GLUT1 expression patterns in different Hodgkin lymphoma subtypes and progressively transformed germinal centers

Hartmann, Sven; Agostinelli, Claudio; Diener, Jürgen; Döring, Claudia; Fanti, Stefano; Zinzani, Pier Luigi; Gallamini, Andrea; Bergmann, Lothar; Pileri, Stefano; Hansmann, Martin‐Leo

doi:10.1186/1471-2407-12-586

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…c ). The present results are consistent with our previous findings demonstrating increased expression patterns of the glucose transporter GLUT1 and decreased levels of the lactate transporters MCT1 and MCT4 in a series of primary Hodgkin cases . Moreover, the higher respiratory control ratios we observed (Figs.…”

Section: Discussionsupporting

confidence: 93%

“…The present results are consistent with our previous findings demonstrating increased expression patterns of the glucose transporter GLUT1 and decreased levels of the lactate transporters MCT1 and MCT4 in a series of primary Hodgkin cases. 28 Moreover, the higher respiratory control ratios we observed ( Figs. 2b and 2c) indicated that the increase in respiration was not associated with an increased proton leak across the inner mitochondrial membrane.…”

Section: Discussion Chl Cells Adapt In a Non-warburg Mannermentioning

confidence: 58%

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Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation

et al. 2016

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The metabolic properties of lymphomas derived from germinal center (GC) B cells have important implications for therapeutic strategies. In this study, we have compared metabolic features of Hodgkin-Reed-Sternberg (HRS) cells, the tumor cells of classical Hodgkin's lymphoma (cHL), one of the most frequent (post-)GC-derived B-cell lymphomas, with their normal GC B cell counterparts. We found that the ratio of oxidative to nonoxidative energy conversion was clearly shifted toward oxidative phosphorylation (OXPHOS)-linked ATP synthesis in HRS cells as compared to GC B cells. Mitochondrial mass, the expression of numerous key proteins of oxidative metabolism and markers of mitochondrial biogenesis were markedly upregulated in cHL cell lines and in primary cHL cases. NFkappaB promoted this shift to OXPHOS. Functional analysis indicated that both cell growth and viability of HRS cells depended on OXPHOS. The high rates of OXPHOS correlated with an almost complete lack of lactate production in HRS cells not observed in other GC B-cell lymphoma cell lines. Overall, we conclude that OXPHOS dominates energy conversion in HRS cells, while nonoxidative ATP production plays a subordinate role. Our results suggest that OXPHOS could be a new therapeutic target and may provide an avenue toward new treatment strategies in cHL.Classical Hodgkin lymphoma (cHL) accounts for approximately 30% of all lymphomas. 1-3 The origin of Hodgkin and Reed-Sternberg (HRS) cells, the tumor cells of cHL, was uncertain for many years. However, several studies demonstrated their derivation from (post-)germinal center (GC) B cells and showed crippling mutations in their B cell receptor genes. [1][2][3] This was a surprising finding since survival of B cells usually depends on the integrity of the B cell receptor (BCR) signaling pathway.The metabolic differences between GC B-cell-derived lymphomas and their precursor cells have not been investigated thoroughly; however, metabolic properties of tumor cells usually diverge significantly from their nonmalignant precursor cells. Generally, energy production in cancer cells is strongly dependent on glycolysis. Furthermore, increased fatty acid synthesis and high rates of glutaminolysis play a pivotal role in the metabolism of cancer cells. [4][5][6][7][8] Warburg and coworkers showed that cancer cells convert approximately tenfold more glucose to lactate than normal tissues under aerobic conditions. 9 Under these conditions, the amount of reducing equivalents available for biosynthesis is limited. 4,10 These observations led to the hypothesis that tumor cells acquire a significant growth advantage by favoring glucose conversion to lactate even under high oxygen supply (aerobic glycolysis). This switch to aerobic glycolysis, often referred to as the Warburg effect, may occur because of mutations in genes involved in oxidative phosphorylation (OXPHOS) as demonstrated for a subset of cancers. 4,[11][12][13][14] Other cancer types carry out enhanced glycolysis and mitochondrial respiration

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Section: Discussionsupporting

confidence: 93%

Section: Discussion Chl Cells Adapt In a Non-warburg Mannermentioning

confidence: 58%

Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation

et al. 2016

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“…Burkitt lymphoma, follicular lymphoma, DLBCL and primary effusion lymphoma (PEL) lines show increased glycolytic flux (Bhatt et al, 2012). In many patients, Hodgkin and Reen Stenberg cells express high levels of the glucose transporter Glut1 and glycolytic enzymes such as lactate dehydrogenase (LDHA) (Hartmann et al, 2012). In comparison to B cells from healthy donors, primary B cell acute lymphoblastic leukemia (B-ALL) cells show increased rates of aerobic glycolysis and decreased survival after 2-DG inhibition (Liu et al, 2014).…”

Section: Metabolic Signatures Of B Cell Derived Malignanciesmentioning

confidence: 99%

The PI3K pathway in B cell metabolism

Jellusova

Rickert

2016

Critical Reviews in Biochemistry and Molecular Biology

107

114

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B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprogramming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.

