Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells In Vitro

Seliger, Corinna; Leukel, Petra; Moeckel, Sylvia; Jachnik, Birgit; Lottaz, Claudio; Kreutz, Marina; Brawanski, Alexander; Proescholdt, Martin; Bogdahn, Ulrich; Bosserhoff, Anja‐Katrin; Vollmann-Zwerenz, Arabel; Hau, Peter

doi:10.1371/journal.pone.0078935

Cited by 79 publications

(69 citation statements)

References 43 publications

(53 reference statements)

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“…TGFβ is a well‐known growth factor that requires an activation step in order to be released from the latent activation protein (LAP). Various stimuli and factors lead to the activation of TGFβ; in the present dataset, increased expression of thrombospondin‐1 ( THBS1 ) and integrin β6 ( ITGB6 ), which are known activators of TGFβ, were observed in the tumour buds . In fact, among the 228 differentially expressed genes, 32% of the changes observed can be explained by activated TGFβ signalling.…”

Section: Discussionmentioning

confidence: 63%

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Molecular profiling of tumour budding implicates TGFβ‐mediated epithelial–mesenchymal transition as a therapeutic target in oral squamous cell carcinoma

Jensen

Dabelsteen

Specht

et al. 2015

The Journal of Pathology

114

130

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Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin-stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA-qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial-mesenchymal transition (EMT) and activated TGFβ signalling. Transcription factors ZEB1 and PRRX1 were up-regulated concomitantly with the decreased expression of mesenchymal-epithelial (MET) transcription factors (eg OVOL1) in addition to Krüppel-like factors and Grainyhead-like factors. Moreover, miR-200 family members were down-regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFβ signalling may prove useful in the treatment of OSCC.

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Section: Discussionmentioning

confidence: 63%

“…integrin β6 (ITGB6), which are known activators of TGFβ, were observed in the tumour buds [40,41]. In fact, among the 228 differentially expressed genes, 32% of the changes observed can be explained by activated TGFβ signalling.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of tumour budding implicates TGFβ‐mediated epithelial–mesenchymal transition as a therapeutic target in oral squamous cell carcinoma

Jensen

Dabelsteen

Specht

et al. 2015

The Journal of Pathology

114

130

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“…Seliger et al found that the knockdown of LDHA resulted in a decrease in lactate concentration, which caused a reduction of THBS‐1 and TGF‐β2 expression and reduced migration by approximately 40% compared with the control siRNA . Furthermore, addition of lactate or synthetic THBS‐1 rescued TGF‐β2 expression and glioma migration . In another study, it was found that MMP‐2, a promoter of migration and invasion which is overexpressed in high‐grade glioma, is also upregulated by LDHA through lactate induction of TGF‐β2 .…”

Section: The Role Of Ldha In Tumor Migration and Metastasismentioning

confidence: 99%

“…There have been a few studies of LDHA and lactate in high‐grade glioma migration. Seliger et al found that the knockdown of LDHA resulted in a decrease in lactate concentration, which caused a reduction of THBS‐1 and TGF‐β2 expression and reduced migration by approximately 40% compared with the control siRNA . Furthermore, addition of lactate or synthetic THBS‐1 rescued TGF‐β2 expression and glioma migration .…”

Section: The Role Of Ldha In Tumor Migration and Metastasismentioning

confidence: 99%

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

et al. 2015

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There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic. LACTATE DEHYDROGENASELactate dehydrogenase (LDH) is a tetrameric enzyme, belonging to the 2-hydroxy acid oxidoreductase family, which increases the rate of the simultaneous inter-conversion of pyruvate to lactate and nicotinamide adenine dinucleotide (NAD)H to NAD + by 14 orders of magnitude (10) (Figure 1). The reaction involves the transfer of a hydride ion from NADH to the C2 carbon of pyruvate (99) and is commonly used by cells for anaerobic respiration. There are four LDH genes: LDHA, LDHB, LDHC and LDHD (Figure 2). LDHA, LDHB and LDHC are L isomers, whereas LDHD is a D isomer. The L isomers use or produce L-lactate, which is the major enantiomer found in vertebrates.The human LDHA gene is located on chromosome 11p15.4, the transcribed protein has 332 amino acids, a predicted molecular weight of 37 kDa and 24 splice variants; the human genome also contains several non-transcribed LDHA pseudogenes (32, 126). Evolutionarily, LDHA and LDHB are thought to have arisen from the duplication of a single LDHA-like LDH gene (82). LDHC, a testes-specific gene, is also thought to have evolved in mammals from the duplication of the LDHA gene after the A-B duplication (82).LDHA is also known as the M subunit as it is predominantly found in skeletal muscle, and LDHB is also known as the H subunit as it is predominantly found in the heart. Unlike the other LDH genes, which can form only homotetramers, LDHA and LDHB can form homo-or heterotetramers. There are five isoenzymes of LDH that can be made from the M and H subunits: LDH-1 (4H), LDH-2 (3H, 1M), LDH-3 (2H, 2M), LDH-4 (1H, 3M), and LDH-5 (5M) (Figure 2). LDH-1 and LDH-5 have identical active site regions and only differ in 81 out of 332 amino acid positions, mo...

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“…Targeting individual parts of the glycolytic pathway such as LDHA 121 may prove promising in cancer therapy, and knockdown of LDHA in glioma cells by siRNA or the inhibitor sodium oxamate has been shown to decrease those cells' migratory potential. 200 The glycolytic enzymes pyruvate dehydrogenase kinase (PDK) and hexokinase II (HKII) are significant markers in the pathogenesis and targeted treatment of GBM. Furthermore, similar to the glycolytic enzymes CA-IX and GLUT-1, other hypoxia-regulated proteins transcribed by HIF-1a, such as the receptor tyrosine kinase c-Met and VEGF, 15,106,117,203 are overexpressed in malignant brain tumors.…”

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confidence: 99%

Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Womeldorff¹,

Gillespie²,

Jensen³

2014

FOC

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Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells In Vitro

Cited by 79 publications

References 43 publications

Molecular profiling of tumour budding implicates TGFβ‐mediated epithelial–mesenchymal transition as a therapeutic target in oral squamous cell carcinoma

Molecular profiling of tumour budding implicates TGFβ‐mediated epithelial–mesenchymal transition as a therapeutic target in oral squamous cell carcinoma

The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

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