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Environmental Carcinogenesis: Potential Pathway to Cancer Prevention

A small and localized breast cancer would most likely be treated by surgical excision and possibly radiation therapy, whereas a large, infiltrative breast cancer would more likely be treated by mastectomy. If the cancer has spread to lymph nodes or distant sites, more aggressive therapy is implemented. The ultimate fate of cells or proliferative tissue masses is influenced by the amount of sustained genetic damage. Cells with minimal DNA damage may persist in a latent form, indistinguishable from surrounding normal cells. If such a latent cell sustains additional damage even long after the initial insult, it may then progress further along the pathway to malignancy see Figure 1.

As additional genetic damage occurs, the altered cell population expands and eventually leads to irreversible uncontrolled growth that may or may not be corrected by aggressive medical intervention. Genetically, the multistage process involves the activation of growth-enhancing protooncogenes, inactivation of the recessive growth-inhibitory tumor suppressor genes as well as epigenetic events that alter gene expression and processes such as those involved in cell death, DNA repair, and methylation Table 4.

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Cancer cells frequently contain mutations in multiple genes as well as large chromosomal abnormalities. Protooncogenes were first discovered in cancer-causing animal viruses that carried them. Intense study of these viruses, particularly by Varmus and Bishop in the s, resulted in the discovery that endogenous animal genes had been picked up by virus ancestors and incorporated into the viral genome.

Soon thereafter a number of these protooncogenes were identified in both the animal and human genome and later found to play a role in cancer development. A widely accepted multistep model of carcinogenesis proposed by Fearon and Vogelstein in serves as the framework for studies in carcinogenesis Figure 5. By studying multiple benign and malignant colonic neoplasms from individuals with multiple tumors it was found that benign neoplasms harbored mutations in genes such as APC, ras , and p53, and that there were frequently multiple mutations per neoplasm, particularly of the malignant neoplasms.

The model describes a progressive acquisition of mutations and it is believed the total accumulation of mutations at least five to seven rather than the order is important in the carcinogenic process. New evidence has been published to further refine this model. Recently it has been proposed that some neoplasms are dependent on the continued activation or overexpression of a particular oncogene for maintaining malignant behavior. In fact, oncogenes were first discovered by studying genetic alterations in cancers.

The term oncogene activation indicates a quantitative or qualitative alteration in the expression or function of the oncogene. The term oncogene is unfortunate since the unaltered nonactivated oncogene usually referred to as a protooncogene actually serves an essential function in the mammalian genome. That protooncogenes are highly conserved in evolution is evidenced by structurally and functionally similar genes in yeast, earthworms, animals, and humans.

The highly conserved nature of protooncogenes is believed to be related to their essential function in normal tissue growth and differentiation. Since their normal function is to control how a tissue grows and develops, it is apparent that, if they do not function appropriately, abnormal growth and development may occur. When a primary manifestation of such abnormal growth was observed to be neoplasia, these protooncogenes were named oncogenes.

The appearance phenotype and function of a tissue is a consequence of which genes are actively producing their programmed product, typically a protein, which in turn affects the structure and function of the cells comprising a given tissue. All somatic cells in the body inherit a complete complement of maternal and paternal genes. The reason that some cells form liver and produce products such as albumin while other cells form kidney tubules that function to excrete substances from the body is a consequence of which genes are expressed in those cells.

In liver cells, several critical genes that are important in kidney function are not expressed and vice versa. Specific gene expression and its effect upon tissue phenotype and function are modulated by several intrinsic and extrinsic factors Figure 6.

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

Since a primary function of many oncogenes is to control cell growth, proliferation, and differentiation, inappropriate expression of these genes would be expected to influence abnormally tissue proliferation and growth. Oncogene activation is a consequence of inappropriate or excessive expression of a protooncogene. Oncogenes can be activated by several different mechanisms e. Either situation may contribute to the neoplastic process by influencing cellular proliferation and differentiation. Examples of activated or amplified oncogenes detected in human and animal neoplasms are listed in Tables 5 and 6.

For some cancers the frequency of oncogene activation is relatively high, while for other cancers the activation of known oncogenes is uncommon. Identification of specific alterations in oncogenes in certain cancers represents a first step in determining the molecular basis of cancer and could eventually lead to the development of molecular intervention and therapeutic strategies.

Toxicity and Carcinogenicity of Dichlorodiphenyltrichloroethane (DDT)

Experimental evidence indicates that oncogene activation can be an early critical event in carcinogenesis, and experimental studies with known chemical carcinogens show that they produce specific alterations in certain oncogenes reflecting the manner in which the carcinogen chemically affects DNA. Tumor suppressor genes, originally called antioncogenes, function to suppress the development of cancerous growth. White oncogenes must be activated to be effective, tumor suppressor genes must be inactivated or lost for cancer to develop.

A well-known and extensively studied tumor suppressor gene is the retinoblastoma gene [RB In hereditary retinoblastoma an affected child is born with deletions of portions of one allele of chromosome 13 containing the RB-1 gene. If a second event leading to a loss or alteration of the remaining RB-1 allele occurs while retinal cells are undergoing growth during development, the ocular neoplasm, retinoblastoma, frequently present in both eyes, will occur early in life. Loss or alteration of both copies of this tumor suppressor gene is sufficient to cause retinoblastoma.

The rate of mutation has been intensely studied in the carcinogenic process. Mutations in cellular DNA can arise during normal cell replication by infidelity in DNA replication mispairing as well as by chromosomal deletions, amplifications, or rearrangements. If each mispair led to a mutation that resulted in a cancer, a typical human would have billions of cancers in one average lifetime. Since such estimates of cancer frequency are clearly in excess of what is observed, it is necessary to postulate that events in addition to a single mutation are necessary for most cancers to occur and that many mispairings are repaired or fatal to the cell.

There are efficient mechanisms to repair DNA damage, thereby precluding successive accumulation of critical mutations. The cell has relatively efficient mechanisms to repair damage provided there is time prior to cell division. If a tissue is proliferating rapidly, cell division could occur before the cell has time to mend damaged DNA.

While all of the above underscore the importance of cell proliferation in carcinogenesis, neoplasia does not occur exclusively or necessarily at higher frequency in tissues that have a rapid intrinsic rate of cell proliferation. Consequently, other important mechanistic factors influence the complex process of carcinogenesis.

In , Loeb et al. It suggests that early mutation in stability genes i.