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ScienceWeek
CELL BIOLOGY: ON CELLULAR INSTABILITY AND CANCER
The following points are made by David A. Sinclair (Science 2003 301:1859):
1) If there's one thing we've learned from the last 50 years of research on bakers' yeast, it is not to underestimate how much this tiny fungus can tell us. We now know that yeast provide key insights into such complex human disorders as variant Creutzfeld-Jacob disease, Parkinson's disease, and cancer. Even so, it is not hard to imagine the skepticism facing Mortimer and Johnston in the 1950s as they tried to convince the scientific community that this unicellular organism might be useful for understanding human aging (1). Less skepticism should greet the recent report by McMurray and Gottschling (2). These investigators demonstrate that yeast cell aging is accompanied by increased genetic instability, a hallmark of cancer. This finding might help researchers to understand the link between cancer and old age in humans.
2) In the final decades of life, one's chance of developing cancer rises exponentially (3). In fact, at age 70 the risk of developing cancer is more than 10 times the risk three decades earlier. It is tempting to think that cancer occurs later in life because of a steady accumulation of mutations. Certainly, cells isolated from the elderly have more chromosomal abnormalities than cells from the young. But the story is not so simple because rates of spontaneous mutation are too low to account for the extensive genome rearrangements found in tumors (3). Experiments in mice have confirmed the suspicion that mutation rates increase with age (4).
3) The molecular basis of this increase in mutation rate is still under debate. The most popular explanation is the "mutator phenotype", which is thought to arise when genes required for preventing or repairing DNA damage are mutated, leading to runaway DNA instability (5). Although this is probably a major part of the story, some researchers argue that it fails to explain fully the gross chromosomal abnormalities and tissue distribution of most adult cancers (3). Experiments investigating a decrease in DNA-repair capacity in old animals have yielded equivocal results because of technical difficulties. Other factors thought to increase the rate of mutation over time include an accumulation of damaged proteins in cells, altered gene regulation, and changes in the tissue surrounding cells (3, 4).
4) Biological switches like the one that triggers DNA instability often indicate one of two mechanisms. Either there is an underlying process that crosses a critical threshold (for example, the shortening of telomeric ends of human chromosomes, leading to sudden growth arrest), or there is a positive-feedback loop that amplifies small changes (for example, the mutator phenotype). In the case of yeast, telomere loss and the mutator phenotype are unlikely to be root causes because yeast telomeres do not shorten with age and the hyperinstability state is not stably inherited.
References (abridged):
1. R. K. Mortimer, J. R. Johnston, Nature 183, 1751 (1959)
2. M. A. McMurray, D. E. Gottschling, Science 301, 1908 (2003)
3. R. A. DePinho, Nature 408, 248 (2000)
4. P. Hasty et al., Science 299, 1355 (2003)
5. L. A. Loeb et al., Proc. Natl. Acad. Sci. U.S.A. 100, 776 (2003)
Science http://www.sciencemag.org
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CELLULAR SENESCENCE, CANCER, AND AGING
The following points are made by A. Krtolica et al (Proc. Nat. Acad. Sci. 2001 98:12072):
1) Multicellular organisms have evolved mechanisms to prevent the unregulated growth and malignant transformation of proliferating cells. One such mechanism is "cellular senescence", which arrests proliferation (essentially irreversibly) in response to potentially oncogenic events. Cellular senescence appears to be a major barrier that cells must overcome to progress to full-blown malignancy.
2) Cellular senescence was first described as a process that limits the proliferation of cultured human fibroblasts ("replicative senescence"). Proliferating cells progressively lose telomere DNA, and short telomeres, which are potentially oncogenic, elicit a senescence response. In addition, DNA damage, expression of oncogenes, and supraphysiological mitogenic signals also cause cellular senescence. Cellular senescence is controlled by tumor suppressor genes and seems to involve a checkpoint that prevents the growth of cells at risk for neoplastic transformation. In this regard, cellular senescence is similar to apoptosis. However, whereas apoptosis kills and eliminates damaged or potential cancer cells, cellular senescence involves a stable arrest of growth.
