Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure

Andersen, Sigve; Solstad, Ørjan; Moi, Line; Dønnem, Tom; Eilertsen, Marte; Nordby, Yngve; Ness, Nora; Richardsen, Elin; Busund, Lill-Tove; Bremnes, Roy M.

doi:10.1016/j.urolonc.2015.05.013

Cited by 24 publications

(32 citation statements)

References 33 publications

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“…Similar findings with metabolic coupling between stromal and cancer cells involving lactate, pyruvate, beta-hydroxybutyrate, acetate, fatty acids, glutamine and alanine have been discovered in many human malignancies including breast, ovarian, prostate, liver, colon, pancreatic and head and neck squamous cell cancer (HNSCC) [23] [29] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]. …”

Section: Monocarboxylate Transporterssupporting

confidence: 57%

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

271

213

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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.

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Section: Monocarboxylate Transporterssupporting

confidence: 57%

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

271

213

View full text Add to dashboard Cite

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“…In the study by Martins et al, 38 MCT4 expression by stromal cells was acquired in near 90% of invasive breast carcinomas. P ertega-Gomes et al 27 and Andersen et al 43 showed that prostate cancer samples with MCT4 overexpression in CAFs and simultaneous MCT1 overexpression in epithelial cancer cells are associated with poor clinical outcome. MCTs differential positivity in these metabolic compartments was also associated with higher disease stage in head and neck cancer.…”

Section: Discussionmentioning

confidence: 99%

Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness

et al. 2016

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Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance.

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“…There are differences in transporter expression in cancer cells in the tumor leading edge versus other cancer cells and stromal cells. The specific combined expression pattern of MCT1 in cancer cells and MCT4 in stromal cells was associated with decreased DFS in prostate cancer [ 104 , 105 ]. Expression patterns and colocalization of MCT1, MCT4, and CD147 are also discussed in breast cancer, ovarian cancer, colorectal cancer, and lung cancer [ 106 ].…”

Section: Discussionmentioning

confidence: 99%

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

Bovenzi

Hamilton

Tassone

et al. 2015

BioMed Research International

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Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147. Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses. Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p < 0.001 for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p < 0.0001 for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival. Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations.

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Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure

Cited by 24 publications

References 33 publications

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

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

Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness

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

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