The Role of Diet in Cancer Prevention and Chemotherapy Efficacy
Annual Review of Nutrition Vol. 40:273-297 (Volume publication date September 2020) Steven D. Mittelman
Cancer Metabolism
To understand how diet can affect cancer treatment and prognosis, first understanding some of the unique aspects of cancer metabolism is important. In 1925, Otto Warburg (178) observed that cancerous tumors take up more glucose than other tissues and metabolize it without relying on oxidative phosphorylation, termed the Warburg effect. Although aerobic glycolysis does not provide as much ATP as oxidative phosphorylation, it is believed to better support cancer cell metabolism for a number of reasons.
First, tumors can grow rapidly, sometimes outpacing their blood supply, leading to a relatively hypoxic environment.
Second, the metabolic machinery needed to perform glycolysis is much less extensive than oxidative phosphorylation, being independent of mitochondria.
Third, carbon atoms from glucose can be used to synthesize amino acids, nucleic acids, and other metabolic intermediates in a process of anapleurosis.
Our understanding of the Warburg effect has significantly evolved over the last century. Many cancer cells have been shown to have high respiratory rates, arguing against their reliance on aerobic metabolism (183). The Lisanti group (129) demonstrated that cancer cells induce stromal cells in their microenvironment to shift to aerobic metabolism, inducing them to release lactate and pyruvate, which are used by the cancer cells for oxidative metabolism. This reverse Warburg effect could result in overall increased glucose uptake and aerobic metabolism in a tumor, mostly due to the stromal cells.
In addition to increased glucose utilization, cancer cells often exhibit a dependence on free fatty acids (FFA). FFA provide the acyl chains of phospholipids, the primary component of cell and organelle lipid bilayer membranes. As a dividing cell duplicates its plasma membranes with every division, a large investment in FFA is required for a cancer cell to proliferate. FFA synthesis is energetically expensive, utilizing 14 NADPH and 7 ATP to synthesize 1 molecule of palmitate. Increased de novo FFA synthesis and exogenous FFA uptake have both been associated with cancer aggressiveness and survival (84, 118, 123, 146).
Conversely, FFA can provide a large amount of energy and are often abundant in tumor microenvironments, particularly those in proximity to adipocytes. Thus, cancer cells in adipocyte-rich environments have been shown to rely heavily on FFA oxidation (119, 166). Adipocytes can also be a source of amino acids. We have shown that adipocyte release of glutamine and asparagine can particularly interfere with ALL treatment with l-asparaginase (49). Glutamine is also extremely important for other cancer cells, where it contributes to the synthesis of nucleotides, amino acids, and tricarboxylic acid (TCA) cycle intermediates (194). Cancer cells use BCAA for protein synthesis and energy metabolism and often overexpress branched chain aminotransferase enzymes needed for BCAA metabolism (5). Thus, cancer cells exhibit unique metabolic needs that may be met in obese, adipose-rich environments
