Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment

Abstract

Background Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL since non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. Methods A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin bleomycin vinblastine and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from 4 subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1 and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in >50% of cells. Results TOMM20, MCT1 and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared to tumor associated macrophages (TAMs) and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1 while TAMs have absent expression of TOMM20 and MCT1 in all but 2 cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but 1 case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenviro...

Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

“…These results were further confirmed in a retrospective DLBCL cohort [48]. A similar phenotype has also been reported in Hodgkin lymphoma, with an elevated mitochondrial metabolism (high expression of MCT1) in the tumour cells and a glycolytic metabolism (high expression of MCT4) in tumour-associated macrophages [49]. This metabolic hijacking is exploited by several neoplasms for cell survival, progression, metastasis and chemotherapy resistance [50,51].…”

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…The energy of electrons is used for ATP biosynthesis with the involvement of ATP-synthase (complex V) in the process denoted as OXPHOS [158]. A growing body of data evidence that the elevated oxidative metabolism with increased uptake of mitochondrial fuels such as lactate, pyruvate, and ketone bodies are characteristic for many cancer types including head and neck cancer, breast cancer, and lymphomas, among others [159][160][161]. For example, up-regulation of mitochondrial OXPHOS featured by succinate dehydrogenase (complex II) and cytochrome c oxidase (complex IV) activation, allowing them to produce a higher amount of ATP, has been observed in epithelial cancer cells [162,163].…”

Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming

“…Strategies that increase supply include metabolic adaptation to use alternative fuels, including glucose, glutamine, alanine, pyruvate, lactate, and lipids (Allen et al, 2016;Jimenez-Valerio and Casanovas, 2016;Nieman et al, 2011;Pavlova and Thompson, 2016;Pisarsky et al, 2016); increased macropinocytosis to take up and degrade proteins and lipids from their environment, including extracellular matrix and necrotic cell debris (Commisso et al, 2013;Davidson et al, 2016;Kamphorst et al, 2015;Kim et al, 2018;Muranen et al, 2017;Palm et al, 2015); secretion of ''feed me'' signals that trigger the release of nutrients, including amino and fatty acids, from other cells in the vicinity, a process termed metabolic symbiosis (Martinez-Outschoorn et al, 2014;Mikkilineni et al, 2017;Nakajima and Van Houten, 2013;Sonveaux et al, 2008;Sousa et al, 2016); and enhancing autophagy, a lysosome-dependent process by which nonessential intracellular components are recycled (Rzymski et al, 2009), which is a key survival strategy in several cancers (Goulielmaki et al, 2016;Guo et al, 2011;Perera et al, 2015;White, 2013;Yang et al, 2011). Tumor cells may also ensure a longerterm increase in nutrient supply by stimulating neoangiogenesis through the expression of vascular endothelial growth factor (VEGF) that promotes formation of new blood vessels (Simons et al, 2016).…”