Global trends in adenocarcinomas and obesity: an epidemiologic link?

Zubair Kabir and Luke Clancy

University of Dublin (Trinity College), CResT Directorate, St James’s Hospital, Dublin 8, Ireland. E-mail: kabirz{at}tcd.ie

Sirs—Recent studies on cancers of lung,1 oesophagus,2 gastric cardia,3 kidney,4 prostate,5 breast,6 colon,7 gall bladder,8 uterine cervix,9 and endometrium10 show an increasing trend in a particular histological sub-type, namely, adenocarcinoma, especially among the relatively young cohorts. The biological implication of this distinct epidemiological and potentially aetiological entity is poorly understood. Long-term trends in cancer incidence do provide significant leads to an underlying causal pathway. However, trends of major cancer sites by histological sub-types have received little attention. Such trends may identify the possible role of any putative risk factors, which may not be apparent in studies looking at the overall cancer trends. For instance, despite a downturn in overall lung cancer incidence, younger females are experiencing a relatively steep increase in lung adenocarcinoma incidence, while the remaining histological sub-types of lung cancer have stabilized in both sexes across the globe, possibly suggesting a different biological mechanism.

The reasons for this emerging pattern in adenocarcinomas are unclear. Variations in coding, classification, and diagnostic technology may contribute partially to the observed trends. However, the consistent upward trends observed worldwide across both sexes possibly argue against any of these. Furthermore, the increasing trends in regions of relatively low socioeconomic development suggest that better or improved medical imaging and diagnostic technologies are unlikely to have resulted in the global increase of adenocarcinomas, which otherwise have poor prognosis.

The contribution of some of the known risk factors to the development of these specific cancers may highlight potential explanations. For example, a declining trend in smoking prevalence may partly explain the decreasing trend in lung squamous-cell carcinoma incidence.11 However, changing designs in cigarettes, as well as changing smoking habits may contribute to the rising incidence of lung adenocarcinoma,11 especially among female smokers,12 consistent with a recent finding.13 Contemporaneously, a rising prevalence in obesity worldwide since 1980, not only in the older cohorts14 but also among the adolescents15 is an interesting phenomenon. There is also evidence linking obesity to cancers of the gall bladder, endometrium, colon, kidney, prostate, and breast,16,17 as well as oesophagus and gastric cardia.3,17 Does this apparent temporality raise the possibility of linking the development of these adenocarcinomas to excess body weight?

The historic findings of linking in utero diethylstilboesterol exposure to vaginal adenocarcinoma, and the recent debate on hormone replacement therapy may well provide some clue to a biological plausibility. There is speculation that females are more likely to develop lung adenocarcinoma, possibly due to interactions between genetic factors and endocrine status,18 indicating an underlying gene—environment interaction. So, is it paradoxical that steroidal oestrogen has been added to the list of known human carcinogens recently,19 or is there a missing link, for example, the influence of physical activity on cancer risk?20

The potential relation between excess body weight and cancer risk suggests that excess energy may be an important risk factor for the development of cancer. In animal models, energy restriction has been shown to confer a strong protection.21 Likewise, biological mechanisms, such as an increase in endogenous production of reactive oxygen species and oxidative DNA damage,22 as well as an alteration in carcinogen-metabolizing enzymes,23 may suggest underlying explanations. More importantly, excess body weight, especially increased abdominal fat, mediates an alteration in the metabolism of endogenous hormones, particularly sex steroids and insulin, as well as insulin growth factor (IGF-1). This may stimulate cell proliferation, inhibit apoptosis and can enhance angiogenesis.24 Recently, ‘hyperinsulinaemia hypothesis’ has gained support, suggesting not only an increased plasma concentration of unbound sex-steroid for bioactivity, but also an increase in IGF-1, which otherwise inhibits the synthesis of sex hormone-binding globulin.25

These observations associating hormonal alterations with excess weight and cancer risk are useful, because they provide corroborating evidence that excess weight may actually cause cancer to develop. Until the cause—effect relation of obesity on cancer risk is clear, it would also seem reasonable to consider whether environmental changes in later life modify the effects of early life experiences. For instance, fetal experience may influence adult obesity with potential consequences for risk of several major cancers.26 This time-course event can be best demonstrated through a ‘life-course approach’, as evident in other chronic conditions.27

The overall impact of obesity on population health is becoming clear, including total health-care costs.28 In addition, excess body mass accounts for 5% of all cancers in the European Union, 3% in men and 6% in women, corresponding to 27 000 male and 45 000 female cancer cases yearly.17 At present, prudent advice is to launch major anti-obesity campaigns as a possible risk-reduction strategy, which may have health benefits beyond cancer (e.g. some 36 000 cancer cases could be avoided by halving the prevalence of overweight and obese people in Europe alone17) as well as a wider impact on other non-communicable diseases, notably cardiovascular disease, because they share the same lifestyle related risk factors.

In conclusion, these apparent observations may provide a new strategic framework not only for large controlled trials in cancer chemoprevention, but also the potential for primary prevention of an underlying adenocarcinoma pandemic in the new millennium. In addition, cancer research should be one of the top priorities in global health agenda, because cancer is going to be one of the biggest killers worldwide by 2020.29 Finally, both the developed and less-developed countries should have an adequate access to quality resources for a comprehensive research on cancer, including the histological sub-types, which may lead to an effective cancer prevention and control programme worldwide.


    Acknowledgments
 
Dr Debbie Lawlor and the two referees’ for their constructive comments.


    References
 Top
 References
 
1 Kabir Z, Manning PJ, Clancy L. Epidemiologic patterns of lung cancer incidence in the Republic of Ireland by major histologic types: 1994–1997. Am J Epidemiol 2002;155(Suppl.):19.

