Seminars in Oncology Nursing, Vol 21, No 4 (November), 2005: pp 229-235 229 OBJECTIVE: To summarize the scientific prin- ciples underlying cancer preven- tion. PRINCIPLES OF DATA SOURCES: Articles, text books, personal com- CANCER munications, and experience. CONCLUSION: PREVENTION The scientific basis of cancer pre- vention is complex and involves experimental and epidemiologic approaches and clinical trials. FRANK L. MEYSKENS,JR AND PATRICIA TULLY IMPLICATIONS FOR NURSING PRACTICE: ANCER prevention has classically encompassed As more information becomes three large areas of clinical practice: prevention, available regarding proven and screening, and early detection. Several excellent potential cancer-prevention strate- reviews and book chapters have been published gies, oncology nurses are regu- involving these topics.1-3 The importance of bio- larly called upon to guide patients Clogical and molecular markers as potential surrogates have been and others in making choices re- emphasized in the past several years,4,5 and more recently precan- garding preventative options. It is cers or intraepithelial neoplasia (IEN) have become a target.6,7 The important for oncology nurses to integration of the well-established approaches of prevention, stay abreast of this growing body screening, and early detection with biological measures of disease of knowledge. risk, progression, and prognosis has become the hallmark of mod- ern cancer prevention (see Fig 1). In this article we will review the principles of cancer prevention and will emphasize the scientific underpinnings of this emerging discipline. The principles of cancer prevention have evolved from three separate scientific disciplines: carcinogenesis, epidemiology, and clinical trials. Many other areas From the Department of Medicine and of science and medicine, including genetics and the behavioral Biological Chemistry, Chao Family Com- sciences, are contributing to this evolving and complex field. prehensive Cancer Center, University of California, Irvine, CA. Frank L. Meyskens, Jr, MD: Professor, Department of Medicine and Biological SCIENTIFIC PRINCIPLES Chemistry, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA. Patricia Tully, RN: Research Carcinogenesis Nurse, Department of Medicine and Bio- logical Chemistry, Chao Family Compre- arcinogenesis is the study of factors that contribute to the hensive Cancer Center, University of Cali- fornia, Irvine, CA. Cpathogenesis of cancer formation, the processes that regu- Supported in part by CA 62203 from the late normal differentiation and maturation of cells, and the genetic National Institutes of Health, Bethesda, MD. and epigenetic factors that enhance or exhibit tumor formation. Address correspondence to Frank L. Meyskens, Jr, MD: 101 The City Drive, UCI The overall relationship of the process of carcinogenesis to cancer Medical Center, Chao Family Comprehen- prevention, screening, and early detection is depicted schemati- sive Cancer Center, Building 56, Room cally in Fig 1 and should be referred to liberally throughout this 215, Orange, CA 92868; e-mail: fl[email protected] article. This figure represents an integrated systematic biological and clinical approach in which the process of cancer formation is related to underlying biologic changes and the influence of the environment © 2005 Elsevier Inc. All rights reserved. and the preclinical detection of clinical outcomes by screening and 0749-2081/05/2104-$30.00/0 early detection strategies or the interruption or suppression of the doi:10.1016/j.soncn.2005.06.002 malignant process by chemoprevention. 230 MEYSKENS AND TULLY FIGURE 1. Prevention of human cancer: A synthetic biological and clinical approach. Classically, carcinogenesis has been separated visual or endoscopic means. During progression, into three distinct phases: initiation, promotion, additional genetic damage occurs, mutations re- and progression.8 Initiation is the first step of sult, and the cell gradually acquires the properties carcinogenesis and results in irreversible damage of a fully transformed phenotype including inva- to DNA by a physical, chemical, or viral agent (ie, sive and metastatic properties. a carcinogen). The events of initiation occur rap- idly. In some cases damage to DNA may be re- The Role of Genetics and Genes paired before it is “fixed” as a mutation. In such situations, initiation does not happen and the cell An increased understanding of the malignant returns to its baseline state. In general, any inter- process in the last 15 to 20 years has established, vention that slows cellular proliferation should beyond a reasonable doubt, that hereditable and provide more time for DNA repair and lessen DNA acquired genetic changes play a role in all cancers damage and