This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schottenfeld, D. Articles by Beebe-Dimmer, J. Search for Related Content PubMed PubMed Citation Articles by Schottenfeld, D. Articles by Beebe-Dimmer, J. Related Collections Epidemiology and Prevention Epidemiology and Prevention: Screening, Behavior, and Survivorship

Alleviating the Burden of Cancer: A Perspective on Advances, Challenges, and Future Directions

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan

Requests for reprints: David Schottenfeld, Department of Epidemiology, University of Michigan, 109 Observatory Street, Ann Arbor, MI 48109-2029. Phone: 734-647-3217; Fax: 734-764-3192. E-mail: daschott{at}umich.edu

	Abstract

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 
The control of the burden of cancer would be achievable by promoting health-maintaining lifestyle behavioral practices in conjunction with facilitated access to affordable and effective periodic screening and early detection examinations combined with comprehensive treatment services. In a global population exceeding six billion in the year 2002, there were 10.9 million new cancer cases, 6.7 million cancer deaths, and 22.4 million persons surviving from cancer diagnosed in the previous 5 years. In 2020, the world's population is projected to increase to 7.5 billion and will experience 15 million new cancer cases and 12 million cancer deaths. This perspective on advances, challenges, and future directions in cancer epidemiology and prevention reviews the conceptual foundation for multistep carcinogenesis, causal mechanisms associated with chronic inflammation and the microenvironment of the cancer cell, and obesity, energy expenditure, and insulin resistance. Strategic priorities in global cancer control initiatives should embrace these fundamental concepts by targeting tobacco and alcohol consumption, the increasing prevalence of obesity and metabolic sequelae, and persistent microbial infections. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2049–55)

	Introduction

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 
The 30th Annual Meeting of the American Society of Preventive Oncology provides an appropriate setting for reflecting on the advances, challenges, and future directions in cancer epidemiology and cancer prevention and control. Whereas the universality of cancer incidence and mortality is established, the burden of cancer by type or organ site is represented by contrasting patterns between developing countries in Africa, Asia, and Latin America, and more industrialized countries in North America, Europe, Australia, and New Zealand. The age-period-cohort patterns observed in individual countries may be quite heterogeneous, as in urban compared with rural regions, or in relationship to racial, cultural, ethnic, and socioeconomic characteristics.

Populations in developing countries are disproportionately susceptible to cancers in which infectious agents are causal (1). These organ sites include the uterine cervix, penis, and oropharynx (human papillomavirus), liver (hepatitis viruses B and C), stomach (Helicobacter pylori, non-Hodgkin lymphoma, including endemic Burkitt lymphoma (EBV)), nasopharynx (EBV), urinary bladder (Schistosoma haematobium), biliary tract (opisthorchis viverrini, clonorchis sinensis, and Kaposi's sarcoma (human herpesvirus type 8)). The public health effect of these infections is substantial. The proportion of total cancer deaths attributable to infectious agents is estimated to be about 20% to 25% in developing countries and 7% to 10% in more industrialized countries.

In a worldwide population exceeding six billion in the year 2002, there were 10.9 million new cancer cases, 6.7 million cancer deaths, and 22.4 million persons surviving from cancer diagnosed in the previous 5 years (2, 3). In 2020, the world's population is projected to increase to 7.5 billion, which will experience 15 million new cancer cases and 12 million cancer deaths (4). In 2002, the most common incident cancers worldwide, excluding keratinocyte skin cancers, were lung (12.3%), breast (10.4%), and colorectum (9.4%). The three cancer sites contributing to the highest proportions of global cancer deaths were lung (17.8%), stomach (10.4%), and liver (8.8%). Of 55 million worldwide deaths in 2002, 12% to 13% were attributed to cancer and 31% to heart disease.

In the United States in 1900, cancer mortality accounted for <4% of all deaths and ranked as the sixth leading cause; by 1940, cancer mortality ranked second and accounted for 11% of all deaths (5). In 2003, there were 556,902 cancer deaths or 22.7% of total deaths. From 1992 to 2002, cancer mortality decreased by 1.5% per year in men and by 0.8% per year in women. Since 1999, in the age-gender combined subgroups younger than 85 years, or in 98% of the population at risk, cancer mortality has surpassed heart disease as the underlying cause of death; in the subgroup older than 85, heart disease deaths were three times more frequent than cancer deaths. In the projected statistics for 2006, among men, cancers of the prostate, lung and bronchus, and colon and rectum will account for at least 56% of all newly diagnosed cases; among women, cancers of the breast, lung and bronchus, and colon and rectum will comprise about 54% of the estimated total cases. In 1987, lung cancer mortality superseded breast cancer mortality in women and, in 2006, will account for 26% of all cancer deaths in women (6).

