Cancer cells are typically held to be rugged and hardy. They take over the body, resisting medical efforts to contain them, and ultimately kill the patient. A great deal of attention has been focused on the special abilities that allow malignant cells to grow, commandeer the body's resources, and acquire drug resistance. One of the exciting developments of the past two decades is the discovery that tumor cells profit from mutation and other types of genomic instability, enabling them to evolve readily. Malignant cells are adapted to their pathological condition, and their genomes bear hallmarks of response to selective pressures of their environment. The most common genetic changes in tumors are activating point mutations in oncogenes like K-ras, inactivating lesions in tumor suppressor genes such as P53, and various forms of aneuploidy, including loss of heterozygosity (LOH) and gene amplification. All tumors display at least a subset of these features. However, evolvability bears a cost. Unstable genomes may have a short-term evolutionary advantage. But nearly all mutagenic processes are random. Therefore, adaptive changes come from a large pool of stochastic alterations, most of which are neutral or deleterious to gene function. Gene mutations that individually produce negligible effects on tumor growth are degenerative, because they erode the information encoded in the cancer cell's genome. Relatively little effort has been expended to investigate, and possibly exploit, this flip side of evolutionary change: nonadaptive alterations. Here I explore the nonadaptive consequences of genome instability for cancer. I present a perspective that tumor cells, though they possess distinct strengths and exceptional abilities, are in some respects weak compared with normal cells. This frailty is rooted in fundamental principles of genetics and evolution and may lead to some new strategies for cancer therapy. Overlapping Gene Function and Genetic Streamlining Early evolutionists, including Darwin and Lamarck, appreciated that useless organs and structures disappear over-time. Sightless crustaceans and flightless birds were of great interest to Darwin in particular. Modern biologists have extended these observations to biochemical pathways and genes. In the absence of selective pressures that maintain gene function, coding sequences degenerate and are ultimately lost entirely. A good example are genomes of obligate parasites such as the intracellular bacterium Rickettsia. On average such parasites possess less than half the number of genes of free-living bacteria (see www.ncbi.nlm.nih.gov/COG). Parasites inhabit a relatively constant, nourishing environment compared with free-living species. Presumably, random mutation and deletion gradually obliterate the unnecessary genes that do not contribute to fitness. This evolutionary process has been called genetic streamlining. Perhaps the ultimate manifestation of streamlining is the mitochondrian, believed to be a distant relative of Rickettsia. Over the countless generations since its establishment as an endosymbiont, the mitochondrial genome has lost nearly all of its original coding capacity. Mitochondrial DNA encodes a handful of electron transport system components and little else. In this respect, it is a highly degenerate genome. At first glance, the observation that a large subset of Escherichia coli and Saccharomyces cerevisiae genes are nonessential appears to fly in the face of genetic streamlining (Ross-Macdonald et al., 1999 ; www.shigen.nig.ac.jp/ecoli/PEC). Exhaustive analysis of loss-of-function mutations reveals that individual disruptions in ∼80% of genes produce viable organisms. Experiments in worms, fruit flies, zebra fish, and mice suggest about the same level of functional overlap (Driever et al., 1996 ; Adams et al., 2000 ), and humans are probably similar. But most nonessential genes may prove helpful or vital under certain conditions that are atypical in the laboratory. For instance, one yeast gene, SAC1, is required for growth only below ∼17°C (Novick et al., 1989 ). It appears that SAC1 evolved to increase the temperature range over which yeast cells could grow, allowing the yeast to occupy more diverse ecological niches. In the wild, low temperatures might kill off yeast that lack SAC1 function, whereas SAC1 makes no difference to cells that grow in a normal laboratory setting. Therefore, nonessential genes may, in general, provide a buffer to various types of stress, including temperature, malnourishment, poisons, pathogens, and lack of water. Under stressful circumstances, these genes may enhance survival. Thus, they are maintained through intermittent selective pressures. An intracellular parasite such as Rickettsia does not need the same level of redundancy as a free-living organism. But, having dispensed with the extra apparatus, it is confined to its habitat and cannot survive without the host. It is hemmed in. Cancer cells are akin to parasites. They are linked less closely to human evolutionary history than the normal cells from which they originate. Normal cells, like free-living bacteria, must be prepared for the unpredictable assaults of the world. Malignant cells have a shorter-term evolutionary memory. Thus, we may expect them to accrue mutations in nonessential genes. What are the specific genetic origins of such degenerative changes and the possible consequences?
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Jun 30, 2024
Meng Xiaoyu 
Open Access