Reappraisal of the Field Effect Concept in Cancer Predisposition
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Modern Pathology (2015) 28, 14–29 14 & 2015 USCAP, Inc All rights reserved 0893-3952/15 $32.00 Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression Paul Lochhead1, Andrew T Chan2,3, Reiko Nishihara4,5, Charles S Fuchs3,4, Andrew H Beck6, Edward Giovannucci3,5,7 and Shuji Ogino4,7,8 1Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK; 2Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; 3Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 4Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 5Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; 6Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 7Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA and 8Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA The term ‘field effect’ (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, ‘etiologic field effect’, which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a ‘field of susceptibility’ to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically focused approach to field effect can: (1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; (2) embrace host–environment–tumor interactions (including gene- environment interactions) occurring in the tumor microenvironment; and, (3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying ‘etiologic field effect’ as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an ‘etiologic field effect’ paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine. Modern Pathology (2015) 28, 14–29; doi:10.1038/modpathol.2014.81; published online 13 June 2014 Correspondence: Dr P Lochhead, MBChB, MRCP, Gastrointestinal Cancers are fundamentally complex, multifactorial, Research Group, Institute of Medical Sciences, University of 1–5 Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK and Dr S Ogino, genomic, and epigenomic diseases, which MD, PhD, MS, Department of Pathology, Brigham and Women’s represent a major burden on societies globally. Hospital, Harvard Medical School, 450 Brookline Avenue, Room However, many cancers are potentially avoidable, M422, Boston, MA 02215, USA. with estimates suggesting that 60% of cancer deaths E-mail: [email protected] and in the United States are attributable to a limited [email protected] 6 Received 20 November 2013; revised 12 February 2014; accepted number of lifestyle factors. A better understanding 2 April 2014; published online 13 June 2014 of modifiable contributors to cancer initiation, www.modernpathology.org Etiologic field effect concept P Lochhead et al 15 evolution, and progression is a prerequisite for tissues have yielded persuasive evidence that a accurate risk prediction and the development of field of cancer-predisposing molecular alterations better strategies for prevention, early detection, can be present even in microscopically normal treatment, and surveillance.1–5,7–10 tissue.13–19,36,37 The existence of field effect has been The revolutionary theory of field effect (also described in a variety of tissues, spanning almost all known as field defect, field cancerization, or field organ systems in the human body.13–19,38–45 More carcinogenesis) has been continually adapted and recently, studies of epigenetic changes in tumors and updated since it was first consolidated by Slaughter normal cells,14,15,46–57 as well as analyses of stromal et al11 in 1953. The description of ‘field canceriza- cells and the tissue microenvironment have contri- tion’11 is regarded as one of the landmarks of the buted to the molecular field effect concept.20–24 past 100 years of cancer research.12 Several authors Consequently, the prevailing interpretation of have recently reviewed the field effect concept and field effect is that a field of somatic molecular its evolution,13–18 and the presence of a recent alteration in a given organ or tissue predisposes to textbook19 entirely devoted to the topic attests to tumor development within that field. The mechan- its continued clinical and scientific importance. isms through which geographic fields of molecu- In this article, we offer a reappraisal of field effect, larly abnormal cells arise are not fully understood, approaching the concept from an etiologic perspec- but clonal expansion and intraepithelial migration tive. We term this alternative model ‘etiologic field of genetically altered cells within contiguous epithe- effect’, where endogenous and exogenous etiologic lial structures has been proposed.36,58 As a result of factors (such as dietary, lifestyle, environmental, supporting evidence that has accrued through histo- microbial, hormonal, and genetic variations), and their pathological, genetic, and, most recently, epigenetic interactions, predispose to an abnormal tissue micro- studies, the field effect concept has become firmly environmental milieu that can influence all stages of established.13–19 Importantly, altered molecular field tumor evolution. We have taken into account the may represent a potential therapeutic target.59,60 possible contribution of stromal cells and the micro- environment,20–24 and developed a paradigm where macroenvironmental and microenvironmental influ- Synchronous primary tumors and field ences, in their totality, contribute to a field of etiologic effect: insights and intrigue predisposition to disease. The etiologic field effect concept embraces tumor–host interactions,3,25–32 and Field effects have been implicated in the gene–environment interactions, which have become co-occurrence of tumors in more than one organ. increasingly important in molecular epidemiology.33 Examples of such multi-organ involvement by field There are several advantages to an etiologically effect include tumors arising within the ductal oriented model of field effect, as elaborated upon in epithelia of the pancreas, ampulla of Vater, extra- the following sections. An etiologic field effect hepatic bile ducts, and gallbladder,44 respiratory concept can enhance the scope of the traditional epithelia of the lung, bronchi, trachea, larynx and field effect model and can effectively explain a variety nose,59,61 and urothelium of the bladder, ureters, of phenomena relevant to cancer causation and and renal pelves.45,62–64 While shared ontogeny has progression. Effective lifestyle interventions, such as been hypothesized to contribute to certain multi- dietary modification and physical activity, can be organ field effects (eg in epithelia derived from thought of as mechanisms through which etiologic embryonic foregut),44 multi-organ involvement can fields can be attenuated throughout the body, preven- span tissues arising from more than one embryonic ting cancer occurrence and progression, and decrea- germ layer, as exemplified by urothelial tumors; sing cancer burden in our society.34,35 upper urinary tract structures derive from the mesonephros (mesoderm), while the bladder and urethra arise from the urogenital sinus (endoderm). Evolution of the field effect concept The term ‘synchronous tumors’ generally refers to two or more primary tumors arising contempora- The concept of field effect was proposed by neously within a single individual. Synchronous Slaughter et al,11 in their 1953 landmark paper, in primary neoplasms, particularly those originating an attempt to explain the phenomenon of synchro- within a single contiguous organ system, may nous or metachronous primary tumors arising develop as a result of field effect phenomena. within the oral mucosa. In this context, ‘field It should be noted, however, that the absence of effect’ implied an inherent predisposition of the synchronous, or even a solitary cancer,