Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

Bovenzi, Cory D.; Hamilton, James; Tassone, Patrick; Johnson, Jennifer M.; Cognetti, David M.; Luginbuhl, Adam; Keane, William M.; Zhan, Tingting; Tuluc, Madalina; Bar‐Ad, Voichita; Martinez‐Outschoorn, Ubaldo; Curry, Joseph M.

doi:10.1155/2015/242437

Cited by 76 publications

(64 citation statements)

References 121 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This shift to catabolism and aerobic glycolysis by tumor stromal cells can be measured by evaluating the expression of monocarboxylate transporter 4 (MCT4), which is the main exporter of intracellular lactate. The expression of MCT4 correlates with glycolytic activity 43 . In turn, the lactate secreted via MCT4 is taken up by cancer cells via monocarboxylate transporter 1 (MCT1), leading to the generation of ATP via OXPHOS 44 .…”

Section: Discussionmentioning

confidence: 99%

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

Mikkilineni

Whitaker‐Menezes

Domingo‐Vidal

et al. 2017

Seminars in Oncology

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

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

Mikkilineni

Whitaker‐Menezes

Domingo‐Vidal

et al. 2017

Seminars in Oncology

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is a key molecule that promotes the proliferation, invasion and metastasis of cancer cells (6)(7)(8)(9)(10)(11). CD147 is an important promoter of cell growth through the reprogramming of glucose metabolism, including glycolysis (12,(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…Since CD147 functions as an oncoprotein (6)(7)(8)(9)(10)(11), the association between CD147 expression and malignancy-associated factors was examined in a number of urothelial cancer cell lines and normal HUC cells. The hTERT promoter-driving activity was measured as an index of the malignancy using the hTERT promoter-driven advanced TSTA system (16).…”

Section: Expression Of Cd147 In Human Urothelial Cancer Cell Linesmentioning

confidence: 99%

“…The expression of the CD147 protein in cancer cells, including urinary bladder, breast, lung, oral cavity, esophageal Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells and skin cancer, as well as malignant lymphoma cells, has been observed to be significantly increased compared with that in the corresponding normal tissue (6). The elevated expression of CD147 is correlated with tumor progression in bladder cancer, glioma, giant cell tumor of bone, laryngeal squamous cell carcinoma, ovarian carcinoma and melanoma, indicating that CD147 serves a significant role in the progression of cancer (6)(7)(8)(9)(10)(11). It has previously been demonstrated that CD147 is involved in the cell glycolytic metabolic pathways that enable cancer cells to divide and rapidly proliferate (12)(13)(14), providing an insight into the molecular mechanisms underlying the role that CD147 serves in cancer progression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells

et al. 2017

View full text Add to dashboard Cite

Abstract. Our group previously developed an adenoviral vector encoding the REIC/Dkk-3 gene (Ad-REIC), a tumor suppressor, for cancer gene therapy. The Ad-REIC agent induces apoptosis and inhibits invasion in a number of cancer cell lines; however, the molecular mechanisms underlying its effects remain unclear. Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a key molecule that promotes cancer proliferation and invasion. In order to elucidate the therapeutic mechanism of Ad-REIC, its effect on the expression of CD147 in human bladder cancer KK47 cells was investigated. Treatment with Ad-REIC markedly downregulated the expression of CD147 and significantly inhibited cellular proliferation. Since the expression of CD147 is reported to be under the positive control of mitogen-activated protein kinase (MAPK) signaling and the c-Myc protein, the correlations between the expression of CD147 and the activation of MAPKs or the expression of c-Myc were examined. Unexpectedly, no positive correlation was observed between the level of CD147 and the potential regulators that were assessed, indicating that another signaling pathway is responsible for the downregulation of CD147. The results from the present study demonstrate that Ad-REIC treatment can significantly downregulate the expression of CD147 in bladder cancer cells. Downregulation of the cancer-progression factor CD147 may be a novel mechanism that underlies the therapeutic effects of Ad-REIC treatment.

show abstract

“…Using biomarker staining, Curry et al identified three, separate metabolic compartments in HNSCC: (1) proliferating cancer cells expressing high MCT1 and high TOMM20, (2) non-proliferating stromal cells expressing high MCT4, and (3) non-proliferating cancer cells expressing high MCT4, highlighting the metabolic heterogeneity within a tumor [23]. High MCT1 expression in cancer cells and high MCT4 expression in the stroma of multiple human malignancies is associated with poor outcomes [48]. …”

Section: Monocarboxylate Transportersmentioning

confidence: 99%

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Wilde

Roche

Domingo‐Vidal

et al. 2017

Seminars in Oncology

Self Cite

242

185

View full text Add to dashboard Cite

Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation (OXPHOS). Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize OXPHOS. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.

show abstract

Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

Cited by 76 publications

References 121 publications

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

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

Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Contact Info

Product

Resources

About