Approximately 200,000 incident cancers registered in 2003 in the United States, or about 16% of the estimated total annual incidence, were diagnosed in patients with one or more prior independent primary cancers (7). Epidemiologic studies in cohorts of patients who have exhibited multiple primary cancers have contributed to our understanding of the complex etiology of human cancers and to the generating and testing of hypotheses on mechanisms of carcinogenesis (8). A salient research question is whether, or to what extent, risk patterns exist that predict metachronous primary cancers in patients with an index primary cancer of a particular organ and histopathology? The identification of specific predictive patterns of multiple primary cancers would facilitate cost-effective targeting of early detection methods or other preventive interventions. At issue is whether apparent increases in risk result from:

common environmental and/or genetic factors in the pathogenesis of index and metachronous primary cancers;

adverse carcinogenic effects of chemotherapy and/or radiotherapy used in the treatment of the index cancer;

random or chance associations; and

spurious associations that are the result of biased ascertainment of multiple primary cancers as a result of more careful medical surveillance in patients with a history of cancer when compared with a referent population.

The multicentric origin of epithelial cancers is demonstrable in patients with oral cancer who manifest an increased incidence of synchronous and metachronous carcinomas of the oropharynx, glottis, supraglottis, esophagus, and lower respiratory tract. The cumulative incidence of metachronous primary cancers in the aerodigestive tract, 6 months after diagnosis of the index primary oral cavity cancer, has been estimated as 3% to 4% per year. These patients exhibit mucosal dysplasias and intraepithelial carcinomas in areas separate from the index primary cancer. The concept of mucosal "field cancerization" would be consistent with protracted exposures to one or more carcinogenic agents (9, 10).

Worldwide, the established causal factors for head and neck cancers include tobacco smoking, heavy alcohol drinking, chewing of betel nut and tobacco, and infection with human papillomavirus. Epidemiologic studies conducted in many countries have established that the risks of lung, upper aerodigestive, stomach, pancreatic, liver, kidney, urinary bladder, and uterine cervical carcinomas; colorectal adenoma and carcinoma; and myelogenous leukemia are significantly increased among cigarette smokers. Approximately 30% of the cancer deaths in the United States are attributable to cigarette smoking, and ethyl alcohol interacts with tobacco smoking in the pathogenesis of >75% of carcinomas of the upper aerodigestive tract (11).

	Molecular and Genetic Events in Neoplastic Transformation

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 
Epidemiologic, experimental, and molecular biological studies have provided a conceptual foundation for multistep carcinogenesis. Experimental models of chemical carcinogenesis have shown distinctive phases of initiation, promotion, neoplastic cell transformation or conversion, and progression resulting from a sequential accumulation of adverse genetic and epigenetic events (12). Chemical agents or mixtures that are tumor promoters are generally not mutagenic and facilitate clonal expansion of initiated cells that are at risk of further genetic mutational events. Notable agents with tumor-promoting properties are tobacco smoke condensate, ethanol, sex steroid hormones, bile acids, dioxin, and agents that are chronic irritants or evoke an inflammatory response (13). Epigenetic events are comprised of stable and heritable, or potentially heritable, alterations in gene expression that do not entail a change in DNA sequence. Patterns of DNA methylation in CpG dinucleotide "island" sequences in the vicinity of a promoter region of a tumor-suppressor gene provide a mechanism by which the gene may be silenced; conversely, genomic demethylation or hypomethylation of a proto-oncogene may result in hyperactivity. Environmental and stochastic factors can affect epigenetic events (14, 15).

As summarized by Hanahan and Weinberg (16), the molecular, genetic, and phenotypic hallmarks in the evolution of a population of cancer cells include unrestrained proliferation, subversion of genetic mechanisms that control apoptosis, interaction of a reactive stroma in the microenvironment of neoplastic tissue that stimulates angiogenesis, the capacity to invade through the basement membrane of the extracellular matrix, and dissemination and proliferation at metastatic sites.

	Genetic and Epigenetic Pathways in the Pathogenesis of Colorectal Cancer: an Instructive Paradigm

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 
The complex molecular pathogenesis of sporadic colorectal cancer may proceed by means of at least three clinical and morphologic pathways. The three pathways include the predominant pattern of the adenoma precursor progressing to cancer (about 80-85%), defective mismatch repair with microsatellite instability (about 15%), and inflammatory bowel disease (17).

