lines and clinical specimens using quantitative real-time PCR (qRT-PCR). Immunohistochemistry (IHC) analysis of tissue microarrays (TMAs) showed that high LDHA expression was associated with cell proliferation, metastasis and poor patient overall survival (OS) and disease free survival (DFS). Furthermore, we found that LDHA promoted glycolysis and cell proliferation in vitro and in vivo. We also performed luciferase reporter assays and found that LDHA was a direct target of miR-34a. Repression of LDHA by miR-34a suppressed glycolysis and cell proliferation in breast cancer cells in vitro. Our findings provide clues regarding the role of miR-34a as a tumor suppressor in breast cancer through the inhibition of LDHA both in vitro and in vivo. Targeting LDHA through miR-34a could be a potential therapeutic strategy in breast cancer.

Xiaojia Huang - One of the best experts on this subject based on the ideXlab platform.

  • PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a
    Journal of Experimental & Clinical Cancer Research, 2017
    Co-Authors: Xiaojia Huang, Hai Lin Tang, Xiangsheng Xiao, Xiaofang Guo, Zhi Tian, Xinhua Xie, Lu Yang, Lijuan Zhang, Hua Wang, Xiaoming Xie
    Abstract:

    BackgroudThe purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a.MethodsWestern blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC.ResultsWe found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC.ConclusionsThis study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

  • PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a.
    Journal of experimental & clinical cancer research : CR, 2017
    Co-Authors: Xiaojia Huang, Hai Lin Tang, Xiangsheng Xiao, Xiaofang Guo, Zhi Tian, Xinhua Xie, Lu Yang, Lijuan Zhang, Hua Wang, Xiaoming Xie
    Abstract:

    The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a. Western blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC. We found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC. This study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

  • expression of LDHA in breast cancer and its clinical significance
    Journal of Chinese Physician, 2017
    Co-Authors: Xiaojia Huang, Xiangsheng Xiao, Hai Lin Tang
    Abstract:

    Objective To investigate the expression and clinical significance of lactate dehydrogenase A (LDHA) in breast cancer. Methods Tissue samples of 76 breast cancers and corresponding paired adjacent normal tissues were collected and made into tissue microarrays (TMAs). Immunohistochemistry (IHC) analysis was performed to detect the expression of LDHA and further analyzed the correlation of LDHA expression and clinicopathological variables and prognosis of breast cancers. Results LDHA was frequently upregulated in breast cancer tissues compared to the normal breast tissues (P<0.05). High LDHA expression was associated with distant metastasis (P<0.05) and worse patient prognosis (P<0.05). Conclusions LDHA is closely related to the occurrence and clinical progress of breast cancers. LDHA might be a potential novel molecular marker for diagnosis, prognosis and therapy in breast cancers. Key words: Lactate dehydrogenases/ME; Breast neoplasms/ME

  • Expression of LDHA in breast cancer and its clinical significance
    Journal of Chinese Physician, 2017
    Co-Authors: Xiaojia Huang, Xiangsheng Xiao, Hai Lin Tang
    Abstract:

    Objective To investigate the expression and clinical significance of lactate dehydrogenase A (LDHA) in breast cancer. Methods Tissue samples of 76 breast cancers and corresponding paired adjacent normal tissues were collected and made into tissue microarrays (TMAs). Immunohistochemistry (IHC) analysis was performed to detect the expression of LDHA and further analyzed the correlation of LDHA expression and clinicopathological variables and prognosis of breast cancers. Results LDHA was frequently upregulated in breast cancer tissues compared to the normal breast tissues (P

  • High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer
    Breast (Edinburgh Scotland), 2016
    Co-Authors: Xiaojia Huang, Hai Lin Tang, Xinhua Xie, Bo Chen, Cailu Song, Xiaoming Xie
    Abstract:

    Abstract Objectives The purpose of this study was to investigate the potential correlation between lactate dehydrogenase A (LDHA) and AMP-activated protein kinase (AMPK) and their clinicopathologic significance in breast cancer. Materials and Methods Western blot and qRT-PCR were used to detect the expression levels of LDHA and AMPK in eight breast cancer lines and eight breast cancer tissues. In addition, LDHA and AMPK were detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs) of 112 patients. The association between LDHA and AMPK expression levels was statistically analyzed. So were the prognostic roles and clinicopathologic significances in breast cancer. Results The expression levels of LDHA and AMPK were relatively higher in triple-negative breast cancer (TNBC) cell lines than in non-triple-negative breast cancer (NTNBC) cell lines. LDHA and AMPK were also further up-regulated in TNBC tissues than in NTNBC tissues. Correlation analysis showed a positive correlation between LDHA and AMPK expression levels. Expression of LDHA and AMPK were significantly correlated with TNM stage, distant metastasis, Ki67 status and survival outcomes of patients. Patients with both positive expression of LDHA and AMPK showed shorter overall survival (OS) and disease-free survival (DFS). Conclusions These findings improve our understanding of the expression pattern of LDHA and AMPK in breast cancer and clarify the role of LDHA and AMPK as promising prognostic biomarkers for breast cancer.

Michael I Koukourakis - One of the best experts on this subject based on the ideXlab platform.

  • Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide
    Biochemical and biophysical research communications, 2017
    Co-Authors: Michael I Koukourakis, Efthimios Sivridis, Avgi Tsolou, Stamatia Pouliliou, Ioannis Lamprou, Maria Z. Papadopoulou, Maria Ilemosoglou, Georgia Kostoglou, Dimitra Ananiadou, Alexandra Giatromanolaki
    Abstract:

    Abstract Purpose Up-regulation of lactate dehydrogenase LDHA, is a frequent event in human malignancies and relate to poor postoperative outcome. In the current study we examined the hypothesis that LDHA and anaerobic glycolysis, may contribute to the resistance of glioblastoma to radiotherapy and to temozolomide. Methods and materials The expression of LDH5 isoenzyme (fully encoded by the LDHA gene) was assessed in human glioblastoma tissues. Experimental in vitro studies involved the T98 and U87 glioblastoma cell lines. Their sensitivity to radiotherapy and to temozolomide, following silencing of LDHA gene or following exposure to the LDHA chemical inhibitor ‘oxamate’ and to the glycolysis inhibitor ‘2-deoxy- d -glucose’ (2DG), was studied. Results Glioblastoma tissues showed strong cytoplasmic and nuclear LDH5 expression in 0–90% (median 20%) of the neoplastic cells. T98 and U87 cell lines showed that blocking glycolysis, either with LDHA gene silencing or exposure to oxamate (30 mM) and blockage of glycolysis with 2DG (500 μM), results in enhanced radiation sensitivity, an effect that was more robust in the T98 radioresistant cell line. Furthermore, all three glycolysis targeting methods, significantly sensitized both cell lines to Temozolomide. Conclusions The current study provides evidence that a large subgroup of human glioblastomas are highly glycolytic, and that inhibitors of glycolysis, like LDHA targeting agents, may prove of therapeutic importance by enhancing the efficacy of radiotherapy and temozolomide against this lethal disease.

  • lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy
    British Journal of Cancer, 2014
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Stamatia Pouliliou, Marianthi Panteliadou, P S Chondrou, S Mavropoulou, Efthimios Sivridis
    Abstract:

    Radiotherapy provides high-cure rates in prostate cancer. Despite its overall slow clinical growth, high proliferation rates documented in a subset of tumours relate to poor radiotherapy outcome. This study examines the role of anaerobic metabolism in prostate cancer growth and resistance to radiotherapy. Biopsy samples from 83 patients with prostate cancer undergoing radical hypofractionated and accelerated radiotherapy were analysed for MIB1 proliferation index and for lactate dehydrogenase isoenzyme LDH5, a marker of tumour anaerobic metabolism. Ninety-five surgical samples were in parallel analysed. Correlation with histopathological variables, PSA and radiotherapy outcome was assessed. Dose–response experiments were performed in PC3 and DU145 cancer cell lines. High MIB1 index (noted in 25% of cases) was directly related to Gleason score (P<0.0001), T3-stage (P=0.0008) and PSA levels (P=0.03). High LDH5 (noted in 65% of cases) was directly related to MIB1 index (P<0.0001), Gleason score (P=0.02) and T3-stage (P=0.001). High Gleason score, MIB1, LDH5 and PSA levels were significantly related to poor BRFS (P=0.007, 0.01, 0.03 and 0.01, respectively). High Gleason score (P=0.04), LDH5 (P=0.01) and PSA levels (P=0.003) were significantly related to local recurrence. MIB1 and T-stage did not affect local control. Silencing of LDHA gene in both prostate cancer cell lines resulted in significant radiosensitisation. LDH5 overexpression is significantly linked to highly proliferating prostate carcinomas and with biochemical failure and local relapse following radiotherapy. Hypoxia and LDHA targeting agents may prove useful to overcome radioresistance in a subgroup of prostate carcinomas with anaerobic metabolic predilection.

  • Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival
    Clinical & Experimental Metastasis, 2012
    Co-Authors: Alexandra Giatromanolaki, Efthimios Sivridis, Adrian L Harris, Kevin C Gatter, Nikolaos E. Bechrakis, Gregor Willerding, Georgios St. Charitoudis, Michael H. Foerster, Michael I Koukourakis
    Abstract:

    Hypoxia and its down-stream activated pathways are commonly involved in tumor progression. Genes involved in angiogenesis and glycolysis, i.e. vascular endothelial growth factor (VEGF) and lactase dehydrogenase A (LDHA), respectively, are transcriptionally controlled by the hypoxia inducible factors 1α and 2α (HIF1α and HIF2α). A series of 60 uveal melanomas were immunohistochemically assessed for the expression of VEGF and the phosphorylated/activated form of VEGF receptor 2 (pVEGFR2/KDR), after binding to VEGF. The expression of HIF1α, HIF2α and LDH5 was also investigated. Uveal melanomas overexpressing HIF2α (but not that of HIF1α) were significantly associated with high VEGF ( P  = 0.005), pVEGFR2/KDR ( P  

  • prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with ptk787 zk 222584 vatalanib antiangiogenic therapy
    Clinical Cancer Research, 2011
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Efthimios Sivridis, Kevin C Gatter, T Trarbach, Gunnar Folprecht, David Lebwohl, Tarja Jalava, Dirk Laurent, Gerold Meinhardt
    Abstract:

    Purpose: The Colorectal Oral Novel therapy For the Inhibition of angiogenesis and Retarding of Metastases (CONFIRM)-randomized trials, investigating the role of the VEGF-receptor inhibitor PTK787/ZK 222584 (vatalanib) in colorectal cancer (FOLFOX 4 ± vatalanib), showed some benefit in patients with high serum lactate dehydrogenase (LDH) levels. Here, we investigated the expression of LDH5 (encoded entirely by the LDHA gene, regulated by the hypoxia inducible factors) in cancer tissues from patients recruited in the CONFIRM trials and relationship to response. Experimental Design: Paraffin-embedded materials from 179 patients recruited in the CONFIRM trials were analyzed by immunohistochemistry for the expression of the LDH5 protein. Correlations with serum LDH, response, and survival were assessed. Results: A significant association of tumor burden and of poor performance status (PS) with serum LDH was noted. Poor PS and high tumor LDH5 expression predicted for poor response rates. High tissue LDH5 was related to poor progression-free survival (PFS) only in the placebo group of patients, whereas the addition of vatalanib seemed to improved response and PFS in this subgroup. High serum LDH levels were linked with significantly poorer overall survival, which however was not sustained in multivariate analysis. Conclusions: Serum LDH and tissue LDH5 levels are complementary features that help to characterize the activity of LDH in colorectal cancer and have a potent value in predicting response to chemotherapy. The addition of vatalanib diminished the impact of LDH expression on the prognosis of patients. Clin Cancer Res; 17(14); 4892–900. ©2011 AACR .

  • comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas a metabolic survival role for tumor associated stroma
    Cancer Research, 2006
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Adrian L Harris, Efthimios Sivridis
    Abstract:

    Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor αs (HIFαs)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFαs/LDH5), and reduced glucose absorption (low GLUT1). The expression profile of the tumor-associated endothelium indicated aerobic metabolism (high LDH1 and low HIFαs/LDH5), high glucose absorption (high GLUT1), and resistance to lactate intake (lack of MCT1). It is suggested that the newly formed stroma and vasculature express complementary metabolic pathways, buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. Tumors survive and grow because they are capable of organizing the regional fibroblasts and endothelial cells into a harmoniously collaborating metabolic domain. (Cancer Res 2006; 66(2): 632-7)

Efthimios Sivridis - One of the best experts on this subject based on the ideXlab platform.

  • Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide
    Biochemical and biophysical research communications, 2017
    Co-Authors: Michael I Koukourakis, Efthimios Sivridis, Avgi Tsolou, Stamatia Pouliliou, Ioannis Lamprou, Maria Z. Papadopoulou, Maria Ilemosoglou, Georgia Kostoglou, Dimitra Ananiadou, Alexandra Giatromanolaki
    Abstract:

    Abstract Purpose Up-regulation of lactate dehydrogenase LDHA, is a frequent event in human malignancies and relate to poor postoperative outcome. In the current study we examined the hypothesis that LDHA and anaerobic glycolysis, may contribute to the resistance of glioblastoma to radiotherapy and to temozolomide. Methods and materials The expression of LDH5 isoenzyme (fully encoded by the LDHA gene) was assessed in human glioblastoma tissues. Experimental in vitro studies involved the T98 and U87 glioblastoma cell lines. Their sensitivity to radiotherapy and to temozolomide, following silencing of LDHA gene or following exposure to the LDHA chemical inhibitor ‘oxamate’ and to the glycolysis inhibitor ‘2-deoxy- d -glucose’ (2DG), was studied. Results Glioblastoma tissues showed strong cytoplasmic and nuclear LDH5 expression in 0–90% (median 20%) of the neoplastic cells. T98 and U87 cell lines showed that blocking glycolysis, either with LDHA gene silencing or exposure to oxamate (30 mM) and blockage of glycolysis with 2DG (500 μM), results in enhanced radiation sensitivity, an effect that was more robust in the T98 radioresistant cell line. Furthermore, all three glycolysis targeting methods, significantly sensitized both cell lines to Temozolomide. Conclusions The current study provides evidence that a large subgroup of human glioblastomas are highly glycolytic, and that inhibitors of glycolysis, like LDHA targeting agents, may prove of therapeutic importance by enhancing the efficacy of radiotherapy and temozolomide against this lethal disease.

  • lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy
    British Journal of Cancer, 2014
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Stamatia Pouliliou, Marianthi Panteliadou, P S Chondrou, S Mavropoulou, Efthimios Sivridis
    Abstract:

    Radiotherapy provides high-cure rates in prostate cancer. Despite its overall slow clinical growth, high proliferation rates documented in a subset of tumours relate to poor radiotherapy outcome. This study examines the role of anaerobic metabolism in prostate cancer growth and resistance to radiotherapy. Biopsy samples from 83 patients with prostate cancer undergoing radical hypofractionated and accelerated radiotherapy were analysed for MIB1 proliferation index and for lactate dehydrogenase isoenzyme LDH5, a marker of tumour anaerobic metabolism. Ninety-five surgical samples were in parallel analysed. Correlation with histopathological variables, PSA and radiotherapy outcome was assessed. Dose–response experiments were performed in PC3 and DU145 cancer cell lines. High MIB1 index (noted in 25% of cases) was directly related to Gleason score (P<0.0001), T3-stage (P=0.0008) and PSA levels (P=0.03). High LDH5 (noted in 65% of cases) was directly related to MIB1 index (P<0.0001), Gleason score (P=0.02) and T3-stage (P=0.001). High Gleason score, MIB1, LDH5 and PSA levels were significantly related to poor BRFS (P=0.007, 0.01, 0.03 and 0.01, respectively). High Gleason score (P=0.04), LDH5 (P=0.01) and PSA levels (P=0.003) were significantly related to local recurrence. MIB1 and T-stage did not affect local control. Silencing of LDHA gene in both prostate cancer cell lines resulted in significant radiosensitisation. LDH5 overexpression is significantly linked to highly proliferating prostate carcinomas and with biochemical failure and local relapse following radiotherapy. Hypoxia and LDHA targeting agents may prove useful to overcome radioresistance in a subgroup of prostate carcinomas with anaerobic metabolic predilection.

  • Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival
    Clinical & Experimental Metastasis, 2012
    Co-Authors: Alexandra Giatromanolaki, Efthimios Sivridis, Adrian L Harris, Kevin C Gatter, Nikolaos E. Bechrakis, Gregor Willerding, Georgios St. Charitoudis, Michael H. Foerster, Michael I Koukourakis
    Abstract:

    Hypoxia and its down-stream activated pathways are commonly involved in tumor progression. Genes involved in angiogenesis and glycolysis, i.e. vascular endothelial growth factor (VEGF) and lactase dehydrogenase A (LDHA), respectively, are transcriptionally controlled by the hypoxia inducible factors 1α and 2α (HIF1α and HIF2α). A series of 60 uveal melanomas were immunohistochemically assessed for the expression of VEGF and the phosphorylated/activated form of VEGF receptor 2 (pVEGFR2/KDR), after binding to VEGF. The expression of HIF1α, HIF2α and LDH5 was also investigated. Uveal melanomas overexpressing HIF2α (but not that of HIF1α) were significantly associated with high VEGF ( P  = 0.005), pVEGFR2/KDR ( P  

  • prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with ptk787 zk 222584 vatalanib antiangiogenic therapy
    Clinical Cancer Research, 2011
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Efthimios Sivridis, Kevin C Gatter, T Trarbach, Gunnar Folprecht, David Lebwohl, Tarja Jalava, Dirk Laurent, Gerold Meinhardt
    Abstract:

    Purpose: The Colorectal Oral Novel therapy For the Inhibition of angiogenesis and Retarding of Metastases (CONFIRM)-randomized trials, investigating the role of the VEGF-receptor inhibitor PTK787/ZK 222584 (vatalanib) in colorectal cancer (FOLFOX 4 ± vatalanib), showed some benefit in patients with high serum lactate dehydrogenase (LDH) levels. Here, we investigated the expression of LDH5 (encoded entirely by the LDHA gene, regulated by the hypoxia inducible factors) in cancer tissues from patients recruited in the CONFIRM trials and relationship to response. Experimental Design: Paraffin-embedded materials from 179 patients recruited in the CONFIRM trials were analyzed by immunohistochemistry for the expression of the LDH5 protein. Correlations with serum LDH, response, and survival were assessed. Results: A significant association of tumor burden and of poor performance status (PS) with serum LDH was noted. Poor PS and high tumor LDH5 expression predicted for poor response rates. High tissue LDH5 was related to poor progression-free survival (PFS) only in the placebo group of patients, whereas the addition of vatalanib seemed to improved response and PFS in this subgroup. High serum LDH levels were linked with significantly poorer overall survival, which however was not sustained in multivariate analysis. Conclusions: Serum LDH and tissue LDH5 levels are complementary features that help to characterize the activity of LDH in colorectal cancer and have a potent value in predicting response to chemotherapy. The addition of vatalanib diminished the impact of LDH expression on the prognosis of patients. Clin Cancer Res; 17(14); 4892–900. ©2011 AACR .

  • comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas a metabolic survival role for tumor associated stroma
    Cancer Research, 2006
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Adrian L Harris, Efthimios Sivridis
    Abstract:

    Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor αs (HIFαs)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFαs/LDH5), and reduced glucose absorption (low GLUT1). The expression profile of the tumor-associated endothelium indicated aerobic metabolism (high LDH1 and low HIFαs/LDH5), high glucose absorption (high GLUT1), and resistance to lactate intake (lack of MCT1). It is suggested that the newly formed stroma and vasculature express complementary metabolic pathways, buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. Tumors survive and grow because they are capable of organizing the regional fibroblasts and endothelial cells into a harmoniously collaborating metabolic domain. (Cancer Res 2006; 66(2): 632-7)

Alexandra Giatromanolaki - One of the best experts on this subject based on the ideXlab platform.

