Context is everything: Mining the normal and preneoplastic microenvironment for insights into the diet and cancer...

This review highlights the context-dependence of epithelial carcinogenesis in order to illuminate the potential for progress in the field of diet and cancer prevention. Estimates drawn from observational epidemiology imply that diet and lifestyle changes have the potential to prevent 30-40% of cancer cases. However, the application of knowledge gleaned from observational epidemiology applied to randomized clinical trials (RCT) has yielded equivocal or negative results. Resolving this conundrum requires: (i) advances in diet assessment methodologies and the design of clinical trials; (ii) greater knowledge of the active components within foods which may impact cancer risk; and (iii) knowledge about the effects of dietary components on susceptible tissues throughout the disease process (Meyskens, F. L., Jr., Szabo, E., Diet and cancer: The disconnect between epidemiology and RCT. Cancer Epidemiol. Biomarkers Prev. 2005, 14, 1366-1369). Explicit consideration of the causal criteria will pay tangible benefits in the design of basic, clinical, and epidemiologic studies in cancer prevention. The rational identification of diet-dependent physiologic targets for cancer prevention is best pursued by appreciating context-dependence of epithelial carcinogenesis. Five contexts, or paradigms useful in understanding the multifactorial nature of carcinogenesis, are offered which describe the potential diet-associated physiologic influences on normal and preneoplastic cells and tumor microenvironments. Taken together with the interactions of systemic, endocrine, and autocrine/paracrine signals that may modulate the process of carcinogenesis, we can appreciate how dietary factors may act collectively in normal tissues or at early stages of carcinogenesis to prevent cancer. Only by understanding the effect of dietary components on the cellular and stromal components of the tissue microenvironment early in the process of epithelial carcinogenesis will yield clues useful for the development of improved strategies for cancer prevention.