Overall, about 10% of adenomas (tubular, villous, and tubulovillous) will progress to invasive cancer over an interval of about 10 years. Histopathologic features that increase the likelihood of progression to cancer include degree of dysplasia and epithelial atypia, predominance of villous histology, and surface diameter exceeding 1 cm (18). The progression from adenoma of increasing size to dysplasia to carcinoma is anticipated by a cascade of molecular genetic events, including mutations of KRAS oncogene on chromosome 12p and mutations of tumor suppressor genes on 5q [adenomatous polyposis coli (APC)], 17p (TP53), and 18q (DCC; ref. 19). An early mutational event resides at the APC gene locus at 5q, which is correlated with an aberrant proliferation rate in the upper one third of epithelial crypts in otherwise normal-appearing mucosa. Mutation of the APC gene alters critical functions of cell adhesion, cell migration, and apoptosis (20, 21). The truncated APC protein results in increased concentrations of ß-catenin, which after adhering to T-cell factor, augments transcription of specific oncogenes. In murine as well as human colon cancer, APC mutations seem earlier in carcinogenesis than mutational and epigenetic events involving KRAS and TP53 (22, 23).

An alternative carcinogenic pathway involves mutations in DNA mismatch repair genes manifested by high-level microsatellite instability and the appearance of mucin-producing poorly differentiated cancers more frequently located in the proximal colon (24). Microsatellites represent a limited number of DNA sequences repeated in tandem that show polymorphisms in length throughout the human genome. Because they are repetitive, microsatellites are prone to strand slippage and errors in replication. Microsatellite instability occurs when there is dysfunction of the DNA mismatch-repair enzyme system. The alterations in microsatellite length are shown as band shifts on gel electrophoresis (25). In the majority of sporadic colorectal cancers associated with microsatellite instability, repression of transcription by hypermethylation of the promoter region most commonly of the hMLH1 mismatch repair gene has been described. In Lynch syndrome patients with HNPCC, 90% of germ line mutations reside at hMSH2 and hMLH1 loci (26, 27).

Inflammatory bowel disease provides an illustrative mechanism of increased risk of neoplasia experienced by patients with chronic inflammation in gastrointestinal tissues. The pathogenesis of inflammatory bowel disease suggests that there has been an aberrant immune response to luminal indigenous microorganisms or ingested foreign antigens. The inflammatory response mediated by CD4⁺ T cells and expressed in the intestinal epithelium is exaggerated, unregulated, and cytotoxic. The mucosal ulcerations would allow for microbial flora to gain access to submucosal lymphoid tissue and thus trigger an immune response (28-30). The risk of colorectal cancer in ulcerative colitis patients increases with longer duration of disease and with extent of involvement of the large intestine. In addition, the risk increases with the appearance of higher-grade dysplastic lesions. Dysplastic areas may seem flat or polypoid, localized, multifocal, or diffuse (31).

Colorectal cancer chemopreventive trials are focusing on targeting segments of the population at increased risk (e.g., history of adenomas or family history) by prescribing nutritional supplements of calcium, vitamin D, and/or folic acid; or treating with nonsteroidal anti-inflammatory agents; or assessing benefits of postmenopausal estrogen replacement therapy (32-36). Combinations of concurrent administration of chemopreventive agents may be more effective than one agent acting independently. As reported by Grau et al., in an analysis of trials in patients with recurrent adenomas, the combination of supplemental calcium (1,200 mg daily of elemental calcium) and "frequent use" of nonsteroidal anti-inflammatory drugs resulted in a reduction of risk of advanced adenomas (i.e., severe dysplasia, villous elements, and 1 cm or larger in diameter) of 65% (P_interaction = 0.01). Similarly, in a trial of daily aspirin (81 mg) and supplemental calcium, there was an 80% risk reduction (37). If corroborated in future randomized clinical trials, investigation of potential synergistic mechanisms in relationship to the pathologic characteristics and anatomic location of colorectal adenomas would be appropriate.

Optimal dietary and supplemental sources of folate over a protracted period of time have been reported to be associated with a 20% to 50% reduction in risk of colorectal adenomas and carcinomas (38-40). In a pooled analysis of nine cohort studies conducted in North America and Europe, the top quintile of folate intake, when compared with the lowest quintile, was associated with a 21% lower risk of colorectal cancer (multivariate-adjusted relative risk, 0.79; 95% confidence interval, 0.70-0.89; ref. 41). The results in various case-control and cohort studies were in particular compelling when folate and ethanol intakes were considered jointly. Among individuals with a low intake of folate and a high intake of ethanol, the risks of colorectal adenoma and cancer were increased >2-fold (42, 43). In patients with chronic excessive consumption of ethanol, folate deficiency may occur because of inadequate dietary intake, malabsorption, or defects in folate-binding proteins or in the enterohepatic absorption and recirculation of folate.