  • Blocking LDHA glycolytic pathway sensitizes glioblastoma cells to radiation and temozolomide
    Biochemical and biophysical research communications, 2017
    Co-Authors: Michael I Koukourakis, Efthimios Sivridis, Avgi Tsolou, Stamatia Pouliliou, Ioannis Lamprou, Maria Z. Papadopoulou, Maria Ilemosoglou, Georgia Kostoglou, Dimitra Ananiadou, Alexandra Giatromanolaki
    Abstract:

    Abstract Purpose Up-regulation of lactate dehydrogenase LDHA, is a frequent event in human malignancies and relate to poor postoperative outcome. In the current study we examined the hypothesis that LDHA and anaerobic glycolysis, may contribute to the resistance of glioblastoma to radiotherapy and to temozolomide. Methods and materials The expression of LDH5 isoenzyme (fully encoded by the LDHA gene) was assessed in human glioblastoma tissues. Experimental in vitro studies involved the T98 and U87 glioblastoma cell lines. Their sensitivity to radiotherapy and to temozolomide, following silencing of LDHA gene or following exposure to the LDHA chemical inhibitor ‘oxamate’ and to the glycolysis inhibitor ‘2-deoxy- d -glucose’ (2DG), was studied. Results Glioblastoma tissues showed strong cytoplasmic and nuclear LDH5 expression in 0–90% (median 20%) of the neoplastic cells. T98 and U87 cell lines showed that blocking glycolysis, either with LDHA gene silencing or exposure to oxamate (30 mM) and blockage of glycolysis with 2DG (500 μM), results in enhanced radiation sensitivity, an effect that was more robust in the T98 radioresistant cell line. Furthermore, all three glycolysis targeting methods, significantly sensitized both cell lines to Temozolomide. Conclusions The current study provides evidence that a large subgroup of human glioblastomas are highly glycolytic, and that inhibitors of glycolysis, like LDHA targeting agents, may prove of therapeutic importance by enhancing the efficacy of radiotherapy and temozolomide against this lethal disease.

  • lactate dehydrogenase 5 isoenzyme overexpression defines resistance of prostate cancer to radiotherapy
    British Journal of Cancer, 2014
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Stamatia Pouliliou, Marianthi Panteliadou, P S Chondrou, S Mavropoulou, Efthimios Sivridis
    Abstract:

    Radiotherapy provides high-cure rates in prostate cancer. Despite its overall slow clinical growth, high proliferation rates documented in a subset of tumours relate to poor radiotherapy outcome. This study examines the role of anaerobic metabolism in prostate cancer growth and resistance to radiotherapy. Biopsy samples from 83 patients with prostate cancer undergoing radical hypofractionated and accelerated radiotherapy were analysed for MIB1 proliferation index and for lactate dehydrogenase isoenzyme LDH5, a marker of tumour anaerobic metabolism. Ninety-five surgical samples were in parallel analysed. Correlation with histopathological variables, PSA and radiotherapy outcome was assessed. Dose–response experiments were performed in PC3 and DU145 cancer cell lines. High MIB1 index (noted in 25% of cases) was directly related to Gleason score (P<0.0001), T3-stage (P=0.0008) and PSA levels (P=0.03). High LDH5 (noted in 65% of cases) was directly related to MIB1 index (P<0.0001), Gleason score (P=0.02) and T3-stage (P=0.001). High Gleason score, MIB1, LDH5 and PSA levels were significantly related to poor BRFS (P=0.007, 0.01, 0.03 and 0.01, respectively). High Gleason score (P=0.04), LDH5 (P=0.01) and PSA levels (P=0.003) were significantly related to local recurrence. MIB1 and T-stage did not affect local control. Silencing of LDHA gene in both prostate cancer cell lines resulted in significant radiosensitisation. LDH5 overexpression is significantly linked to highly proliferating prostate carcinomas and with biochemical failure and local relapse following radiotherapy. Hypoxia and LDHA targeting agents may prove useful to overcome radioresistance in a subgroup of prostate carcinomas with anaerobic metabolic predilection.

