We end this chapter with a brief discussion of the relationship between lactic acid, insulin, and angiogenesis in wound healing and cancer. As mentioned earlier, vascular cells proliferate and migrate toward an angiogenic stimulus, usually toward a low-oxygen (hypoxic) environment. In wound healing, hypoxia occurs from a lack of blood circulation in the traumatized area. In tumors, hypoxic conditions occur both through inflammation, which reduces blood flow, and the chaotic development of blood vessels within tumors.
Hypoxic environments alter the pathway by which immune cells and tumor cells burn fuel (specifically, glucose) for energy. The result of hypoxia is that affected cells produce excessive lactic acid, which is an angiogenic factor. Under aerobic, or oxygen-rich, conditions, glucose is burned in an efficient process that produces a maximal amount of energy and a minimal amount of lactic acid. Under hypoxic conditions, however, glucose is burned in an inefficient process that produces a small amount of energy and a large amount of lactic acid (see Figure 7.7). Note that lactic acid is an angiogenic factor because it causes macrophages to secrete other angiogenic factors.55
In tumor cells, the chronic hypoxic conditions cause excessive production of lactic acid and a prolonged inefficient utilization of glucose. The reduced energy output stimulates tumor cells to burn more glucose, which makes even more lactic acid. Thus the glycolysis (glucose-burning) pathway is greatly stimulated in tumor cells. Tumor cells consume glucose at a rate three to five times higher than normal cells.56,57 Not only can this waste the energy reserves of a cancer patient, but as stated, the lactic acid produced can stimulate macrophages to produce more angiogenic factors.20
One growth factor that is intimately involved in glycolysis is insulin. Insulin stimulates not only glycolysis but also proliferation of many cancer cell lines.54'58-60 It
Energy Production from Glucose glucose (blood sugar) enzymes ■
pyruvate aerobic conditions anaerobic conditions carbon dioxide and water
Small Energy Gain may facilitate angiogenesis by increasing lactic acid production in hypoxic tumor cells and by stimulating the proliferation of vascular cells. For example, insulin injection can increase angiogenesis in mice.61 High insulin levels are common in cancerous tissue and in the plasma of cancer patients.62 In addition, the high insulin levels found in the early stages of non-insulin-dependent diabetes mellitus type II (NIDDM) have been implicated as a risk factor for a variety of cancers.63 Chapter 8 discusses natural compounds that can reduce lactic acid and insulin production.
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