Folic acid has multiple metabolic effects, including biosynthesis of purines and pyrimidines and production of S-adenosylmethionine, a requisite metabolite for methylation of DNA cytosines, histones, and phospholipids. Methylene tetrahydrofolate reductase catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the principal folate congener supplied to tissues, and a vital methyl donor, in concert with vitamins B¹² and B⁶, and dietary choline upon conversion to betaine. The folate congener (5,10-methylenetetrahydrofolate) is the source of a complementary vital function (i.e., the transfer of a methylene group to deoxyuridylate for the synthesis of thymidylate in the DNA nucleotide sequence). Thus, when in the presence of folate deficiency there is increasing methylene tetrahydrofolate reductase activity, the resulting increase in 5-methyltetrahydrofolate occurs at the "cost" of reduced thymidylate synthesis (44-46).

A thermolabile variant of methylene tetrahydrofolate reductase is associated with reduced enzyme activity. The molecular structure of the methylene tetrahydrofolate reductase variant is a substitution at nucleotide 677 of a cytosine (C) for thymine (T), which converts an alanine to valine amino acid. In relationship to low folate intake, a homozygous TT variant, when compared with CC or CT genotypes, would be associated with markedly elevated levels of homocysteine, a putative risk factor for cardiovascular disease (47). However, with adequate intake of folate and vitamin B¹², TT individuals are reported to be at decreased risk of colorectal cancer when compared with the CC or CT genotype (48). Various studies have suggested that individuals with TT genotype and low intake of folate were more susceptible to the carcinogenic effects of alcohol (49-51). A plausible inference based on the apparent gene-nutrient interactions would be that reduced activity of methylene tetrahydrofolate reductase in TT carriers, with normal folate intake, favored 5,10-methylenetetrahydrofolate, the pathway affecting DNA synthesis and repair.

	Chronic Inflammation and the Microenvironment of the Cancer Cell

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 
Recurrent or persistent inflammation, resulting from an exposure to a specific microbial or chemical agent, ionizing or UV radiation, or physical injury, may induce, promote, or influence susceptibility to carcinogenesis by causing DNA damage, inciting aberrant tissue reparative proliferation, and/or by creating a stromal "soil" that is enriched with proinflammatory cytokines and growth factors (e.g., vascular endothelial growth factor). Various pathologic conditions prominently associated with chronic inflammation are linked with cancers in gastrointestinal, respiratory, anogenital, and lymphoid organs and tissues (Table 1 ; ref. 52).

Phases of cancer promotion and progression are intimately linked to a dysfunctional cytokine network. Cytokines represent a family of biological response modifiers, including interleukins, chemokines, IFNs, growth factors, leukocyte colony-stimulating factors, and tumor necrosis factor-. Chemokines stimulate leukocyte recruitment and migration as part of the host response to foreign antigens. Dvorak, in contrasting mechanisms involved in physiologic wound healing with those in neoplastic cell proliferation and invasion, referred to tumors as "wounds that do not heal" (55, 56). The dysfunctional network of cytokines, chemokines, growth factors, and extracellular proteases interact with cell surface receptors and target genes that ultimately influence tumor cell proliferation and survival, angiogenesis, and migration of tumor cells into the stromal matrix (57, 58). An additionally important component in the cytokine signaling pathway is activation of the nuclear transcription factor-B. Activation of nuclear transcription factor-B by proinflammatory cytokines is expressed in a second messenger system, with potential pathologic effects on tumor promotion (59).

Chronic inflammation and the metabolic products of phagocytosis are often accompanied by the excessive formation of reactive oxygen and nitrogen species that are potentially damaging to DNA, lipoproteins, and cell membranes (60). Inflammatory cells also release metabolites of arachidonic acid, or eicosanoids, including prostanoids or prostaglandins and leukotrienes. The cyclooxygenases are key enzymes that control rate-limiting steps in prostaglandin synthesis. The expression of the isoform cyclooxygenase-2 is induced by inflammatory and neoplastic cells, and metabolites produced by the action of cyclooxygenase-2 on arachidonic acid have been shown to affect carcinogenic pathways (61-63).

Future studies of the complex cascade of cellular and humoral factors participating in the chronic inflammatory response will further understanding of the pathogenesis of various cancers and provide a rationale for targeted chemopreventive interventions. Preclinical and clinical investigations of agents that target the tumor microenvironment and epithelial-stromal signaling pathways are evaluating, for example, the efficacy of inducers of apoptosis and inhibitors of angiogenesis, collagen synthesis and cyclooxygenase-2-dependent and prostaglandin-independent pathways (64-66). The anticarcinogenic properties of nonsteroidal anti-inflammatory drugs in the colorectum are well documented by experimental and epidemiologic studies and by randomized trials. Regular use of aspirin for at least 10 years, for example, has been associated with a reduced risk of colorectal adenomas in addition to adenocarcinomas, suggesting an early-stage mechanistic pathway in colorectal neoplasia (33, 67-69).