3) Cellular senescence is also thought to contribute to aging, although how it does so is poorly understood. In addition to arresting growth, senescent cells show changes in function. Because senescent cells accumulate with age, they may contribute to age-related declines in tissue function. If so, cellular senescence may be an example of "antagonistic pleiotropy". Aging phenotypes are thought to result from the declining force of natural selection with age. Consequently, traits selected to maintain early life fitness can have unselected deleterious effects late in life, a phenomenon termed "antagonistic pleiotropy". The senescence-induced growth arrest may suppress the development of cancer in young organisms. The functional changes, by contrast, may be unselected consequences of the growth arrest and thus compromise tissue function as senescent cells accumulate.
Proc. Nat. Acad. Sci. http://www.pnas.org
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ON MUTATIONS AND THE ODDS OF DEVELOPING CANCER
The following points are made by K.C. Quon and A. Berns (Genes & Development 2001 15:2917):
1) During the course of cancer development, a normal cell progresses toward malignancy by acquiring a specific series of mutations. These include mutations that activate otherwise innocuous proto-oncogenes, and other mutations that inactivate recessive tumor suppressor genes. By acquiring these mutations, a cell progressively alters its phenotype, and thereby eludes the various controls that normally prevent malignant growth in an organism.
2) Based on epidemiological data, and consistent with in-vitro experimental data, it is estimated that between 4 and 8 rate-limiting mutations occur during the development of most human cancers. But this raises a conundrum. The incidence of cancer should be proportional to the number of rate-limiting events necessary for tumorigenesis, the frequency of these events, and the size of the target-cell population for these events. Therefore, given that somatic mutations arise at a frequency of less than 6 x 10^(-6) per locus, an overly simplistic calculation would suggest that even a tumor requiring only 4 mutations would only arise at a frequency of approximately 1 in 10^(-21) cells, a vanishingly low frequency even in an organism composed of approximately 10^(14) cells, as humans are. Why, then, are the odds of developing cancer during one's lifetime approximately 1 in 3, and what does this tell us about the mechanisms that operate during tumorigenesis?
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MEDICAL BIOLOGY: ON MUTATIONS AND CANCER
The term "cancer", which means "crab" in Latin, was introduced by Hippocrates (460-370 B.C.) to describe diseases in which tissues grow and spread unrestrained throughout the body, eventually causing death. Cancers can originate in almost any tissue of the body, including nerve, muscle, blood, connective tissue, etc. Depending on the cell type involved, cancers are grouped into 3 main categories:
a) carcinomas, the most common types of cancer, arise from the *epithelial cells that cover external and internal body surfaces, with lung, breast, and colon cancers the most frequent cancers of this type;
b) sarcomas originate in supporting tissues of *mesodermal origin, such as bone, cartilage, fat, connective tissue, and muscle;
c) lymphomas and leukemias arise from cells of blood and *lymphatic origin, the term "leukemia" used when such cancer cells circulate in large numbers in the bloodstream rather than growing mainly as solid masses of tissue.
Cancer is a disease of the genomic apparatus of the cell, in particular of the growth-regulation apparatus, and considering the vast number of activities that must be coordinated and regulated by the genomic apparatus during the lifetime of each cell, it is not surprising that malfunctions arise. In general, cancer is the most prominent of the many diseases arising from aberrations in cell function, with more than 25 percent of people in the US now expected to develop cancer in their lifetime.
The following points are made by C.R. Boland and L. Ricciardiello (Proc. Nat. Acad. Sci. 1999 96:14675):
1) It has been known during most of this century that cancer is often associated with visible derangements in the nucleus of the cell. The cells of solid tumors commonly exhibit chromosome duplications, deletions, and rearrangements, but before the organization of the human cell nucleus was understood, these chromosome aberrations were difficult to categorize and were of little help in understanding the biological basis of cancer.
