A recent New York Times article, "In Sickness and in Health: A Wedding in the Shadows of Cancer," struck a particularly sensitive chord. It profiled the courageous journey of two of my patients, a husband with advanced pancreatic cancer and his wife with metastatic breast cancer and their preparation for the wedding of their daughter in the face of their battle with cancer. Among the responses of readers an interesting and common concern stood out: why we continue to have an epidemic of cancer and why have we not dealt with the toxic mix of chemicals in our environment that they assume are a major cause of these cancers.
This perception is widespread. While there is little doubt that there are adverse health effects from these exposures, their role in the origin of the typical "Western cancers" (breast, colorectal, prostate, etc.) remains uncertain. Certainly the central role of tobacco in lung cancer and several other cancers is undisputed.
What is most striking is the lack of awareness among the public and health care providers alike about the growing evidence that many non-smoking related cancers may actually be, in part, a direct effect of modern good health. The marked improvement in maternal and early childhood nutrition has played an important role in the health and well being of modern populations.
The seminal work "The Changing Body" (1) by the late Nobel laureate in Economics Robert Fogel and colleagues, detailed the dramatic improvement in health, nutrition and human development in the Western world since the 1700s. The single best indicator of improved population health is adult height. Indeed, increasing height is linked to improved longevity, decreased mortality from heart disease and improved socioeconomic status (2).
Perhaps the single most important benefit has been the significant decrease in early childhood mortality, declining from 30 to 50 percent before age 10 prior to the 20th century to under 2 percent now. While maximal height is in part an inherited trait, our attained height is largely determined by both pre- and post-natal influences, including maternal weight and diet as well as early childhood calorie and protein intake.
Why do I suggest a direct effect of good health on the origins of cancer? One of the most consistent associations with cancer risk, recognized over the last 25 years (3-6), is the increased risk of cancer with increasing adult height. A recent study published in the Journal of the National Cancer Institute (7) suggested that height may in large part explain the higher risk of cancer in men compared with women. It has been speculated that increased height associated with earlier puberty may be a potential explanation for some hormone related cancers such as breast (8).
The height-cancer association, in fact, extends well beyond these cancers and appears to be a marker of cancer risk in general. Many non-hormonal cancers such as melanoma, lymphoma and leukemia share this association (9). That something as simple as one's height could contribute to a disease that occurs 50 or 60 years later seems difficult to understand at first.
But we now know that late adult cancers have their origins decades prior to diagnosis. The earliest event in cancer is a random mutation in a critical gene of a specific cell, the tissue stem cell (10). Within each organ, the tissue stem cells represent a tiny fraction of all the cells present. When these stem cells divide, one cell may grow to provide new tissue cells and one remains behind as a stem cell, allowing for continued "self renewal." These stem cells provide a source of new cells that maintain the viability of the tissues over the life of the individual.
This critical "initiating" mutation is passed to that cell's progeny. Over time, additional mutations may occur in additional critical genes that are necessary for the emergence of a fully malignant cancer. There are hundreds if not thousands of mutations within the cells in a newly-diagnosed cancer, only some of which may play a crucial role in the malignant process (11). While exogenous carcinogens (tobacco, organic chemicals, radiation) are in part responsible for these mutations, many result from endogenously generated radicals as an inherent part of cellular metabolism (12).
How does height influence cancer risk? Height does not cause cancer. But what height does reflect is an increased numbers of cells in every organ. Robust prenatal and early postnatal growth are accompanied by an increase in the number of tissue stem cells in each organ, each vulnerable to that initiating mutation, in what I have called the "lottery ticket effect" or pre-initiation. This has been referred to as "the stem cell burden hypothesis" (13), though it may be less a burden than a natural consequence of robust early growth.
The central hormone involved in fetal growth and a major determinant of childhood and later adult height is Insulin-like growth factor -1(IGF-1). Dimitri Trichopoulos and colleagues, leaders in the research linking height to cancer, showed that IGF-1 levels are closely correlated with specific stem cells (blood-related -- hematopoietic -- and breast tissue stem cells) when measured at birth in umbilical cord blood (14) and those stem cells are closely linked to birth length, an important predictor of adult height.