	Obesity, Energy Expenditure, and Insulin Resistance

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 
The prevalence of obesity has been increasing over the past two decades in many industrialized countries and in urban areas of developing countries and is incurring substantial public health and economic costs. In 2003 to 2004, among adults in the United States, ages 20 years, 32% were classified as obese (body mass index 30 kg/m²) and 34% as overweight (body mass index = 25-29.9 kg/m²). In the National Health and Nutrition Examination Survey of children and adolescents ages 2 to 19 years, conducted in 2003 to 2004, 17% were classified as overweight; this represented, over the past 25 years, more than doubling of prevalence rates among children under 12 years of age and tripling among those 12 to 19 years of age. Among overweight children and adolescents, the younger the age of onset, the higher the correlation with obesity in adulthood (70, 71).

Results from epidemiologic studies have indicated that central or visceral adiposity [waist circumference >40 in. (102 cm) in men and >35 in. (88 cm) in women] is associated with increased incidence or mortality from cancers of the endometrium, breast (postmenopausal women), kidney, gallbladder, pancreas, esophagus and gastric cardia (adenocarcinoma), colon, and prostate (Table 2 ). Other suggested organ sites at increased risk include thyroid, multiple myeloma, and liver. In the American Cancer Society Cancer Prevention Study II, 15% to 20% of cancer deaths in women and 10% to 14% in men were attributed to being overweight or obese (72, 73).

Cardiovascular disease, cerebrovascular disease, type II diabetes, and neoplastic diseases associated with obesity are highly correlated with the presence of total body fat mass and intra-abdominal (visceral) fat. Patients with abdominal obesity tend to have elevated glucose and insulin levels during an oral glucose tolerance test and high rates of lipolysis. Lipolysis is the catabolic process leading to the breakdown of triglycerides into fatty acids and glycerol. The metabolic and endocrine effects of obesity are intimately connected with elevated production of free fatty acids from triglycerides in adipose tissue and impaired insulin-mediated glucose metabolism. Being overweight or obese and sedentary decreases insulin sensitivity in target tissues as in the liver, skeletal muscle, and fat and is accompanied by hyperinsulinemia (77-79).

In Table 3 , the metabolic and endocrine systemic effects of obesity are listed, suggesting possible mechanisms for tumorigenesis in hormone-dependent organs and colon and gallbladder. The adipocyte in secreting free fatty acids and hormones, such as leptin, adiponectin, and resistin, and cytokines, such as interleukin-6 and tumor necrosis factor-, participates as a central mediator of the insulin-resistance syndrome in obese individuals (80). The physiologic dynamics of insulin resistance and compensatory hyperinsulinemia greatly increases the risk of metabolic sequelae of residual glucose intolerance, high plasma triglyceride, low high-density lipoprotein cholesterol, hypertension, and increased levels of proinflammatory cytokines and of pro-coagulation factors, such as fibrinogen and plasminogen activator inhibitor. It has been estimated that 23% or 47 million adults in the United States report symptoms and clinical sequelae of the metabolic or insulin resistance syndrome (81, 82).

	Global Priorities in Alleviating the Cancer Burden

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

In a recent American Cancer Society report, it was concluded that >50% of the cancer deaths in the United States could be prevented with modification in lifestyle risk factors and greater use of cost-effective cancer screening tests (84). In the National Cancer Institute Cancer Trends Progress Report (2005), it was estimated that 20% to 30% of cancer incidence in the United States would be attributed to obesity and lack of physical activity (85). Risk reduction associated with maintaining moderate or vigorous physical activity, independently of weight reduction in overweight or obese individuals, has been shown consistently in studies of colon cancer and adenomatous polyps and to a somewhat lesser degree, of breast cancer (86-91).

A collaborating group participating in the Comparative Risk Assessment Project reviewed behavioral and environmental risk factors that would offer "the best option for reducing the large and increasing burden of cancer worldwide" (92). Risk factors selected were those with a high likelihood of causality, reasonably complete data on population exposure levels, and a leading potentially modifiable cause of worldwide or regional disease burden. Tobacco was estimated to have caused 21% of cancer deaths worldwide, with a higher attributable fraction of 29% in high-income countries and 18% in low- and middle-income regions. Regular use of moderate to high levels of alcohol (i.e., exceeding 25 g of ethanol per day) accounted for an estimated 5% of global cancer deaths, including upper aerodigestive organ cancers, liver cancer and breast cancer (93, 94). Overweight and obesity and physical inactivity (i.e., <2.5 hours per week of moderate intensity activity or <4,000 kJ/wk) were causally associated with <5% of all cancer deaths worldwide, but of 20% of global colorectal and breast cancer deaths.