mutation. Alternatively, initiated (Fig 2). The process is complex and the specifics cells are damaged and, if recognized as such, un- vary from cancer to cancer, but the essential dergo apoptosis (“cell death”) and are removed elements are probably quite similar.8 Vis-à-vis the before they can evolve into a malignancy. malignant process, two major changes occur to Progression occurs over a prolonged period of genes: a loss or gain in function. Genes that sup- time (many years in humans) and results in ex- press proliferation or enhance apoptosis are pansion of an initiated clone of cells without fur- known as tumor suppressor genes.9,10 Genes that ther or minimal genetic change. Exogenous or enhance proliferation or inhibit apoptosis are endogenous factors that enhance the cell cycle or known as oncogenes.11 One useful way to think of endocrine responsiveness of the cell play a major these two major types of genes is as the brake and role in this stage of cancer formation. The fault gas pedal of the genome. line between promotion and progression is gener- When a key gene is altered at a constitutive or ally regarded as the appearance of a clinically hereditable level, a malignant outcome is nearly detectable lesion, frequently referred to as a pre- inevitable early in life (eg, loss of the Rb gene and cancer, premalignancy, or in solid tumors, an IEN. development of a retinoblastoma) or is highly The systematic characterization of IEN and the likely in adult life and occurs earlier (eg, loss or biologic factors that determine risk and evolution mutation of the adenomatosis polyposis gene, have been a major issue in the past few years.6 leading to thousands of colorectal polyps early in Colorectal adenomas, cervical IEN, oral leukopla- life and colon cancer at a young age). In both these kia, and actinic keratoses of the skin are repre- cases a key gene that represses growth has been sentative examples of IEN that can be detected by lost; this element is called a tumor suppressor PRINCIPLES OF CANCER PREVENTION 231 FIGURE 2. Constitutive and ac- quired genetic changes play a clini- cal role in cancer formation and pre- vention. gene. Other genes can be altered in a less severe Almost all human cancers seem to evolve to fashion, for example, the BRCA1 and BRCA2 genes their malignant state over a long period of time, at that, if altered, lead to breast cancer at an earlier least in immunologically competent individuals. age and at a higher frequency. A large number of Influencing the fate of this genetic background are genes have now been identified that contribute to a wide range of potential direct and indirect car- a high risk of human cancer.12 Taken together, cinogens. Among the more potent direct carcino- however, they contribute perhaps at most 15% to gens to which human populations are exposed 20% of the major risk for human cancers. include viruses, chemicals, and radiation. Potent So what might the contribution of other genetic indirect influences include products of inflamma- factors be? Changes in genes can be lumped into tion and infection, endogenous and exogenous a general category called polymorphisms, which hormones, and dietary constituents. account for variation in genes. The study of single The nature of the defined genetic changes in nucleotide polymorphisms, or changes in the sin- many of the major malignancies has now been gle base of a gene and their possible role in cancer characterized with a substantial understanding of risk or outcome, has exploded in the last few the changes in colon and head and neck malignan- years. A wide variety of genes may be affected cies.4,7 Molecular classifications have emerged such as those that regulate hormone and carcin- that will profoundly influence the prognostic clas- ogen metabolism, each an important property that sification of tumors; for example, recent work contributes to risk that is dependent on the par- using chromosomal genomic hybridization has led ticular property of the protein coded for by the to a new understanding of melanoma and its pre- gene in question.9,13 This constellation of heredi- cursor that has etiologic and prognostic implica- table/familial genetic changes provides an individ- tions.16 Although treatment decisions have been ualized baseline “set-point,” from which malig- driven less by specific genetic alterations, the re- nancy or other disease processes evolves in an cent recognition that the same specific genetic individual. Only in the most extreme cases is alteration in diseases as histologically and clini- cancer inevitable, and in most cases the interac- cally diverse as chronic myelogenous leukemia tion of environmental parameters with the genetic and gastrointestinal malignancies predict respon- material determines phenotypic