Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer

Abstract

The microenvironment influences gene expression so that the behavior of a cell is largely determined by its interactions with the extracellular matrix, neighboring cells, and soluble local and systemic cues. We describe the essential roles of context and organ structure in directing mammary gland development and differentiated function and in determining the response to oncogenic insults, including mutations. We expand on the concept of "dynamic reciprocity" to present an integrated view of development, cancer, and aging and posit that genes are like the keys on a piano: Although they are essential, it is the context that makes the music.

Figure 1

(a) The original model of dynamic reciprocity, or the minimum required unit for tissue-specific functions. N, nucleus; MT, microtubules; IF, intermediate filaments; MF, microfilaments; C, collagen. Reprinted from Bissell et al. (1982) with permission from Elsevier. (b) A more complete view of dynamic reciprocity.

Figure 2

The dramatic effect of tissue-tissue interactions. (a) Embryonic ectoderm/mesoderm recombination experiments determined that the identity of the mesoderm dictated the identity of the ectodermal appendage. (b) Epithelial/mesenchymal recombination experiments determined that the identity of the mesenchyme dictated the architecture of the developing epithelium. When mammary gland (MG) epithelium is recombined with salivary gland (SG) mesenchyme, the resulting structure can still produce milk, although the epithelial tree resembles a salivary gland. Panel b adapted from Parmar & Cunha (2004).

Figure 3

The structure and function of the mammary gland are influenced by communication with distant organs and between constituent tissues. (a) The human breast is a bilayered epithelial ductal tree (pink) embedded in a complex stroma. Signals released from distant organs influence ductal and acinar morphogenesis during puberty (^*) and pregnancy (#) (reviewed in Hovey et al. 2002). (b) The epithelium consists of a layer of luminal epithelial cells (LEP) surrounded by myoepithelial cells (MEP) and basement membrane (BM). The epithelium is surrounded by a fibrous stromal compartment and adjacent fatty stroma. Molecular details of epithelial-mesenchymal interactions are described in Table 1.