Membrane Cholesterol, Tumorigenesis, and the Biochemical Phenotype of Neoplasia

Abstract

The loss of sensitivity to feedback control of lipid synthesis in tumors is especially manifest with regard to cholesterol biosynthesis. This phenomenon has been documented in a wide variety of cells soon after exposure to a carcinogenic insult, and results in the progressive enrichment of diverse cellular membranes with cholesterol during the tumorigenic process. By the time a tumor is identifiable histopathologically, such membrane enrichment with cholesterol can lead to significant changes in the activities of membrane-affiliated enzymes. This, in turn, can effect a wide variety of altered metabolic patterns within the afflicted cell, thereby promoting altered cell function. Some of the altered metabolic patterns in tumors that are consistent with events leading to cholesterol-enriched membranes include increased glutamate and glutamine oxidation in support of tumor bioenergetics; reduced rates of glucose oxidation via respiration together with enhanced levels of aerobic glycolysis; diminished urea cycle activity in hepatomas; increased polyamine accumulation; shifts in the pattern of reducing equivalent activities in mitochondria; and in the tumor-burdened host, the exfoliation of cholesterol-rich microvesicles from the tumor cell plasma membrane, which decoy the host's immune surveillance away from the tumor itself. The obligatory presence of cholesterol in cell membranes thus acquires a greater significance, not only to normal cell dynamics, but to metabolic phenomena that are characteristic of the neoplastic phenotype.