Multistage Carcinogenesis Process and Targets for Prevention

Humans are exposed to a wide variety of endogenous and exogenous carcinogenic insults, including chemicals, radiation, physical agents, bacteria, and viruses. Recent progress in the study of the multistep process of carcinogenesis, particularly on the mechanisms of chemically and virally induced cancer, has revealed several points along the car-cinogenesis pathway that may be amenable to cancer prevention strategies. The classic view of experimental car-cinogenesis, in which tumor initiation is followed by tumor promotion and progression in a sequential fashion, has undergone significant revision as our understanding of cancer-related genes and the biosystem has evolved. However, the concepts and underlying processes of initiation, promotion, and progression remain theoretically important. Tumor initiation begins in cells with DNA alterations resulting from inherent genetic mutations or, more commonly, from spontaneous or carcinogen-induced genetic or epigenetic changes. Alterations in specific genes modify the responsiveness of the initiated cell to its microenvironment, eventually providing a growth advantage relative to normal cells. The tumor promotion stage is characterized by clonal expansion of initiated cells caused by alterations in the expression of genes whose products are associated with hyper-proliferation, apoptosis, tissue remodeling, and inflammation.3 During the tumor progression stage, preneoplastic cells develop into invasive tumors through further clonal expansion, usually associated with alterations in gene expression

Anti-Initiation Strategies

• Alter Carcinogen Metabolism

• Enhance Carcinogen Detoxification

• Scavange Electrophiles/Reactive Oxygen Species

• Enhance DNA Repair

Anti-Promotion/Progression Strategies

• Scavenge Reactive Oxygen Species

• Decrease Inflammation

• Suppress Proliferation/Enhance Apoptosis

• Enhance Immunity

• Discourage Angiogenesis

Anti-Initiation Strategies

• Alter Carcinogen Metabolism

• Enhance Carcinogen Detoxification

• Scavange Electrophiles/Reactive Oxygen Species

• Enhance DNA Repair

Genetic/Epigenetic Alterations figure 23.1. Multistage carcinogenesis model: a schematic presentation of stage-specific prevention strategies. The initiation stage is characterized by the conversion of a normal cell to an initiated cell in response to genetic or epigenetic changes in the cell's DNA. The conversion of an initiated cell to a preneoplastic population of cells

Increased Cell Proliferation Additional Genetic/Epigenetic Alterations and ultimately to a tumor is determined by additional genetic/epi-genetic changes that affect the balance between growth and death in these cells. Strategies to intervene in these processes to decrease rates of mutation epigenetic change and maintain the growth-death balance in cancer cells are listed in the boxes.

Genetic/Epigenetic Alterations figure 23.1. Multistage carcinogenesis model: a schematic presentation of stage-specific prevention strategies. The initiation stage is characterized by the conversion of a normal cell to an initiated cell in response to genetic or epigenetic changes in the cell's DNA. The conversion of an initiated cell to a preneoplastic population of cells

Increased Cell Proliferation Additional Genetic/Epigenetic Alterations and ultimately to a tumor is determined by additional genetic/epi-genetic changes that affect the balance between growth and death in these cells. Strategies to intervene in these processes to decrease rates of mutation epigenetic change and maintain the growth-death balance in cancer cells are listed in the boxes.

and additional genetic damage due to progressive genomic instability.3

As depicted in Figure 23.1, possible ways of interfering with tumor initiation events include (i) modifying carcinogen activation by inhibiting the enzymes responsible for that activation or by directly scavenging DNA-reactive electrophiles and free radicals; (ii) enhancing carcinogen detoxification by altering the activity of detoxifying enzymes; and (iii) modulating certain DNA repair processes. Possible ways of blocking the processes involved in the promotion and progression stages of carcinogenesis include (i) scavenging reactive oxygen species; (ii) altering the expression of genes involved in cell signaling, particularly those regulating cell proliferation, apoptosis, and differentiation; (iii) decreasing inflammation; (iv) enhancing immune function; or (v) suppressing angiogenesis.

We now appreciate that the nature of initiation, promotion, and progression events is complex. For instance, we know from the work of Fearon and Vogelstein and others that multiple mutational and epigenetic events are involved in the formation of cancers.4 Furthermore, humans are generally exposed to mixtures of agents that can simultaneously act at different stages of the carcinogenesis process. Thus, rather than three discrete stages occurring in a predictable order, human carcinogenesis is best characterized as an accumulation of alterations in genes regulating cellular growth, death, and malignant properties. These alterations occur through a series of clonal selections influenced by endogenous and exogenous factors. Epigenetic changes often develop in a cancer or the microenvironment and may also drive this multistep process.5 Nonetheless, the processes involved in cancer initiation, promotion, and progression already described remain important and relevant targets for cancer prevention. Interventions that increase or decrease rates of mutation, rates of epigenetic change, or the balance between growth and death in cancer cells can significantly influence the ultimate development of cancer. One of the most important questions in contemporary cancer research is this: What safe and effective interventions should be recommended to prevent cancer?

Natural Detox

Natural Detox

Are you looking for a full total body detox? If so, then you might want to try a 10 day detox or some refer to it as the 2-week detox. A 10-day detox is a full body detox that usually means taking several different steps to reach your total body transformation. It might involve a change in diet, exercise and more.

Get My Free Ebook


Post a comment