|
ScienceWeek
CELL BIOLOGY: CANCER AND CELL SENESCENCE
The following points are made by Judith Campisi (Science 2005 309:886):
1) Cancer is a potentially lethal disease in mammals and other complex organisms with renewable tissues. Tumors originate from cells that are actively dividing. Such cells are at much greater risk than postmitotic (nondividing) cells for acquiring mutations, a major driving force for cancer development. Cell division is extensive during development and continues during maturation and adulthood. Yet cancer is typically an age-related disease, developing primarily in older adults.
2) Why, then, don't mammals develop cancer earlier and more frequently? The answer lies in the tumor suppressor mechanisms that evolved to protect complex organisms from malignant tumors [1]. Some of these mechanisms protect the genome from damage or mutation. Others eliminate or arrest the proliferation of potential cancer cells by processes called apoptosis or cellular senescence. There is ample evidence that apoptosis, or cellular suicide, suppresses tumorigenesis in vivo. However, evidence that cellular senescence, the permanent arrest of cell division, suppresses cancer has been largely circumstantial.
3) Four recent reports dispel doubts that cellular senescence is an important anticancer defense in vivo [2-5]. Furthermore, they show that activated oncogenes -- mutant genes that have the potential to transform normal cells into a cancerous state --induce cellular senescence in vivo, a phenomenon previously seen only in cell culture. The findings support the idea that the senescence response is a failsafe mechanism that prevents the proliferation of cells at risk for neoplastic transformation.
4) Cellular senescence was first identified as a process that limits the ability of normal human cells to proliferate in culture. We now know that this limit is caused by at least two intertwined mechanisms [1]. First, the erosion of telomeres, regions at the ends of chromosomes that stabilize DNA, elicits a DNA damage response that causes the cell division cycle to arrest. This response requires the activity of a signaling pathway that includes the tumor suppressor protein p53. Second, cumulative stress of an unknown nature induces expression of the p16 tumor suppressor. This activates a signaling pathway that involves another tumor suppressor protein, pRB, which in turn halts cell cycle progression. We also now know that many stimuli induce a senescence response. These include nontelomeric DNA damage that engages the p53 pathway and certain oncogenes that trigger the p16-pRB pathway.
References (abridged):
1. J. Campisi, Cell 120, 513 (2005)
2. M. Collado et al., Nature 436, 642 (2005)
3. Z. Chen et al., Nature 436, 725 (2005)
4. C. Michaloglou et al., Nature 436, 720 (2005)
5. M. Braig et al., Nature 436, 660 (2005)
Science http://www.sciencemag.org
--------------------------------
Related Material:
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
--------------------------------
Related Material:
AGING, LIFESPAN, AND SENESCENCE
Notes by ScienceWeek:
Our knowledge of the basis of senescence of cells, tissues, and organisms (including humans) has entered a new phase in recent decades because of the new vistas opened by molecular biology. Model systems have started to provide insights, and one important approach has been the identification of genes that determine the lifespan of an organism. The very existence of genes that when mutated can extend lifespan suggests to many researchers that one or a few processes may be critical in aging, and that a slowing of these processes may slow aging itself.
The following points are made by L. Guarente et al (Proc. Nat. Acad. Sci. 1998 95:11034):
1) In the budding yeast Saccharomyces cerevisiae, aging results from the asymmetry of cell division, which produces a large mother cell and a small daughter cell arising from the bud. Much of the macromolecular composition of the daughter cell is newly synthesized, whereas the composition of the mother cell grows older with each cell division. It has been shown that mother cells of this yeast species divide a relatively fixed number of times, and exhibit a slowing of the cell cycle, cell enlargement, and sterility. Analysis of *ribosomal DNA in old cells reveals an accumulation of *extrachromosomal ribosomal DNA of discrete sizes, apparently representing a cumulative fragmentation of chromosomal ribosomal DNA. The authors suggest it will be of great interest to assess the generality of this process as an aging mechanism.
2) In Caenorhabditis elegans, the *neurosecretory system regulates whether animals enter the reproductive life cycle or arrest development at a primitive *diapause stage. Developmental arrest is apparently induced by a *pheromone and involves behavioral and morphological changes in many tissues of the animal, with the lifespan becoming 4 to 8 times longer than that of the normal 3-week lifespan of fully developed animals. Declines in pheromone concentration induce recovery to reproductive adults with normal metabolism and lifespan. Genes that regulate the function of the C. elegans diapause and the neuroendocrine aging pathway have been identified, and at least one of these genes codes for an *insulin-like receptor apparently involved in metabolism. The authors suggest that if the association of longevity and diapause is general, it is possible that *polymorphisms in the human insulin receptor-signaling pathway genes and related gene *homologues may underlie genetic variation in human longevity.
3) In plants, there is a large range of lifespans in the various plant kingdoms. Certain tree species live for well over a century, whereas other plants complete their life cycle in a few weeks. The "yellowing" of leaves is often referred to in the plant literature as leaf senescence or the "senescence syndrome" -- referring to the process by which nutrients are mobilized from the dying leaf to other parts of the plant to support their growth. The senescence syndrome is characterized by distinct cellular and molecular changes, with the chloroplast the first part of the cell to undergo disassembly (producing the "yellowing"). In many plant species, certain hormones can either enhance or delay senescence. Although the genes that are expressed during the plant senescence syndrome (as well as ways to manipulate such senescence) have been identified, much remains to be done to understand the molecular basis of aging in plants. For example, nothing is known about the signal transduction pathways that lead to altered gene expression during senescence, or how plant hormones such as *cytokinin influence senescence. But there are now many tools to explore this process. The authors conclude: "It remains to be seen whether common mechanisms link the aging process in diverse organisms."
Proc. Nat. Acad. Sci. http://www.pnas.org
--------------------------------
Notes by ScienceWeek:
ribosomal DNA: A ribosome (not to be confused with riboZYME) is a small particle, a complex of various ribonucleic acid component subunits and proteins that functions as the site of protein synthesis. The term "ribosomal DNA" refers to the gene or genes that code for the RNA in ribosomes. In other words, the term "ribosomal DNA" does not refer to any DNA in ribosomes (there is no DNA in ribosomes).
extrachromosomal: In general, this refers to anything outside of chromosomes, and in this case to DNA fragments unincorporated into chromosomal DNA.
neurosecretory system: In general, all neural systems contain both neurons that themselves secrete chemical messengers and neurons that signal special secretory cells to secrete chemical messengers. A neurosecretory pathway is a delineated signaling system that involves such a resultant secretion.
diapause: In general, this refers to any programmed period of suspended development in invertebrates.
pheromone: In general, a chemical substance which, when released into an animal's surroundings, influences the development or behavior of other individuals of the same species.
insulin: A protein hormone that promotes uptake by body cells of free glucose and/or amino acids, depending on target cell type.
polymorphisms: A genetic polymorphism is a naturally occurring variation in the normal nucleotide sequence of the genome within individuals in a population. Variations are denoted as polymorphisms only if they cannot be accounted for by recurrent mutation and occur with a frequency of at least about 1 percent.
homologues: In general, the term "homologous" means having the same structure. But the term has special uses in genetics and evolution biology.
cytokinin: A group of plant growth substances. They are chemically identified as derivatives of the purine base adenine. They stimulate cell division and determine the course of differentiation. They work synergistically with other plant hormones called "auxins".
ScienceWeek http://scienceweek.com
|