Hodgkin lymphoma (HL) is a common lymphoma in the Western world. Most individuals affected are adolescents. The tumor cells in HL, the Hodgkin- and Reed-Sternberg (HRS) cells, are derived from germinal center B cells
, which have lost their B cell phenotype
. HRS cells represent only a minority in their reactive microenvironment, which is mainly composed of T cells, epithelioid histiocytes, and eosinophils
. Several signaling pathways have been found to be constitutively deregulated in HL including NF-kappaB, JAK-STAT, PI3K-Akt, ERK, AP1, NOTCH1 and receptor tyrosine kinases
A hallmark of malignant tumors is the “Warburg effect”—high glucose consumption and increased glycolytic activity
[9, 10], which occurs as cancer cells shift their metabolism from oxidative phosphorylation to much less efficient glycolysis independent of their oxygen supply
. This needs to be compensated by increased glucoseconsumption. High glucose uptake by malignant tumors is the pathophysiologic basis for imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Thus, different PET studies have shown high FDG uptake in HL
[12, 13]. Interim-PET, accomplished after the first cycles of chemotherapy, has proven to be an important prognostic tool in HL
[14–16]. Energy independent glucose uptake into malignant and non-malignant cells is regulated via the expression of glucose transporter (GLUT) proteins
[17, 18]. GLUT1 and GLUT3, which are both members of the SLC2A group, have high affinity for glucose
. HRS cells were shown to express GLUT1, whereas GLUT3 and Hexokinase II were either not expressed or were only weakly expressed
[20, 21]. Because a correlation between GLUT1 protein expression in lymphoma cells and FDG uptake in PET scan was recently demonstrated
[20–23], we investigated the possibility that GLUT1 expression in HRS cells might also predict clinical behavior.
In the cytoplasm, glucose is cleaved by glycolytic enzymes into two molecules of pyruvate and is then transformed into lactate by lactate dehydrogenase (LDH), which is a tetramer composed of two different polypeptide chains, LDHA and LDHB. Whereas LDHA favors the conversion of pyruvate into lactate, LDHB is more efficient in converting lactate into pyruvate
. Lactate efflux results via membrane-bound monocarboxylate transporters (MCT) such as MCT1-4. MCT1 and 4 have low affinity for lactate, which makes them ideal export molecules when the metabolite is generated at high levels in the cytoplasm
In the current study, we investigated the expression of GLUT1, LDHA, MCT1 and MCT4 in tumor cells and reactive bystander cells in different HL subtypes and in respect to treatment outcome in a large number of patients. All four proteins would be expected to be highly expressed in cells exhibiting a high level of glucose metabolism, but with exception of GLUT1, to our knowledge, have not been investigated in Hodgkin lymphoma.