That IGF-1 would play such a critical role is reflected in the abundant research in animal models of cancer, indicating that calorie restriction markedly reduces cancer development, as a result of lower IGF-1 levels (15). In the large body of research in humans, increased IGF-1 levels are associated with the risk of many cancers (16).
Thus, the beginnings of the modern cancer epidemic may well start in these early events that ironically reflect an early environment promoting vigorous childhood growth (17). Later events including increased exposure to exogenous carcinogens, the continued exposure to this same rich caloric environment of modern life and our sedentary lifestyle, provide the fuel necessary to accelerate the evolution of the cancer process, resulting in the high cancer burden we now experience.
We cannot and should not want to limit the early and healthy growth of children. But we can target these later factors that ultimately are at the heart of the cancer epidemic.
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References:
1. The Changing Body. Health, Nutrition and Human Development in the Western World since 1700.
Roderick FLoud, Robert Fogel, Bernard Harris and Sok Chul Hong. Cambridge University Press, Cambridge, UK, 2011.
2. Height, wealth, and health: an overview with new data from three longitudinal studies. Batty GD, Shipley MJ, Gunnell D, Huxley R, Kivimaki M, Woodward M, Lee CM, Smith GD. Econ Hum Biol. 2009 Jul;7 (2):137-52.
3. Adult stature and risk of cancer at different anatomic sites in a cohort of postmenopausal women. Kabat GC, Anderson ML, Heo M, Hosgood HD 3rd,et al. Cancer Epidemiol Biomarkers Prev. 2013 Aug;22(8):1353-63.
4. Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk.Green J, Cairns BJ, Casabonne D, Wright FL, Reeves G, Beral V; Million Women Study collaborators.Lancet Oncol. 2011 Aug;12(8):785-94.
5. Adult height in relation to mortality from 14 cancer sites in men in London (UK): evidence from the original Whitehall study. Batty GD, Shipley MJ, Langenberg C, Marmot MG, Davey Smith G. Ann Oncol. 2006 Jan;17(1):157-66.
6. Height and site-specific cancer risk: A cohort study of a korean adult population.Sung J, Song YM, Lawlor DA, Smith GD, Ebrahim S. Am J Epidemiol. 2009 Jul 1;170(1):53-64.
7. Height as an explanatory factor for sex differences in human cancer.Walter RB, Brasky TM, Buckley SA, Potter JD, White E. J Natl Cancer Inst. 2013 Jun 19;105(12):860-8.
8. Body measurements, estrogen availability and the risk of human breast cancer: a case-control study. Bruning PF, Bonfrèr JM, Hart AA, van Noord PA, et.al. Int J Cancer. 1992 Apr 22; 51(1):14-9.
9. Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. Emerging Risk Factors Collaboration Collaborators. Int J Epidemiol. 2012 Oct;41 (5):1419-33.
10. A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms. Gentry SN, Jackson TL. PLoS One. 2013 Aug 19; 8(8):e71128.
11. Human cancers express mutator phenotypes: origin, consequences and targeting. Loeb L A. Nat Rev Cancer. 2011 Jun;11(6):450-7.
12. Links between metabolism and cancer. Dang CV. Genes Dev. 2012 May 1; 26(9):877-90.
13. Association of fetal hormone levels with stem cell potential: evidence for early life roots of human cancer. Baik I, Devito WJ, Ballen K, Becker PS, et. al.Cancer Res. 2005 Jan 1;65(1):358-63.
14. Correlation of umbilical cord blood haematopoietic stem and progenitor cell levels with birth weight: implications for a prenatal influence on cancer risk. Strohsnitter WC, Savarese TM, Low HP, Chelmow DP, et. al. Br J Cancer. 2008 Feb 12;98(3):660-3.
15. Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. Kari FW, Dunn SE, French JE, Barrett JC. J Nutr Health Aging. 1999;3(2):92-101.
16. The insulin-like growth factor system in cancer. Weroha SJ, Haluska P.
Endocrinol Metab Clin North Am. 2012 Jun; 41(2):335-50.
17. Are cell number and cell proliferation risk factors for cancer? Albanes D, Winick M. J Natl Cancer Inst 188; 80:772-74.