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7.3Factors of Carcinogesis, Oncogenes, and Tumor Suppressor Genes

Fig. 7-3. Factors Inducing Carcinogenesis

In the previous section, we touched upon the outline of what sort of changes in normal cells cause cellular carcinogenesis. Then, what brings forth such changes? You may have heard the word "carcinogenicity" in the context of environmental and food safety. This section explicates the mechanism of such "carcinogenicity."
At the beginning of this chapter, we mentioned that deaths from cancer are steadily increasing. That said, cancer itself is not a recently emerged disease; it has been in existence from antiquity, for cancer lesions have been discovered in Egyptian mummies as well. At the turn of the 18th century, an epidemiological discovery was made in Britain regarding the detection of cancer. The frequent incidence of scrotum cancer among chimney cleaners led to a suspicion that chimney soot might have been the cause. Studies conducted later corroborated that tar contained in soot is carcinogenic. These chemical substances were called carcinogens in connection with cancer. Carcinogenesis by carcinogens is referred to as chemical carcinogenesis and occupies a vital position in the carcinogenic mechanism along with radiation carcinogenesis by radioactive rays and carcinogenesis by viral infections (Fig. 7-3).

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Viruses and Cancer

Apart from chemical and radioactive carcinogenesis, another important carcinogenic mechanism is associated with viral infections. Viruses play pivotal roles in the pathogenesis of adult T-cell leukemia caused by HTLV-1, cervical cancer caused by papillomaviruses, and hepatocellular carcinoma caused by hepatitis B and C viruses. Although many aspects of viral carcinogenesis still remain to be understood, unlike other mechanisms of carcinogenesis, viral gene-derived proteins that are produced in the virus-infected host cells basically disrupt the normal cell cycle in a direct or an indirect manner, eventually leading to carcinogenesis. How a virus acts on host cells varies depending on the virus type, and the carcinogenic risks of viral infections differ considerably from one virus to another. The expectation that the prevention of viral infections will contribute to a decrease in carcinogenesis is spurring the development of antiviral vaccines. Some vaccines such as the ones for papillomaviruses have already been put to practical use.

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7.3.1

Damage to Genes

The uptake of carcinogens in cells induces gene mutation by eliciting reactions with intranuclear DNA. This mutation occurs randomly in the genome and is irreversible. A majority of these cells, not having acquired autonomous proliferation ability yet, die shortly. A fraction of the cells, however, survives after undergoing additional changes by other chemical substances etc. As these cells proliferate, new genetic abnormalities appear and accumulate. The accumulated genetic abnormalities then impart proliferative, invasive, and metastatic potencies to the cells, thereby making them proliferate as cancer cells*6. Cells in this stage possess extremely unstable genes, and hence, give rise to various mutations, among which those superior to others in terms of proliferation go on proliferating.
In the case of radiation carcinogenesis, radiation is postulated to cause a phenomenon similar to that of the early-stage changes of chemical carcinogenesis in cells causing damage to DNA. Since radiation has high energy, their hitting DNA damages it—sometimes irreparably.

*6 We have been focusing on the autonomous proliferation potency of cancer as its important feature. Apart from that, the ability of cancer to invade normal tissues by destroying the extracellular matrices (infiltration) and to move to distant sites via the bloodstream and take root there to proliferate and infiltrate (metastasis) is also its important and onerous property.

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7.3.2

Oncogenes and Tumor Suppressor Genes

Only about 1.3% of the entire DNA sequence in the human cell nucleus is considered to possess genetic information. A major portion of damage to DNA caused randomly by oncogenes and radiation is thought to occur in parts containing no genes, thus resulting in ambiguous changes to cellular functions*7. However, the occurrence of one such "flaw" within a gene would result in an abnormality in the protein synthesized from the gene in question. The type of aberrant cells thus produced depends upon the gene in which the abnormality occurs. That said, cells are inherently equipped with functions to detect and rectify such abnormalities, and the body's immune system can eliminate cells with any aberrations. Once an abnormality occurs in genes in charge of crucial cellular functions such as proliferation and death, the likelihood of cellular carcinogenesis increases. Normally, it is rare for a single gene abnormality to trigger off the process of carcinogenesis; abnormalities need to accumulate in several important genes. Of such important genes, those which can enhance the possibility of cellular carcinogenesis by letting their proteins exert their functions incessantly as a result of the occurrence of abnormalities (e.g., EGFR mentioned above), and thus, rendering their proteins uncontrollable, are referred to as oncogenes*8. In contrast, genes, in a normal state, that produce proteins acting suppressively on carcinogenesis (e.g. Rb mentioned above) by regulating cell proliferation or inducing death in abnormal cells are referred to as tumor suppressor genes. When oncogene-derived proteins being activated unremittingly and an uncontrollable state due to abnormalities in tumor suppressor genes coincide "well," cellular carcinogenesis takes place.

*7 It has recently been revealed that the parts other than the gene regions of the entire DNA sequence play diverse roles. In that sense, "flaws" in the non-gene regions may bring some changes to cellular functions in a manner similar to alterations in the gene regions of DNA.
*8 Oncogenes are in a state to cause cancer, whereas normal genes prior to the occurrence of abnormalities are called proto-oncogenes.

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7.3.3

Multistep Carcinogenesis Model

The carcinogenesis process of colorectal cancer is one of the most researched subjects (Fig. 7-4). Colorectal cancer is considered to occur when an abnormality arises in APC, one of the tumor suppressor genes, in the nucleus of one normal mucosal cell. In fact, abnormal APC can be found in the cancer lesions of at least 80% of colorectal cancer patients. Abnormal APC precipitates an excessive proliferation of mucosal cells, thereby giving rise to a benign*9 proliferative lesion called adenoma. In addition, when an abnormality occurs in the oncogene K-ras, the adenoma enlarges, making differences between each cell shape conspicuous. Moreover, another tumor suppressor gene p53 is added with yet another abnormality to bring forth the disorderly proliferation of the cells, i.e., canceration of the adenoma*10. Then, further accumulation of abnormalities accruing to several other genes is believed to endow cancer cells with the potency to infiltrate and metastasize. Nonetheless, this kind of process is not applicable to every colorectal cancer. Taking into account other types of cancer as well, there appears to be a variety of patterns of carcinogenic steps.

Fig. 7-4 Multistep Model of Colorectal Cancer

As normal tissues change into cancer, several genetic abnormalities accumulate. APC is a tumor suppressor gene and is originally engaged in the formation of the cytoskeleton. K-ras is an oncogene and is a type of ras. Their abnormalities make adenoma appear in the colorectal mucosa. If further abnormalities arise in p53 engaged in the transcriptional control of tumor suppressor genes, cancer occurs. Even further accumulation of genetic abnormalities would result in metastasis etc.

*9 This is the expression used to describe a neoplastic lesion, which neither proliferates infinitely nor exhibits properties such as infiltration and metastasis.
*10 There have been attempts to find cancer in its early stages by detecting abnormalities in K-ras and p53 from feces.

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