In Table 4 , priority is assigned to potentially modifiable lifestyle risk factors that affect the global burden of cancer. As suggested in the publication by Byers et al., ideally, the control of the burden of cancer would be achievable through the integration of population-based, health-maintaining lifestyle behavioral practices, and access to affordable and effective periodic screening and early detection examinations in conjunction with comprehensive treatment services (83). In arriving at evidence-based recommendations in cancer screening, clinicians and public health professionals are reviewing alternative methods that are culturally sensitive and in tune with individual preferences (95). Of particular interest is the substantial effect of exposures to microbial agents that potentially may be lessened by the availability and use of effective antimicrobial therapy, immunization to reduce rates of persistent infection, and the application of global surveillance and early detection methods in high-risk populations. Primary preventive measures that effectively control the persistence or transmission of infectious agents causing gastric cancer (H. pylori), hepatocellular cancer (hepatitis B virus), and uterine cervical cancer (human papillomaviruses) are high-priority strategic interventions. Although further understanding of causal factors and pathways as a result of experimental and epidemiologic research will continue to contribute to innovative preventive strategies, there are already at hand compelling opportunities for behavioral and therapeutic interventions that have the potential to reduce substantially the global cancer burden.

	Footnotes

Note: Submission to Cancer Epidemiology Biomarkers Prevention.

Based on presentation at 30th Annual Meeting of the American Society of Preventive Oncology, February 27, 2006, Bethesda, Maryland.

Received 7/20/06; revised 8/23/06; accepted 9/13/06.

	References

Top Abstract Introduction Molecular and Genetic Events... Genetic and Epigenetic Pathways... Chronic Inflammation and the... Obesity, Energy Expenditure, and... Global Priorities in Alleviating... References

 

