Tumour-stromal interactions. Role of the stroma in mammary development

Abstract

Mammary development depends on branching morphogenesis, namely the bifurcation and extension of ductal growth points (end buds) and secretory lobules into a more or less fatty stroma. Because breast carcinomas are overwhelmingly ductal in origin, this review focuses on stromal influences guiding postnatal ductal development and there is only the briefest account of the role of embryonic stroma (mesenchyme). The stroma as the necessary target for endocrine mammogens and the source of stimulatory growth factors is described and the importance of mammary epithelium-induced modifications of the periductal stroma is emphasized. Evidence is presented that if they are to grow, end buds must condition proximal fatty stroma by recruiting white blood cells as well as inducing stromal cell division and, possibly, estrogen receptors. The induction of a fibrous stromal tunic around the end bud is described and its likely role as a complex ductal morphogen is discussed; a possible role in growth inhibition is also considered. Although the signals governing fibrotic induction, ductal morphogenesis, and growth inhibition are unknown, a role for transforming growth factor-beta is highly likely and is discussed. Finally, a need for new conceptual and experimental approaches to understanding stromal-epithelial signaling is discussed.

Figure 1

Ducts and end buds in the juvenile mouse mammary gland. (a) Photomicrograph illustrating the mammary ductal system in a 5-week-old nulliparous mouse. Note the 'open' ductal architecture, which leaves 80% or more of the gland parenchyma-free. End buds (large arrows) identify growing ducts. Those end buds that are arrayed along the right-hand side of the gland are in various stages of regression. Blunt-tipped branches (small arrows) mark growth-quiescent ducts. The nipple (asterisk) is at base of the gland. Magnification approximately ×15. (b) Photomicrograph of a longitudinal section through an end bud and subtending duct. The induction of a fibrous connective tissue sheath (large arrows) coincides with the constriction of the end bud to ductal dimensions. The alcian blue stain used in this preparation detects glycosaminoglycans and highlights the extracellular matrix/basal lamina complex at the epithelial-stromal interface (small arrows) [19]. Magnification ×250.

Figure 2

Photomicrographs illustrating patterns of DNA synthesis in an end bud, its immediately subtending duct, and a lateral branch (a), as well as in a duct distant from the growth front (b). [³H]Thymidine autoradiographs were stained with alcian blue. Large arrows, fibrous sheath around end bud; small arrows, DNA synthetic cells. Magnification ×250.

Figure 3

Diagrams depicting stromal-epithelial signaling affecting mammary ductal growth and its inhibition. (a) Growth stimulatory signals. Endocrine mammogens [estrogen (E), growth hormone (GH)], acting on stromal targets in front of the end bud, stimulate the synthesis of the local mammogens epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and members of the activin/inhibin family. From the end bud, unknown retrograde signals (broken lines) stimulate vicinal DNA synthesis and attract macrophages and eosinophils. The stimulation of lateral branches along mature ducts involves the focal loss or inactivation of transforming growth factor-β₁ (TGF-β1), relieving the inhibition of hepatocyte growth factor (HGF) synthesis and permitting lateral branch development. Outer shaded zone, fibrous sheath; L, lumen. (b) TGF-β in growth inhibition and induction of the periductal fibrous sheath. Although end buds are inhibited by exogenous TGF-β, it remains unproven as the natural mechanism for end bud growth termination. In a purely speculative model for fibrous induction, TGF-β, acting in a paracrine mode on cap/myoepithelial cells (black layer), induces parathyroid-hormone-related protein (P). Secreted parathyroid-hormone-related protein then acts on stromal targets, inducing highly localized fibrosis. Finally, along the duct, TGF-β₁ inhibits lateral branching by blocking HGF action.