2 Powell J, McConkey CC, Gillison EW, Spychal RT. Continuing rising trend in oesophageal adeonocarcinoma. Int J Cancer 2002;102: 422–27.[CrossRef][ISI][Medline]

3 Mayne ST, Navarro SA. Diet, obesity and reflux in the etiology of adenocarcinomas of the esophagus and gastric cardia in humans. J Nutr 2002;132(Suppl.):3467–70.

4 Cheon J, Kim CS, Lee ES et al. Survey of incidence of urological cancer in South Korea: a 15-year summary. Int J Urol 2002;9:445–54.[CrossRef][ISI][Medline]

5 Coldman AJ, Phillips N, Pickles TA. Trends in prostate cancer incidence and mortality: an analysis of mortality change by screening intensity. CMAJ 2003;168:31–35.[Abstract/Free Full Text]

6 Prehn A, Clarke C, Topol B, Glaser S, West D. Increase in breast cancer incidence in middle-aged women during the 1990s. Ann Epidemiol 2002;12:476–81.[CrossRef][ISI][Medline]

7 Kim DW, Bang YJ, Heo DS, Kim NK. Colorectal cancer in Korea: characteristics and trends. Tumori 2002;88:262–65.[ISI][Medline]

8 Dhir V, Mohandas KM. Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas. Indian J Gastroenterol 1999; 18:24–28.[Medline]

9 Krishnamurthy S, Yecole BB, Jussawalla DJ. Uterine cervical adenocarcinomas and squamous carcinomas in Bombay: 1965–1990. J Obstet Gynaecol Res 1997;23:521–27.[Medline]

10 Beard CM, Hartmann LC, Keeney GL et al. Endometrial cancer in Olmsted County, MN: trends in incidence, risk factors and survival. Ann Epidemiol 2000;10:97–105.[CrossRef][ISI][Medline]

11 Yang CP, Gallagher RP, Weiss NS et al. Differences in incidence rates of cancer of respiratory tract by anatomic subsite and histopathologic type: an etiologic implication. J Natl Cancer Inst 1989;81: 1828–31.[Abstract]

12 Kabir Z, Clancy L. An epidemic of lung adenocarcinoma in females: emerging risk factors? BMJ 25 March 2003. (http://bmj.com/cgi/eletters/326/7389/570/b#30731)

13 Yang P, Cerhan JR, Vierkant RA et al. Adenocarcinoma of the lung is strongly associated with cigarette smoking: further evidence from a prospective study of women. Am J Epidemiol 2002;156:1114–22.[Abstract/Free Full Text]

14 Wang Y, Monteiro C, Popkin BM. Trends of obesity and underweight in older children and adolescents in the United States, Brazil, China and Russia. Am J Clin Nutr 2002;75:971–77.[Abstract/Free Full Text]

15 Okasha M, McCarron P, McEwen J, Smith GD. Body mass index in young adulthood and cancer mortality: retrospective cohort study.J Epidemiol Community Health 2002;56:780–84.[Abstract/Free Full Text]

16 Schottenfeld D, Fraumeni JF Jr (eds). In: Cancer Epidemiology and Prevention (2nd Edn). New York: Oxford University Press, 1996.

17 Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as an avoidable cause of cancer in Europe. Int J Cancer 2001;91:421–30.[CrossRef][ISI][Medline]

18 Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women (letter). J Natl Cancer Inst 1994;86:869–70.[ISI][Medline]

19 Nelson R. Steroidal oestrogens added to list of known human carcinogens. Lancet 2002;360:2053.

20 Batty D, Thune I. Does physical activity prevent cancer? BMJ 2000;321:1424–25.[Free Full Text]

21 Reddy BS, Wang CX, Maruyama H. Effect of restricted caloric intake of azoxymethane-induced colon tumor incidence in male F344 rats. Cancer Res 1987;47:1226–28.[Abstract]

22 Chung MH, Kasai H, Nishimura S, Yu BP. Protection of DNA damage by dietary restriction. Free Radic Biol Med 1992;12:523–25.[CrossRef][ISI][Medline]

23 Manjgaladze M, Chen S, Frame LT et al. Effects of caloric restriction on rodent drug and carcinogen metabolising enzymes: implications for mutagenesis and cancer. Cancer Res 1993;295:201–22.

24 Dickson RB, Thompson EW, Lippman ME. Regulation of proliferation, invasion and growth factor synthesis in breast cancer by steroids. J Steroid Biochem Mol Biol 1990;37:305–16.[CrossRef][ISI]

25 Pugeat M, Crave JC, Elmidani M et al. Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol 1991;40:841–49.[CrossRef][ISI][Medline]

26 Leong NM, Mignone LI, Newcomb PA et al. Early life risk factors in cancer: the relation of birth weight to adult obesity. Int J Cancer 2003;103:789–91.[CrossRef][ISI][Medline]

27 Youssef AA, Valdez R, Elkasabany A, Srinivasan SR, Berenson GS. Time-course of adiposity and fasting insulin from childhood to young adulthood in offspring of parents with coronary artery disease. Ann Epidemiol 2002;12:553–59.[CrossRef][ISI][Medline]

28 Thompson D, Brown JB, Nichols GA, Elmer PJ, Oster G. Body mass index and future healthcare costs: a retrospective cohort study. Obes Res 2001;9:210–18.[Abstract/Free Full Text]

29 World Health Organization. World Cancer Report. Lyon: International Agency for Research on Cancer, 2003.





This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Request Permissions
Google Scholar
Articles by Kabir, Z.
Articles by Clancy, L.
PubMed
PubMed Citation
Articles by Kabir, Z.
Articles by Clancy, L.