Lactate and cancer: a "lactatic" perspective on spinal tumor metabolism (part 1)

Abstract

Spine tumors are among the most difficult tumors to treat given their proximity to the spinal cord. Despite advances in adjuvant therapies, surgery remains a critical component of treatment, both in primary tumors and metastatic disease. Given the significant morbidity of these surgeries and with other current adjuvant therapies (e.g., radiation, chemotherapy), interest has grown in other methods of targeting tumors of the spine. Recent efforts have highlighted the tumor microenvironment, and specifically lactate, as central to tumorigenesis. Once erroneously considered a waste product that indicated hypoxia/hypoperfusion, lactate is now known to be at the center of whole-body metabolism, shuttling between tissues and being used as a fuel. Diffusion-driven transporters and the near-equilibrium enzyme lactate dehydrogenase (LDH) allow rapid mobilization of large stores of muscle glycogen in the form of lactate. In times of stress, catecholamines can bind muscle cell receptors and trigger the breakdown of glycogen to lactate, which can then diffuse out into circulation and be used as a fuel where needed. Hypoxia, in contrast, is rarely the reason for an elevated arterial [lactate]. Tumors were originally described in the 1920's as being "glucose-avid" and "lactate-producing" even in normoxia (the "Warburg effect"). We now know that a broad range of metabolic behaviors likely exist, including cancer cells that consume lactate as a fuel, others that may produce it, and still others that may change their behavior based on the local microenvironment. In this review we will examine the relationship between lactate and tumor metabolism with a brief look at spine-specific tumors. Lactate is a valuable fuel and potent signaling molecule that has now been implicated in multiple steps in tumorigenesis [e.g., driving vascular endothelial growth factor (VEGF) expression in normoxia]. Future work should utilize translational animal models to target tumors by altering the local tumor microenvironment, of which lactate is a critical part.

Keywords: Lactate; cancer; lactic acid; neoplasm metastasis; neoplasms; neurosurgery; spinal; spine; tumor.

Figure 1

Simplified cartoon demonstrating our current understanding of lactate metabolism [here shown driving vascular endothelial growth factor (VEGF) during times of normoxia in a tumor cell]. Note that lactate is always being formed regardless of the oxygen tension due to the near equilibrium nature of the lactate dehydrogenase (LDH) reaction. While near equilibrium and the fastest reaction in glycolysis, the LDH reaction lies heavily toward lactate thermodynamically. Monocarboxylate transporters (MCTs) facilitate transport of lactate down its concentration gradient, although MCT1s are often associated with importation and MCT4s with exportation. Finally, note that imported lactate can be converted to pyruvate and used as a fuel in the mitochondria, and/or that pyruvate can lead to the degradation of 2-oxoglutarate, which is responsible for tagging HIF-1α for degradation in the proteosome. In the scenario of a high lactate concentration, this ultimately drives expression of VEGF, leading to angiogenesis. Used with permission from Goodwin et al. (10).

Figure 2

The lactate threshold. In numerous experiments plasma catecholamines have been shown to mirror lactate kinetics. For example, shown here is the response to progressive, incremental exercise; the catecholamine response mirrors the lactate response. Used with permission from Mazzeo et al. (35).

Figure 3

Lactate replaces glucose as a fuel. (A) Rat hippocampus slices show a marked decline when substrate is removed from medium, as evidence by rapid decline in mV. However, when lactate is administered to one group there is near complete recovery of brain tissue function. (B) In dogs made critically hypoglycemic (<20 mg/dL), death occurred within 30 min (top graph). (C) In the same experiment but with hypoglycemia and a lactate infusion to “clamp” lactate at 9× normal (≈9 mM), animals lived well past 5 h, indicating for the first time the presence of a lactate-protected hypoglycemia (LPH) in living animals (bottom graph). In (B) and (C), circles represent glucose and squares represent lactate. Note the difference in scale between (B) and (C). Used with permission from Schurr et al. (62) and Ferguson et al. (11).

Figure 4

Lactate drives vascular endothelial growth factor (VEGF)/angiogenesis in normoxic conditions. In genetically engineered mice that formed tumors, lactate was administered intraperitoneally for 2 weeks. (A) Anti-CD31 stain shows a marked increase in vascularity when compared to saline control injections. (B) Tumors demonstrated marked increase in HIF1α despite normoxic conditions, shown by lack of stain from anti-pimo (pimonidazole). Kidney is shown as control. Scale bar: 10 µm. Used with permission from Goodwin et al. (12).

Figure 5

The anesthetized canine model. Note that the anesthetized animal is supine and mechanically ventilated. The femoral artery and vein are dissected. The artery can be cannulated to direct blood out of the animal to a pump-perfusion system, where selected infusates can be mixed with the blood before returning to the animal via the femoral vein. Arterial blood pressure is also monitored on the arterial line, and arterial blood samples can be taken as desired. Electroencephalogram (EEG) leads are also placed on the head, electrocardiogram (ECG) leads on the chest, the bladder is catheterized, a rectal temperature probe is placed, and various solutions are shown in warmed bathes beside the animal for precise pump-controlled infusions. (Personal photo).