Journal of the National Cancer Institute Advance Access originally published online on October 26, 2009
JNCI Journal of the National Cancer Institute 2009 101(21):1436-1437; doi:10.1093/jnci/djp357
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© The Author 2009. Published by Oxford University Press.
EDITORIAL |
Cancer Risk From Extreme Stressors: Lessons From European Jewish Survivors of World War II
Affiliations of authors: Department of Nutritional Sciences, The University of Texas, Austin, TX (SDH); Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX (SDH); Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX (MRF)
Correspondence to: Stephen D. Hursting, PhD, MPH, Department of Nutritional Sciences, The University of Texas, Painter Hall, Rm 5.32, Austin, TX 78712 (e-mail: shursting{at}austin.utexas.edu).
In this issue of the Journal, Keinan-Boker et al. (1) reported higher cancer incidence in a cohort of European Jews who immigrated to Israel after World War II (and thus were potentially exposed to and survived the Holocaust) relative to a cohort of European Jews who immigrated to present-day Israel before the war (and thus were considered unexposed to the conditions of the Holocaust). Because data on individual exposures of Holocaust survivors were unavailable, exposure status was crafted from historical data sources of immigration dates for European-born Israeli Jews. Statistically significantly higher rates for all-site, breast, and colorectal cancers were observed among the exposed group than among the unexposed group across five categories of birth cohorts from 1920 through 1945. The strongest associations between the exposure and cancer risk occurred in the youngest birth cohort (1940–1945), suggesting that early-life exposure had the greatest impact on subsequent cancer risk. The article contributes importantly to the growing body of literature on the effects of stressful exposures, including that of severely restricted energy intake, on cancer risk.
As Keinan-Boker et al. (1) noted, calorie restriction inhibits a broad spectrum of cancers in rodent model systems (2). Recent reports of extended life span and delayed cancer development in calorie-restricted rhesus monkeys (3) and reports that calorie restriction during the premenopausal years decreases postmenopausal breast cancer risk in women (4) suggest that the anticancer effects of calorie restriction extend to primates, including humans. Observational studies further support the hypothesis that calorie restriction has beneficial effects on longevity and cancer risk in humans. For example, moderately reduced caloric intake decreased morbidity and mortality among Spanish nursing home residents (5). In addition, inhabitants of Okinawa, Japan, who until recently consumed fewer calories per capita than residents of the main Japanese islands, have lower death rates from cancer and cardiovascular diseases than inhabitants of the Japanese mainland (5).
The research to date on cancer risk in relation to World War II conditions, including the study by Keinan-Boker et al. (1), has largely been based on ecological data. Despite this limitation, the World War II–related exposures to very low calorie diets, particularly within the cohort of Jewish survivors, provide additional clues about the connection between calorie intake and cancer in humans. The European Jews interred in concentration camps or ghettos experienced long-term, severe (220–800 kcal/d) energy restriction, combined with protein and micronutrient deficiencies and exposure to cold, infectious agents, and extreme physical and emotional stressors. These multifaceted stressful conditions were very different than the experimental conditions characteristic of the majority of the published calorie restriction studies in animal models that consistently show anticancer effects. Calorie restriction is often referred to as "undernutrition without malnutrition," and calorie restriction experiments typically involve a moderate (10%–30%) reduction in calories coupled with adequate nutrition and a controlled physical environment (2). Even severe (40%–80%) calorie restriction under controlled environmental conditions suppresses tumor development in the few animal models in which it has been studied (6). Furthermore, patients with early-onset anorexia nervosa, and hence periods of severe energy restriction, have reduced risk of breast cancer (7). Clearly, factors beyond severe calorie restriction underlie the increase in cancer risk observed in the exposed cohort by Keinan-Boker et al. (1).
European Jewish survivors also experienced different stresses and cancer outcomes than non-Jewish survivors of World War II, as discussed by Keinan-Boker et al. (1). For example, a cohort of Norwegians showed reduced cancer risk in the face of more acute (<1 year) and less severe (approximately 50% reduction in calorie intake without substantial changes in diet quality) energy restriction than did the exposed Jewish cohort during World War II (8). In addition, survivors of the Dutch Famine of 1944, in which energy restriction (approximately 70% reduction in rations for adults and 50% reduction in rations for children) was more severe than the Norwegian exposure but less severe than the Jewish exposure, had higher breast cancer rates but no statistically significant difference in rates of any other cancer (9).
The birth cohorts analyzed by Keinan-Boker et al. (1) were born in Europe between 1920 and 1945, a period of diverse economic and psychosocial conditions. For example, the early 1920s cohort was born in an era of relative wealth with childhoods that were likely to have been comfortable, including a nutritionally adequate diet or even overnutrition. The cohorts born during the Great Depression or World War II likely experienced increasingly challenging early-life conditions (such as inadequate nutrition in utero, in infancy, or in early childhood) that may result in maladaptive metabolic programming for life. This early-life maladaptive response was hypothesized by Barker (10) and confirmed by others (11–15) to influence programming of endocrine and other metabolic regulatory systems and increase the risk of developing obesity, diabetes, and numerous other chronic diseases, including breast and colorectal cancer. Consistent with the Barker hypothesis, the 1940–1945 cohort that was born in the midst of the Holocaust and soon thereafter immigrated to Israel (where food was relatively abundant) had the highest rates of cancer, especially of breast and colorectal cancer. Unfortunately, Keinan-Boker et al. (1) did not have the individual-level data necessary to fully characterize early-life (in Europe) or later-life (in Israel) exposures and their effect on the carcinogenesis process over the life course.
Given the extraordinary extent and duration of deficiencies in protein, energy, and micronutrients among European Jews during World War II and the impact of malnutrition on fertility and perinatal survival (16), few women would have been able to conceive, only some of those who did conceive would have delivered a live birth, and only a limited number of their offspring would have survived and ultimately immigrated to Israel. Keinan-Boker et al. (1) recognized the selective nature of the cohort and, because the cohort is aging rapidly, recommended further research that would include the collection of data at the individual level. Biospecimens to examine genetic, epigenetic, and hormonal profiles would help to uncover reasons for differences in cancer incidence by exposure status. Just as importantly, information should be collected on all participants to refine exposure status regarding place of birth, location before and during World War II, number of relatives lost to the Holocaust, date of and age at time of immigration, anthropometric data, smoking history, reproductive history, and comorbidities.
Thus, data from animal and human studies indicate that although calorie restriction is typically associated with decreased cancer risk, the anticancer effects of calorie restriction may be neutralized or overwhelmed by extreme stressors. Furthermore, early-life exposures to extreme stressors may be particularly influential on cancer risk, and breast cancer in women appears to be particularly responsive to early-life stressors. European Jewish survivors of World War II endured unimaginable psychosocial and physical hardships, including severe nutritional deprivations. From this unique cohort, we can learn lessons about adaptation to extreme hardships in early life, resilience during life, and cancer susceptibility later in life.
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