Cancer Today Origins, Prevention, and Treatment (1984) / Chapter Skim
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Biology of Cancer
Biology of Cancer
Pages 17-48
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From page 17... ...
When those controls fail, cancer may arise. The carefully ordered pattern of cell growth, division, and differentiation is lost.
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From page 18... ...
Molecular biologists have found in the chromosomes of both animal and human cells a set of genes that can trigger cancer's unbridled growth. These oncogenes, as they are called, are normal genes that have gone awry.
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From page 19... ...
When the host cell DNA then replicates and undergoes transcription into RNA, it expresses the inserted viral genes along with its own genes. As a result, the host animal cell begins to make the proteins coded for by the viral genes, becoming, in essence, a virus factory.
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From page 20... ...
All of these genes are able to transform cells in culture, that is, to trigger cancerous growth. Oncogenes, like other genes, direct the synthesis of a specific protein, and it is these oncogene proteins that must be the actual culprits.
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From page 21... ...
This finding added an unexpected twist to the oncogene hypothesis: it turns out that retroviral oncogenes are actually wayward cellular genes, picked up by the virus during its evolution. Since this initial discovery by Bishop and Varmus, close relatives of all the retroviral oncogenes have been found in normal cells.
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From page 22... ...
to a piece of viral DNA -- a piece that dictates brisk expression of nearby genes -- the proto-oncogene was able to convert normal cells to cancer cells. It is not clear how oncogenes disrupt normal cellular behavior.
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From page 23... ...
In another human cancer, Burkitt lymphoma, the myc oncogene appears to be activated when a chromosome breaks and the gene is plucked from its usual site and inserted into a more active site on another chromosome. These modes of activation will be described in detail in the following two chapters.
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From page 24... ...
In 1977, he and Joan S Brugge reported the isolation of the protein encoded by the src gene of the Rous sarcoma virus, the first retroviral oncogene detected.
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From page 25... ...
Soon after, it was found that the src protein works in an unconventional way. Most protein kinases attach proteins to one of two amino acids, threonine or serine.
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From page 26... ...
While the activation of an oncogene may be a necessary part of the process, it is not sufficient in and of itself to induce cancerous growth; From the start, molecular biologists have suspected that several oncogenes may cooperate in transforming cells. That hunch has been borne out in recent experiments.
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From page 27... ...
Investigators speculate that once the molecular events that start the disease are understood, it may be possible to interrupt them. It may, perhaps, be possible to develop biological agents specifically targeted to kill cancer cells, or to somehow disrupt the action of an oncogene protein.
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From page 29... ...
Yet once they are captured by a virus and then reintroduced into an animal cell, they can trigger cancerous growth. Since this discovery, one of the most intriguing questions in cancer research has been what, if anything, these oncogenes can This chapter is based on the presentation given by Mariano Barbacid, National Cancer Institute-Frederick Cancer Research Facility, at the 1983 annual meeting of the Institute of Medicine.
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From page 30... ...
The next task was to isolate these human oncogenes and clone additional copies for study. Weinberg, Cooper, and scientists in two other laboratories, those of Mariano Barbacid at the National Cancer Institute and Michael Wigler of Cold Spring Harbor, began trying to fish out the oncogene activated in human bladder cancer.
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From page 31... ...
The ras genes from the rat sarcoma viruses have innocuous counterparts in the rat genome from which they are derived. Similarly, investigators found that the human oncogenes also have related proto-oncogenes in normal cells.
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From page 32... ...
The other possibility is that some human cancers arise by mechanisms that do not involve oncogenes. Most of the human oncogenes belong to the ras family of genes.
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From page 33... ...
In 1982, Weinberg at MIT, Barbacid at the National Cancer Institute, and Wigler at Cold Spring Harbor found the answer for the human bladder oncogene. In repeated tests, the investigators had been unable to detect a structural difference between this oncogene and its normal counterpart, the proto-oncogene.
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From page 34... ...
: -.-. : •': •': -1 V///////////////////777A V/////////////////A I LIGATE BECOMES INACTIVE '/////////////////A BECOMES ACTIVE BECOMES INACTIVE V////////, y////////////////A BECOMES ACTIVE 350-BASE SEGMENT -- GLYCINE V//////////////77/ BECOMES INACTIVE BECOMES ACTIVE VALINE FIGURE 3-1 Point mutation in the EJ bladder carcinoma cell line.
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From page 35... ...
Although it is tempting to suppose that the altered oncogene initiates the tumor, it could nonetheless be a consequence, not a cause. The point mutation in the human bladder oncogene could be a product of the genetic disarray of a cancer cell.
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From page 36... ...
By using induced tumors in rats to study chemical carcinogenesis, the NCI researchers hope to learn the exact role of oncogenes in human cancer. So far, their work has provided another piece of evidence, albeit indirect, that some human cancers arise when a chemical or other environmental insult activates an oncogene, creating a slightly altered protein, which then disrupts normal cell behavior.
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From page 37... ...
Additional mechanisms of activation probably remain to be discovered. In short, there seem to be many ways to convert a normal gene to a cancer gene.
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From page 39... ...
Using this technique, Yunis examined the malignant cells in This chapter is based on the presentation given by Philip Leder, Harvard University School of Medicine, at the 1983 annual meeting of the Institute of Med39
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From page 40... ...
As geneticists were cataloging the chromosome defects in cancer cells, molecular biologists were pursuing specific cancercausing genes, the oncogenes. Part of the normal genetic complement of all cells, these oncogenes can be stirred to malignant action when they are disturbed in some way, perhaps by the action of a mutagen or a virus.
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From page 41... ...
Suspicion that the normal process might somehow be involved in carcinogenesis increased when various investigators began mapping the antibody genes to their respective chromosomes. They found that the antibody genes reside on three chromosomes, numbers 14, 2, and 22 -- precisely the same chromosomes that exchange pieces with chromosome 8 in Burkitt lymphoma.
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From page 42... ...
Hayward of the Memorial Sloan-Kettering Cancer Center had found that this gene is activated in other forms of lymphoma. Hayward, Gallo, and Croce found that indeed, the myc gene is located on chromosome 8, on the segment that is swapped in Burkitt lymphoma.
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From page 43... ...
The translocation could disturb the regulation of the gene, turning it on at the wrong time or in the wrong amount, as has been found for many retroviral oncogenes. Alternately, the reshuffling could mutate the coding region of the gene, resulting in the production of a slightly different protein.
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From page 44... ...
This strongly suggests that their protein products must also be identical. If so, then the transforming gene and the normal gene must differ chiefly in their expression, at least in the particular line of Burkitt cells that the Harvard team examined.
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From page 45... ...
In comparing expression of the two versions of the myc gene, the Harvard researchers have detected subtle changes in expression, specifically, in the way in which the gene is transcribed. They have also noted another intriguing phenomenon: in Burkitt cells, the translocated gene is active -- that is, it is producing protein -- while the normal gene is silent.
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From page 46... ...
The translocations in Burkitt cells suggest that some cancers arise when this normal process goes awry -- when genes end up in the wrong place. It is intriguing to view Burkitt lymphoma as a perversion of the normal process of antibody production.
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From page 47... ...
BROKEN CHROMOSOMES chromosomes begin exhanging bits with chromosome 8, which bears the myc oncogene. Chromosomal abnormalities are not restricted to Burkitt cells; as mentioned earlier, some type of chromosome defect occurs in most cancer cells.
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