  • Phosphorylated pVEGFR2/KDR receptor expression in uveal melanomas: relation with HIF2α and survival
    Clinical & Experimental Metastasis, 2012
    Co-Authors: Alexandra Giatromanolaki, Efthimios Sivridis, Adrian L Harris, Kevin C Gatter, Nikolaos E. Bechrakis, Gregor Willerding, Georgios St. Charitoudis, Michael H. Foerster, Michael I Koukourakis
    Abstract:

    Hypoxia and its down-stream activated pathways are commonly involved in tumor progression. Genes involved in angiogenesis and glycolysis, i.e. vascular endothelial growth factor (VEGF) and lactase dehydrogenase A (LDHA), respectively, are transcriptionally controlled by the hypoxia inducible factors 1α and 2α (HIF1α and HIF2α). A series of 60 uveal melanomas were immunohistochemically assessed for the expression of VEGF and the phosphorylated/activated form of VEGF receptor 2 (pVEGFR2/KDR), after binding to VEGF. The expression of HIF1α, HIF2α and LDH5 was also investigated. Uveal melanomas overexpressing HIF2α (but not that of HIF1α) were significantly associated with high VEGF ( P  = 0.005), pVEGFR2/KDR ( P  

  • prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with ptk787 zk 222584 vatalanib antiangiogenic therapy
    Clinical Cancer Research, 2011
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Efthimios Sivridis, Kevin C Gatter, T Trarbach, Gunnar Folprecht, David Lebwohl, Tarja Jalava, Dirk Laurent, Gerold Meinhardt
    Abstract:

    Purpose: The Colorectal Oral Novel therapy For the Inhibition of angiogenesis and Retarding of Metastases (CONFIRM)-randomized trials, investigating the role of the VEGF-receptor inhibitor PTK787/ZK 222584 (vatalanib) in colorectal cancer (FOLFOX 4 ± vatalanib), showed some benefit in patients with high serum lactate dehydrogenase (LDH) levels. Here, we investigated the expression of LDH5 (encoded entirely by the LDHA gene, regulated by the hypoxia inducible factors) in cancer tissues from patients recruited in the CONFIRM trials and relationship to response. Experimental Design: Paraffin-embedded materials from 179 patients recruited in the CONFIRM trials were analyzed by immunohistochemistry for the expression of the LDH5 protein. Correlations with serum LDH, response, and survival were assessed. Results: A significant association of tumor burden and of poor performance status (PS) with serum LDH was noted. Poor PS and high tumor LDH5 expression predicted for poor response rates. High tissue LDH5 was related to poor progression-free survival (PFS) only in the placebo group of patients, whereas the addition of vatalanib seemed to improved response and PFS in this subgroup. High serum LDH levels were linked with significantly poorer overall survival, which however was not sustained in multivariate analysis. Conclusions: Serum LDH and tissue LDH5 levels are complementary features that help to characterize the activity of LDH in colorectal cancer and have a potent value in predicting response to chemotherapy. The addition of vatalanib diminished the impact of LDH expression on the prognosis of patients. Clin Cancer Res; 17(14); 4892–900. ©2011 AACR .

  • comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas a metabolic survival role for tumor associated stroma
    Cancer Research, 2006
    Co-Authors: Michael I Koukourakis, Alexandra Giatromanolaki, Adrian L Harris, Efthimios Sivridis
    Abstract:

    Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor αs (HIFαs)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFαs/LDH5), and reduced glucose absorption (low GLUT1). The expression profile of the tumor-associated endothelium indicated aerobic metabolism (high LDH1 and low HIFαs/LDH5), high glucose absorption (high GLUT1), and resistance to lactate intake (lack of MCT1). It is suggested that the newly formed stroma and vasculature express complementary metabolic pathways, buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. Tumors survive and grow because they are capable of organizing the regional fibroblasts and endothelial cells into a harmoniously collaborating metabolic domain. (Cancer Res 2006; 66(2): 632-7)