Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers.
We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis. In this model, cancer cells secrete hydrogen peroxide (H2O2), initiating oxidative stress and aerobic glycolysis in the tumor stroma. This, in turn, drives L-lactate secretion from cancer-associated fibroblasts. Secreted L-lactate then fuels oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells, by acting as a paracrine onco-metabolite. We have previously termed this type of two-compartment tumor metabolism the "Reverse Warburg Effect," as aerobic glycolysis takes place in stromal fibroblasts, rather than epithelial cancer cells. Here, we used MCT4 immuno-staining of human breast cancer tissue microarrays (TMAs; > 180 triple-negative patients) to directly assess the prognostic value of the "Reverse Warburg Effect." MCT4 expression is a functional marker of hypoxia, oxidative stress, aerobic glycolysis, and L-lactate efflux. Remarkably, high stromal MCT4 levels (score = 2) were specifically associated with decreased overall survival (< 18% survival at 10 y post-diagnosis). In contrast, patients with absent stromal MCT4 expression (score = 0), had 10-y survival rates of ~97% (p-value < 10 (-32) ). High stromal levels of MCT4 were strictly correlated with a loss of stromal Cav-1 (p-value < 10 (-14) ), a known marker of early tumor recurrence and metastasis. In fact, the combined use of stromal Cav-1 and stromal MCT4 allowed us to more precisely identify high-risk triple-negative breast cancer patients, consistent with the goal of individualized risk-assessment and personalized cancer treatment. However, epithelial MCT4 staining had no prognostic value, indicating that the "conventional" Warburg effect does not predict clinical outcome. Thus, the "Reverse Warburg Effect" or "parasitic" energy-transfer is a key determinant of poor overall patient survival. As MCT4 is a druggable-target, MCT4 inhibitors should be developed for the treatment of aggressive breast cancers, and possibly other types of human cancers. Similarly, we discuss how stromal MCT4 could be used as a biomarker for identifying high-risk cancer patients that could likely benefit from treatment with FDA-approved drugs or existing MCT-inhibitors (such as, AR-C155858, AR-C117977, and AZD-3965).
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. agnieszka.witkiewicz@jefferson.edu
Agnieszka K
AK
Witkiewicz
Diana
D
Whitaker-Menezes
Abhijit
A
Dasgupta
Nancy J
NJ
Philp
Zhao
Z
Lin
Ricardo
R
Gandara
Sharon
S
Sneddon
Ubaldo E
UE
Martinez-Outschoorn
Federica
F
Sotgia
Michael P
MP
Lisanti
D000328:Adult; D000368:Aged; D015415:Biomarkers; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D015331:Cohort Studies; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007118:Immunoassay / Q000379:methods; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000378:metabolism; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D060787:Neoplasm Grading; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D013194:Staining and Labeling; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; C495540:CAV1 protein, human; D051242:Caveolin 1; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C406962:SLC16A4 protein, human; D019344:Lactic Acid; D006861:Hydrogen Peroxide