Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression

Abstract

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.

Figure 1

An example of evidence for an “etiologic field effect” phenomenon. Smoking has been shown to increase the incidence of colorectal cancer displaying CpG island methylator phenotype, microsatellite instability, and BRAF mutation, as well as the incidence of synchronous colorectal cancers. Smoking, as an etiologic exposure, creates a field effect manifest as altered colonic tissue microenvironment. Microenvironmental change induced by smoking promotes carcinogenesis via specific pathways resulting in synchronous tumors with shared molecular features. As one might expect of an etiologic field, somatic alterations (such as CpG island methylator phenotype, microsatellite instability, and BRAF mutation) are absent from non-neoplastic tissue within the field.

Figure 2

Comparison of conventional and etiologic field effect models, using colon cancer as an example. A. In the conventional field effect model, a field of alteration ‘X’ in normal tissue (e.g., colon) makes an individual prone to cancer development within that field. Normal colon in the field, and resulting synchronous tumors, show the same molecular alteration ‘X’. B. In an “etiologic field effect” model, etiologic factors (which can be multifactorial) generate a field of tissue microenvironmental changes, favoring the development of cancers through a common carcinogenic pathway characterized by molecular alteration ‘X’. In this setting, resulting synchronous tumors demonstrate the same alteration ‘X’, but normal tissue (e.g., colon) need not necessarily display the same molecular feature.

Figure 3

One of the principal differences between the “etiologic field effect” and conventional field effect concepts is their temporal associations. The conventional field effect typically spans a relatively narrow part of neoplastic evolution spectrum, from the acquisition of somatic aberrations to histologically dysplastic pre-malignancy. The “etiologic field effect”, by comparison, is relevant at all stages from neoplasia initiation to patient death. The presence of “etiologic field effect” precedes the acquisition of pathologic somatic changes, and extends to be influential in tumor evolution, invasion, and metastatic growth.