2) Within a few decades after the discovery of the structure of DNA, cancer-related genes (oncogenes) were isolated, and these were frequently found to be mutant versions of normal cellular genes in which an activating *point mutation or an aberrant *genetic amplification process resulted in a gain of function for that gene product, and a growth advantage for that aberrant cell. But as more and more oncogenes were identified, researchers realized that tumor growth was also associated with loss of function of certain "tumor suppressor genes". These tumor suppressor genes were often inactivated by their deletion from the nucleus, and the phrase "loss of heterozygosity" (LOH) was applied to genetic loci in which both *alleles were present in normal tissues, but one copy was lost in tumor tissue. In many instances, tumor suppressor genes were first identified by virtue of germ-line mutations that were present at a high frequency in a rare tumor, e.g., retinoblastoma, but it soon became apparent to researchers that many tumor suppressor genes were associated with a variety of different tumors, many of which were not rare at all.
3) There are no oncogenes or tumor suppressor genes that are activated or deleted in and from all cancers. Even tumors of a single organ rarely have uniform genetic alterations, although tumor types from one specific organ do have a tendency to share mutations in certain genes or in different genes within a single growth-regulatory pathway.
4) At the present time, it is not known how many critical mutations are required to convert a single normal cell into a malignant cell. Human cells have been difficult to transform in vitro, and the basis for this difficulty is not yet understood. The simplest model of tumorigenesis is as follows:
a) Human cells experience a certain number of mutations each day as a result of exposure to carcinogens or as a result of ordinary biological degradation, both of which can alter nucleotide sequences. Errors will also occur during new DNA synthesis and in the process of disentangling the chromosomes during *mitosis. Most of these errors would be either irrelevant to the life of the cell or deleterious because of the loss of a gene critical for cellular viability.
b) By chance, an occasional genomic mutation might create a growth advantage for a cell, permitting increased net cellular growth, because of increased proliferation or a reduction in programmed cell death (reduction in apoptosis), with a resulting *clonal expansion of that lineage. A second genomic alteration might then occur within this expanding clone, again by chance, providing an additional growth advantage for that cell and its progeny. By virtue of these two advantages, the cells of this clone would eventually overgrow neighboring cells, creating yet another expanding clone. This scenario would repeat as a consequence of each new mutation that provided an additional growth advantage. The accumulation of these growth promoting mutations is the basis of the current view of "multistep carcinogenesis".
Proc. Nat. Acad. Sci. http://www.pnas.org
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Notes:
epithelial cells: In animals, "epithelial cells" compose the cell layers that form the interface between a tissue and the external environment, for example, the cells of the skin, the lining of the intestinal tract, and the lung airway passages.
mesodermal: In the embryos of higher animals, there occurs the transformation of a single-layer "blastula" into a 3-layered "gastrula" consisting of ectoderm (outermost layer), mesoderm (middle layer), and endoderm (innermost layer) surrounding a cavity with one opening. The 3 layers are called the "germ layer", and these layers, via further cell differentiation and proliferation, determine the development of all the major body systems and organs.
lymphatic: The lymphatic system is a complex network for the distribution of lymph fluid (which is similar to blood plasma --blood without red cells). Lymph is collected by drainage from the tissues throughout the body, flows in the lymphatic vessels through the lymph nodes, and is eventually added to the venous blood circulation.
point mutation: A minor changes in the genome; a single base-pair substitution.
genetic amplification process: The production, by various means, of additional copies of a stretch of genomic DNA.
alleles: One of two or more forms of a given gene that control a particular characteristic, with the alternative forms occupying corresponding loci on homologous chromosomes.
mitosis: Programmed division of the nucleus during cell replication.
clonal expansion: This refers to the expansion of a population of cells all derived from repeated replications of progeny of a single cell.
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