1. Pisani P, Parkin DM, Munoz N, Ferlay J. Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev 1997;6:387–400.[Abstract]
2. Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 1999;83:18–29.[Medline]
3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.[Abstract/Free Full Text]
4. Bray F, Moller B. Predicting the future burden of cancer. Nat Rev Cancer 2006;6:63–74.[CrossRef][Medline]
5. Lilienfeld AM, Levin ML, Kessler II. Cancer in the United States. Cambridge: Harvard University Press; 1972.
6. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–30.[Abstract/Free Full Text]
7. Travis LB, Rabkin CS, Brown LM, et al. Cancer survivorship-genetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst 2006;98:15–25.[Abstract/Free Full Text]
8. Hemminki K, Boffetta P. Multiple primary cancers as clues to environmental and heritable causes of cancer and mechanisms of carcinogenesis. In: Buffler P, Rice J, Baan R, Bird M, Boffetta P. Mechanisms of carcinogenesis: contributions of molecular epidemiology. Lyon: IARC Publications; No. 157; 2004. p. 289–97.
9. Schottenfeld D. Primary and secondary prevention. In: Neugut AI, Meadows AT, Robinson E, editors. Multiple primary cancers. Philadelphia: Lipincott Williams and Wilkins; 1999. p. 67–88.
10. Day GL, Blot WJ, Shore RE, et al. Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 1994;86:131–7.[Abstract/Free Full Text]
11. Schottenfeld D, Beebe-Dimmer JL. Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions. Annu Rev Public Health 2005;26:37–60.[CrossRef][Medline]
12. Michor F, Iwasa Y, Nowak MA. Dynamics of cancer progression. Nat Rev Cancer 2004;4:197–205.[CrossRef][Medline]
13. Boutwell RK. The function and mechanism of promoters of carcinogenesis. CRC Crit Rev Toxicol 1974;2:419–43.[Medline]
14. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–28.[Medline]
15. Jiang YH, Bressler J, Beaudet AL. Epigenetics and human disease. Annu Rev Genomics Hum Genet 2004;5:479–510.[CrossRef][Medline]
16. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.[CrossRef][Medline]
17. Potter JD. Colorectal cancer: molecules and populations. J Natl Cancer Inst 1999;91:916–32.[Abstract/Free Full Text]
18. Baron JA. Colon and Rectum. In: Franco EL, Rohan TE, editors. Cancer precursors: epidemiology, detection and prevention. New York: Springer-Verlag; 2002. p. 127–50.
19. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–67.[CrossRef][Medline]
20. Lamlum H, Papadopoulou A, Ilyas M, et al. APC mutations are sufficient for the growth of early colorectal adenomas. Proc Natl Acad Sci U S A 2000;97:2225–8.[Abstract/Free Full Text]
21. Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235–7.[CrossRef][Medline]
22. Morin PJ, Sparks AB, Korinek V, et al. Activation of ß-catenin-Tcf signaling in colon cancer by mutations in ßcatenin or APC. Science 1997;275:1787–90.[Abstract/Free Full Text]
23. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855–78.[Free Full Text]
24. Jass JR, Do KA, Simms LA, et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 1998;42:673–9.[Abstract/Free Full Text]
25. Peltomaki P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 2001;10:735–40.[Abstract/Free Full Text]
26. Wheeler JM, Loukola A, Aaltonen LA, Mortensen NJ, Bodmer WF. The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI⁺ sporadic colorectal cancers. J Med Genet 2000;37:588–92.[Abstract/Free Full Text]
27. Rowley PT. Inherited susceptibility to colorectal cancer. Annu Rev Med 2005;56:539–54.[CrossRef]
28. Bamias G, Nyce MR, De La Rue SA, Cominelli F. New concepts in the pathophysiology of inflammatory bowel disease. Ann Intern Med 2005;143:895–904.[Free Full Text]
29. Wong NA, Harrison DJ. Colorectal neoplasia in ulcerative colitis: recent advances. Histopathology 2001;39:221–34.[CrossRef][Medline]
30. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;347:417–29.[Free Full Text]
31. D'Inca R, Cardin R, Benazzato L, Angriman I, Martines D, Sturniolo GC. Oxidative DNA damage in the mucosa of ulcerative colitis increases with disease duration and dysplasia. Inflamm Bowel Dis 2004;10:23–7.[CrossRef][Medline]
32. Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 2003;3:601–14.[CrossRef][Medline]
33. Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002;94:252–66.[Abstract/Free Full Text]
34. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684–96.[Abstract/Free Full Text]
35. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.[Abstract/Free Full Text]
36. Grau MV, Baron JA, Barry EL, et al. Interaction of calcium supplementation and nonsteroidal anti-inflammatory drugs and the risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2005;14:2353–8.[Abstract/Free Full Text]
37. Lieberman DA, Prindiville S, Weiss DG, Willett W. Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 2003;290:2959–67.[Abstract/Free Full Text]
38. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129:517–24.[Abstract/Free Full Text]
39. Tseng M, Murray SC, Kupper LL, Sandler RS. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol 1996;144:1005–14.[Abstract/Free Full Text]
40. Glynn SA, Albanes D, Pietinen P, et al. Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev 1996;5:487–94.[Abstract]
41. Kim DH, Smith-Warner SA, Hunter DJ. Pooled analysis of prospective cohort studies on folate and colorectal cancer. Pooling Project of Diet and Cancer Investigators. Am J Epidemiol 2001;153:S118.
42. Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265–73.[Abstract/Free Full Text]
43. Baron JA, Sandler RS, Haile RW, Mandel JS, Mott LA, Greenberg ER. Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl Cancer Inst 1998;90:57–62.[Abstract/Free Full Text]
44. Ulrich CM, Robien K, Sparks R. Pharmacogenetics and folate metabolism: a promising direction. Pharmacogenomics 2002;3:299–313.[CrossRef][Medline]
45. Bohnsack BL, Hirschi KK. Nutrient regulation of cell cycle progression. Annu Rev Nutr 2004;24:433–53.[CrossRef]
46. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 2006;15:189–93.[Free Full Text]
47. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023–31.[Abstract/Free Full Text]
48. Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 1999;8:513–8.[Abstract/Free Full Text]
49. Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997;57:1098–102.[Abstract/Free Full Text]
50. Levine AJ, Siegmund KD, Ervin CM, et al. The methylenetetrahydrofolate reductase 677C->T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2000;9:657–63.[Abstract/Free Full Text]
