|
ScienceWeek
MEDICAL BIOLOGY: ON ABORTING EARLY CANCER
The following points are made by Ashok R. Venkitaraman (Nature 2005 434:829):
1) Why human cancer is not more frequent remains a mystery, given our trillions of susceptible cells, each with many genes subject to mutations that could ignite uncontrolled cell proliferation. One intuitive concept -- which has been in the spotlight for decades -- is that normal cells can somehow perceive and arrest aberrant cycles of cell division that are triggered by cancer-promoting (oncogenic) stimuli, such as the inappropriate activation of oncogenes. But how cells might do so remains elusive.
2) New work[1,2] supplies evidence that oncogene-driven cell-division cycles trigger DNA damage associated with DNA replication (the process that faithfully copies the genome in preparation for division). This DNA damage raises a barrier to sustained proliferation. From these findings, a fresh picture emerges, in which progression towards full-blown cancer requires the wayward cell to inactivate the mechanisms that monitor damage during DNA replication. This would help to explain the close link between genomic instability and cancer evolution, and extend our theoretical framework for understanding how cancers develop.
3) Early clues to the existence of mechanisms that prevent uncontrolled cell division came from the observation, more than 20 years ago, that viral oncogenes arrest the proliferation of normal cells in culture[3,4]. Later, the tumour-suppressor proteins p53 and ARF were found to be vital for constraining oncogene-driven proliferation[5]. Their activation was variously attributed to excessive stimulation to proliferate, oxidative stress, or the loss of appropriate signals from the tissue microenvironment -- all triggered by oncogenic stimuli. Activation of these tumour suppressors causes cells either to become dormant (senesce) or to commit suicide (by the process of "apoptosis"). But evidence that these constraints on proliferation operate during human cancer development has been hard to find.
4) Bartkova, Gorgoulis and their colleagues[1,2], propose from studies of human cancer samples that another constraint limits aberrant cell division. They provide evidence that the cellular response to DNA damage -- specifically, to double-strand breaks in DNA -- is activated in early lesions from lung or bladder tumours. This evidence includes the presence of active forms of ATM or Chk2, participants in the enzymatic cascade that responds to double-strand breaks. Notably, these markers are detected in precancerous lesions -- where there is evidence for oncogene-induced aberrant division, but not yet for the changes typical of full-blown cancers -- suggesting that the DNA-damage response (DDR) is activated at the earliest stages in carcinogenesis. Moreover, the markers are absent from normal proliferating epithelial cells, and from inflammatory lesions, indicating that they discriminate normal from aberrant cell cycles.
References (abridged):
1. Bartkova, J. et al. Nature 434, 864-870 (2005)
2. Gorgoulis, V. G. et al. Nature 434, 907-913 (2005)
3. Tarpley, W. G. & Temin, H. M. Mol. Cell. Biol. 4, 2653-2660 (1984)
4. Franza, B. R. Jr, Maruyama, K., Garrels, J. I. & Ruley, H. E. Cell 44, 409-418 (1986)
5. Kamijo, T. et al. Cell 91, 649-659 (1997)
Nature http://www.nature.com/nature
--------------------------------
Related Material:
CANCER BIOLOGY: ON HEAT SHOCK PROTEINS AND TUMOR CELLS
The following points are made by L. Neckers and Y-S. Lee (Nature 2003 425:357):
1) Targeting a specific protein or a single signalling pathway that is required for the survival of tumour cells but not normal cells would seem to be a promising anticancer strategy. Unfortunately, few such unique targets exist, and it is becoming clear that inhibiting a single pathway might not be enough to tackle cancers that result from several genetic abnormalities. Instead, attention is turning to proteins such as heat-shock protein 90 (Hsp90) that regulate many signalling pathways in cancer cells.
2) In 1962, while looking at the salivary-gland chromosomes of the fruitfly Drosophila, Ferruccio Ritossa noticed that certain regions of the chromosomes puffed out in response to a sudden increase in temperature(3). The gene products encoded on these chromosome puffs were later isolated and termed "heat-shock proteins", or Hsps. The production of Hsps accelerates in response to temperature stress, but these proteins are abundant even in unstressed cells. Hsps have been more accurately called "molecular chaperones", because they protect other cellular proteins from becoming misshapen as a result of high temperature or other environmental insults, and certain Hsps also enable newly synthesized proteins to attain the correct conformation.
3) One particular chaperone, Hsp90, has been implicated in the survival of cancer cells(4). Hsp90 regulates the function and stability of many key signalling proteins that help cancer cells to escape the inherent toxicity of their environment, to evade the effects of chemotherapy, and to protect themselves from the results of their own genetic instability. So inhibitors of Hsp90 could mount a multi-pronged assault on cancer cells that, if not lethal itself, might leave them sufficiently debilitated to allow control by chemotherapy or radiotherapy.
4) One feature of Hsp90 has concerned investigators -- although cancer cells can produce high levels of the protein(1), it is also abundant in normal cells. This might mean that drugs targeting Hsp90 prove to be unacceptably toxic. Surprisingly, however, the first Hsp90 inhibitor to be tested in clinical trials, the drug 17-AAG, has been well tolerated by patients. Kamal et al(2) have provided data that begin to explain this apparent paradox. These authors have reported that Hsp90 found in tumour cells has a much higher affinity for 17-AAG than does Hsp90 from normal cells.(5)
References (abridged):
1. Ferrarini, M., Heltai, S., Zocchi, M. R. & Rugarli, C. Int. J. Cancer 51, 613-619 (1992)
2. Kamal, A. et al. Nature 425, 407-410 (2003)
3. Ritossa, F. Cell Stress Chaperones 1, 97-98 (1996)
4. Maloney, A. & Workman, P. Expert Opin. Biol. Ther. 2, 3-24 (2002)
5. Chiosis, G. et al. Chem. Biol. 8, 289-299 (2001)
Nature http://www.nature.com/nature
--------------------------------
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
ScienceWeek http://scienceweek.com
|