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“…It has been shown that different mechanisms of glucose uptake, e.g. via GLUT1 in HRS cells and via GLUT3 in the microenvironment, contribute to PET positivity of the tumour [8]. In a recent study no correlation was found between GLUT1 expression in HRS cells and PET standard uptake values, and significant differences in progression-free survival (PFS) or OS between patients exhibiting different GLUT1 expression patterns could not be demonstrated.…”

mentioning

confidence: 92%

“…In a recent study no correlation was found between GLUT1 expression in HRS cells and PET standard uptake values, and significant differences in progression-free survival (PFS) or OS between patients exhibiting different GLUT1 expression patterns could not be demonstrated. Indeed the surrounding mononuclear cells account for 99 % of the Hodgkin tumour and it has been shown that HL cell lines cultured in vitro were characterized by a very high metabolic activity [8]. This suggests that these environmental cells are responsible in vivo for the FDG uptake in baseline FDG PET scans.…”

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confidence: 94%

Baseline metabolic tumour volume in Hodgkin lymphoma: the prognostic value of accessory cells

Meignan

2014

Eur J Nucl Med Mol Imaging

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At the present time Hodgkin lymphoma (HL) can be cured in more than 80 % of all patients [1]. Over 90 % of patients with early-stage HL are cured with contemporary combinedmodality therapy, but there are still 25 -30 % of patients with advanced-stage disease who are not cured with the ABVD regimen alone [1,2]. The International Prognostic Score (IPS) fails to recognize these patients with a high risk of treatment failure since the range of outcomes it delineates has narrowed with treatment improvement [1]. Although clinical prognostic scores continue to be routinely used, the need to identify patients with poorer risk has focused research on the tumoral microenvironment to find valuable prognostic information. Indeed, the tumour tissue in HL is composed of a few scattered neoplastic cells called Hodgkin and ReedSternberg (HRS) cells, which account for less than 1 % of all the cells found in biopsy specimens, that are surrounded by an overwhelming population of nonneoplastic mononuclear bystander cells. These cells (CCR4-expressing cell subsets, including eosinophils, histiocytes, macrophages, plasma cells, and Th2 and Treg lymphocytes) are recruited by chemokines produced by the HRS cells and induce the expression of antiapoptotic proteins in HRS cells and their immortalization via a paracrine loop [3,4]. There is an intimate relationship between the HRS cells and reactive cells of the microenvironment that enables the tumour to thrive and evade immune surveillance. Some recent studies have suggested a prognostic role for the nonneoplastic surrounding cells.In classic HL (CHL) tumour-associated macrophages (TAMs) have been shown to be associated with inferior outcomes [5]. Steidl et al. showed that a macrophage gene expression signature is associated with primary treatment failure in CHL and subsequently showed, using an independent validation cohort, that an increase in CD68-positive macrophages in the microenvironment is associated with inferior outcomes [5]. In the E2496 Intergroup trial, a multicentre phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in 287 patients with locally extensive and advanced stage CHL, increased CD68 or CD163 expression was significantly associated with inferior 5-year failure-free survival (FFS; 64 % vs. 78 % and 63 % vs. 82 %) and 5-year overall survival (OS; 81 % vs. 94 % and 81 % vs. 96 %). Multivariate analysis with clinical and biological factors linked to FFS (lymphocyte count, stage 4 disease) and OS (age ≥45 years) showed that increased CD68 or CD163 expression are significant independent predictors of inferior FFS and OS [6]. However, prognostic indices using these results in routine have not yet been built.HL is a lymphoma showing FDG avidity with 100 % of patients positive at baseline, and FDG PET is currently the most accurate staging modality [7]. It has been shown that different mechanisms of glucose uptake, e.g. via GLUT1 in HRS cells and via GLUT3 in the microenvironment, contribute to PET positivity of the tumour [8]. In a recent study...

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GLUT1 expression patterns in different Hodgkin lymphoma subtypes and progressively transformed germinal centers

Cited by 26 publications

References 33 publications

Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation

Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation

The PI3K pathway in B cell metabolism

Baseline metabolic tumour volume in Hodgkin lymphoma: the prognostic value of accessory cells

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