Press-pulse: a novel therapeutic strategy for the metabolic management of cancer 癌症代謝管理的新治療策略

Human evolution and adaptive versatility

Rick Potts, a paleoanthropologist at the Smithsonian Institution, suggested that the evolutionary success of our species has been due largely to the germline inheritance of traits that bestowed adaptive versatility [151, 152, 153]. Adaptability was defined in terms of, 1) the ability of an organism to persist through major environmental shifts, 2) to spread to new habitats, and 3) to respond in novel ways to its surroundings [153]. These characteristics were honed over millions of years and enabled humans to adapt rapidly to abrupt changes in the physical environment including changes in moisture, temperature, food resources etc. Adaptability to abrupt environmental change is a property of the genome, which was selected for in order to ensure survival under environmental extremes [65, 154].

Potts’ hypothesis is an extension of Darwin’s original theory (Chapter IV, Natural Selection) and can be applied to the individual cells of the organism, which exist as an integrated society of cells [65,154]. The success in dealing with environmental stress and disease is therefore dependent on the integrated action of all cells in the organism. Further, this integrated action depends on the flexibility of each cell’s genome, which responds to both internal and external signals according to the needs of the organism. More specifically, only those cells possessing flexibility in nutrient utilization will be able to survive under nutrient stress. Environmental forcing has therefore selected those genomes most capable of adapting to change in order to maintain metabolic homeostasis [65, 152, 153, 155]. This concept was first discussed in relationship to the management of brain cancer [65].

The widely held notion that tumor cells have a growth advantage and are more fit than normal cells are in contrast to Darwin’s theory of evolution and also to Potts’ theory of adaptive versatility [65,153, 154]. It is difficult to conceive how a random accumulation of somatic mutations could enhance the adaptability and fitness of cancer cells. It is important to recognize that mutations in p53, K-Ras, and Raf impact negatively on mitochondrial energy efficiency thus making cells with these mutations less metabolically flexible than normal cells [28, 44, 53, 135, 156, 157, 158, 159]. Indeed activating mutations in K-Ras target mitochondria, thus enhancing glycolysis [53, 160]. Enhanced glycolysis will make tumor cells appear more metabolically fit than normal cells in hypoxic environments [161,162]. Most normal cells, however, cannot grow in hypoxia and will often die in hypoxic environments due to respiratory failure. Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment. Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function [31,32, 162, 163]. The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs [163]. Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS [164]. As long as the tumor cells have access to the metabolic fuels needed for glycolysis and TCA cycle substrate level phosphorylation (glucose and glutamine, respectively) they will give the appearance of having a growth advantage over most normal cells [2]. According to Darwin and Potts, mutations that bestow a selective advantage are those that will enhance survival under environmental stress. If the multiple pathogenic point mutations, chromosomal rearrangements, and mitochondrial abnormalities confer a fitness or survival advantage to tumor cells, then survival under environmental stress and nutrient deprivation should be better in tumor cells than in normal cells [165]. This is not what actually happens, however, when the hypothesis is tested.

For example, when mice or people with tumors are placed under energy stress using dietary energy reduction (glucose restriction), many tumor cells die while normal cells survive. Indeed, the health and vitality of the normal cells improves with time under dietary energy reduction while hyper-glycolytic tumor cells undergo energetic crisis triggering apoptotic death [166, 167]. Support for this contention comes from studies of treating brain tumors with dietary energy stress [114, 168, 169,170, 171, 172, 173, 174]. It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting. Mitochondrial oxidative phosphorylation is less robust in tumor cells than in normal cells while glucose utilization through lactic acid fermentation is greater in tumor cells than in normal cells. Targeting glucose availability will therefore cause greater death in the tumor cells than in the normal cells. Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy [145]. Consequently, glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism [160, 163].

It is also possible that therapeutic energy stress could restore the microenvironment thus reversing abnormal energy metabolism and growth behavior in tumor cells not containing genetic mutations [19, 175]. In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation. Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells. These cells are often those that eventually become heavily dependent on fermentation for energy.

The greater adaptability of normal cells than tumor cells to energy stress is predicted based on the theories of Darwin and Potts [154]. Metabolic flexibility allows the organism to respond in a coordinated way to environmental stress and limited substrate availability. Energy stress will force all normal cells to work together for the survival of the organism [154]. Pathogenic mutations and genomic instability will reduce adaptability and metabolic flexibility under energy stress. The greater the genomic instability in tumor cells, the less will be their adaptability to stress. This concept is similar to that of Nowell’s except in viewing genomic instability as a liability rather than as an advantage to progression [154, 176]. Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine) [94]. With few exceptions, most normal cells shift energy metabolism from glucose to ketone bodies and fats when placed under energy stress from glucose deprivation, insulin deficiency, and prolonged fasting. This shift is the result of adaptive versatility and genomic stability, which is lacking in the tumor cells but is prominent in cells and tissues with robust mitochondrial function.