Serendipity; Close Encounter of Tenascin C.

Abstract

In 1924, Hans Spemann and Hilde Mangold established the concept of embryonic induction (1). They transplanted the dorsal grey crescent region of one newt gastrula to the ventral part of another newt gastrula and found that a piece of the transplant induced the host tissue into the formation of a secondary embryo. With this as a starting point, the interactions among various tissues became the subject of follow up research during the next decade. In the 1950s, Clifford Grobstein discovered that organogenesis of glandular tissues in prenatal mice required morphogenetic interactions between epithelium and mesenchyme (2). Consequently, epithelial-mesenchymal interactions became a hot topic for developmental biologists worldwide. From 1967 to 1981, similar experiments were done on various organs such as salivary glands, kidney, pancreas, digestive tract, prostate, tooth, lung and mammary gland, etc. In 1969, Klaus Kratochwil observed typical mammary gland morphogenesis by monopodial branching pattern in recombinant cultures of embryonic mammary epithelium with mammary mesenchyme. By contrast, mammary epithelium cultured in contact with salivary gland mesenchyme showed salivary gland like morphogenesis by dichotomous branching pattern (3). Prompted by this observation, Teruyo Sakakura and her colleagues conducted further analysis using in vivo system in 1976. They transplanted embryonic mammary epithelium combined with mammary or salivary mesenchyme under the kidney capsule and made the host female mice pregnant and lactating. The results were clear cut. Both grafted tissues produced milk (4). That is, mammary gland morphogenesis is mesenchyme-dependent, and cytodifferentiation is epithelium-specific. The ability to recapitulate morphogenesis persists in adult mammary epithelium. When embryonic mammary or salivary mesenchyme is transplanted into adult mammary gland, the epithelial cells in contact with the mesenchymal graft proliferate in multiple layers, forming duct-alveolar hyperplasia with nodular structure rapidly becoming cancerous (5, 6). Based upon these results, she built up a hypothesis that embryonic changes in the stroma must occur during cancer development.