Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer

Cell Cycle. 2013 May 1;12(9):1371-84. doi: 10.4161/cc.24092. Epub 2013 Apr 10.


Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67-/TOMM20-/COX-/MCT1-); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67-/TOMM20-/COX-/MCT1-). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target "three-compartment tumor metabolism" in head and neck cancers. It is remarkable that two "non-proliferating" populations of cells (Ki-67-/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial "fuels" for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial "stem cell" layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target "metabolic symbiosis."

Keywords: MCT1; MCT4; OXPHOS; TOMM20; glycolysis; head and neck cancer; metabolic symbiosis; mitochondria; monocarboxylate transporters (MCT); oxidative stress; stem cells; tumor recurrence; tumor stroma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Glycolysis
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology*
  • Humans
  • Kaplan-Meier Estimate
  • Ketone Bodies / metabolism
  • Lactic Acid / metabolism
  • Male
  • Membrane Transport Proteins / metabolism
  • Middle Aged
  • Mitochondria / metabolism
  • Monocarboxylic Acid Transporters / metabolism*
  • Muscle Proteins / metabolism*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology*
  • Neoplasm Staging
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Oxidative Phosphorylation
  • Oxidative Stress
  • Receptors, Cell Surface / metabolism
  • Symporters / metabolism*


  • Biomarkers, Tumor
  • Ketone Bodies
  • Membrane Transport Proteins
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • Receptors, Cell Surface
  • SLC16A4 protein, human
  • Symporters
  • TOMM20 protein, human
  • monocarboxylate transport protein 1
  • Lactic Acid