51. Chen J, Giovannucci E, Kelsey K, et al. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 1996;56:4862–4.[Abstract/Free Full Text]
52. Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J Clin 2006;56:69–83.[Abstract/Free Full Text]
53. Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol: Mechanims of Disease 2006;1:119–50.
54. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392–401.[CrossRef][Medline]
55. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315:1650–9.[Medline]
56. Dvorak HF. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. Am J Pathol 2003;162:1747–57.[Free Full Text]
57. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4:540–50.[CrossRef][Medline]
58. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006;354:610–21.[Free Full Text]
59. Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-B: its role in health and disease. J Mol Med 2004;82:434–48.[Medline]
60. Maeda H, Akaike T. Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 1998;63:854–65.[CrossRef][Medline]
61. Fosslien E. Molecular pathology of cyclooxygenase-2 in neoplasia. Ann Clin Lab Sci 2000;30:3–21.[Abstract]
62. Hawk ET, Viner JL, Dannenberg A, DuBois RN. COX-2 in cancer: a player that's defining the rules. J Natl Cancer Inst 2002;94:545–6.[Free Full Text]
63. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001;294:1871–5.[Abstract/Free Full Text]
64. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401–10.[CrossRef][Medline]
65. Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 2000;60:5040–4.[Abstract/Free Full Text]
66. Grosch S, Maier TJ, Schiffmann S, Geisslinger G. Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 2006;98:736–47.[Abstract/Free Full Text]
67. Turini ME, DuBois RN. Cyclooxygenase-2: a therapeutic target. Annu Rev Med 2002;53:35–57.[CrossRef][Medline]
68. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 2006;6:130–40.[CrossRef][Medline]
69. Clevers H. Colon cancer: understanding how NSAIDs work. N Engl J Med 2006;354:761–3.[Free Full Text]
70. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295:1549–55.[Abstract/Free Full Text]
71. Freedman DS, Khan LK, Serdula MK, Galuska DA, Dietz WH. Trends and correlates of class 3 obesity in the United States from 1990 through 2000. JAMA 2002;288:1758–61.[Abstract/Free Full Text]
72. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579–91.[CrossRef][Medline]
73. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38.[Abstract/Free Full Text]
74. Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go fron here? Science 2003;299:853–5.[Abstract/Free Full Text]
75. Briefel RR, Johnson CL. Secular trends in dietary intake in the United States. Annu Rev Nutr 2004;24:401–31.[CrossRef][Medline]
76. Tollotson JE. America's Obesity: conflicting public policies, industrial economic development,unintended human consequences. Annu Rev Nutr 2004;24:617–43.[CrossRef][Medline]
77. Badman MK, Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science 2005;307:1909–14.[Abstract/Free Full Text]
78. Froguel P, Boutin P. Genetics of pathways regulating body weight in the development of obesity in humans. Exp Biol Med (Maywood) 2001;226:991–6.[Abstract/Free Full Text]
79. Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annu Rev Med 2003;54:453–71.[CrossRef][Medline]
80. Reaven GM. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr 2005;25:391–406.[CrossRef][Medline]
81. Moller DE, Kaufman KD. Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 2005;56:45–62.[CrossRef]
82. Wood PA. How fat works. Cambridge: Harvard University Press; 2006.
83. Byers T, Mouchawar J, Marks J, et al. The American Cancer Society challenge goals. How far can cancer rates decline in the U.S. by the year 2015? Cancer 1999;86:715–27.[CrossRef][Medline]
84. American Cancer Society. Half of cancer deaths could be prevented. CA Cancer J Clin 2005;55:209–10.[Free Full Text]
85. National Cancer Institute. Cancer Trends Progress Report: percent of adults at healthy weight, overweight or obese 1971–2002. J Natl Cancer Inst 2006;98:233.[Free Full Text]
86. International Agency for Research on Cancer (IARC) Monographs on the evaluation of carcinogenic risk to humans: human papillomaviruses. Vol. 64. Lyon (France): IARC Publications; 2005.
87. Slattery ML, Edwards SL, Ma KN, Friedman GD, Potter JD. Physical activity and colon cancer: a public health perspective. Ann Epidemiol 1997;7:137–45.[CrossRef][Medline]
88. Chang SC, Ziegler RG, Dunn B, et al. Association of energy intake and energy balance with postmenopausal breast cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 2006;15:334–41.[Abstract/Free Full Text]
89. Bernstein L, Patel AV, Ursin G, et al. Lifetime recreational exercise activity and breast cancer risk among black women and white women. J Natl Cancer Inst 2005;97:1671–9.[Abstract/Free Full Text]
90. McTiernan A, Kooperberg C, White E, et al. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study. JAMA 2003;290:1331–6.[Abstract/Free Full Text]
91. Chao A, Connell CJ, Jacobs EJ, et al. Amount, type, and timing of recreational physical activity in relation to colon and rectal cancer in older adults: the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2004;13:2187–95.[Abstract/Free Full Text]
92. Danei G, Vander H, Lopez AD, Murray CGL, Ezzati M. Causes of cancer in the world: comparative risk assessment of nine behavioral and environmental risk factors. Lancet 2005;366:784–93.
93. Boffetta P, Hashibe M. Alcohol and cancer. Lancet Oncol 2006;7:149–56.[CrossRef][Medline]
94. Bray I, Brennan P, Boffetta P. Projections of alcohol- and tobacco-related cancer mortality in Central Europe. Int J Cancer 2000;87:122–8.[CrossRef][Medline]
95. Woolf SH. Potential of screening to reduce the burden of cancer. In: Curry SJ, Byers T, Hewitt M. Fulfilling the potential of cancer prevention and early detection. Washington (DC): National Academies Press; 2001. p. 156–223.

This article has been cited by other articles:

				S. S. Coughlin Surviving Cancer or Other Serious Illness: A Review of Individual and Community Resources CA Cancer J Clin, January 1, 2008; 58(1): 60 - 64. [Abstract] [Full Text] [PDF]

				L. Kuller Is Phenomenology the Best Approach to Health Research? Am. J. Epidemiol., November 15, 2007; 166(10): 1109 - 1115. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schottenfeld, D. Articles by Beebe-Dimmer, J. Search for Related Content PubMed PubMed Citation Articles by Schottenfeld, D. Articles by Beebe-Dimmer, J. Related Collections Epidemiology and Prevention Epidemiology and Prevention: Screening, Behavior, and Survivorship