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Fig. 1. (A) Malignant transformation of an epithelium occurs within the context of a three dimensional tissue that is accompanied by (1) fibroblast proliferation and transdifferentiation, (2) extracellular matrix deposition and remodeling, (3) increased matrix metalloproteinase expression and activity, (4) infiltration of immune cells, and (5) angiogenesis. The tumor microenvironment therefore is a dynamically evolving microenvironment that fosters tumor cell invasion, survival and growth. (B) Diagram showing potential NMU targets in the mammary tissue in vivo. Although the epithelium has been classically viewed as the critical mutagenic target of chemical carcinogens, cells within the stroma and the extracellular matrix may also constitute viable chemical targets. (C) Experimental scheme used by Maffini and colleagues to test the tissue organization field theory of carcinogenesis. Animal manipulations included: (a) stromal fat pad treated with NMU and reconstituted with vehicle treated MECs, (b) stromal fat pad and MECs both treated with NMU, (c) normal stromal fat pad reconstituted with NMU-treated MECs, (d) stromal fat pad and MECs treated with vehicle only, (e) intact mammary gland treated with NMU, and (f) intact mammary gland treated with vehicle only.
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