Extracellular matrix (ECM) is an intricate network composed of an array of macromolecules, the importance of which is becoming increasingly apparent. The ECM is an integral part of the machinery that regulates cell function; its role in cell differentiation and tissue-specific gene expression, although essential, is not yet understood. It can act as a positive as well as a negative regulator of functional differentiation depending on the cell type and the genes studied. It also acts in a hierarchical fashion, exacting higher and higher degrees of stringency to achieve full functional differentiation. Regulation by ECM is closely interrelated with the action of other regulators of cellular function, such as growth factors and hormones. But ECM may exert its regulation of gene expression by mechanisms distinct from those known for soluble transcription factors. In this short review, we describe three systems in which ECM has been shown to play a crucial role in functional differentiation, but we emphasize mainly the work from our own laboratory to provide a more in-depth analysis of one system. The three systems are: mouse mammary epithelial cells, rat hepatocytes, and human keratinocytes. The crucial role of ECM in normal cell differentiation implies that its alteration may have serious consequences in malignancies and other diseases. The current functional cell culture models could provide powerful tools not only for understanding regulation of normal cell function but also for the studies of tumorigenesis and possibly cancer therapy.
Mammary epithelial cells undergo changes in growth, invasion, and differentiation throughout much of adulthood, and most strikingly during pregnancy, lactation, and involution. Although the pathways of milk protein expression are being elucidated, little is known, at a molecular level, about control of mammary epithelial cell phenotypes during normal tissue morphogenesis and evolution of aggressive breast cancer. We developed a murine mammary epithelial cell line, SCp2, that arrests growth and functionally differentiates in response to a basement membrane and lactogenic hormones. In these cells, expression of Id-1, an inhibitor of basic helix-loop-helix transcription factors, declines prior to differentiation, and constitutive Id-1 expression blocks differentiation. Here, we show that SCp2 cells that constitutively express Id-1 slowly invade the basement membrane but remain anchorage dependent for growth and do not form tumors in nude mice. Cells expressing Id-1 secreted a ϳ120-kDa gelatinase. From inhibitor studies, this gelatinase appeared to be a metalloproteinase, and it was the only metalloproteinase detectable in conditioned medium from these cells. A nontoxic inhibitor diminished the activity of this metalloproteinase in vitro and repressed the invasive phenotype of Id-1-expressing cells in culture. The implications of these findings for normal mammary-gland development and human breast cancer were investigated. A gelatinase of ϳ120 kDa was expressed by the mammary gland during involution, a time when Id-1 expression is high and there is extensive tissue remodeling. Moreover, high levels of Id-1 expression and the activity of a ϳ120-kDa gelatinase correlated with a less-differentiated and more-aggressive phenotype in human breast cancer cells. We suggest that Id-1 controls invasion by normal and neoplastic mammary epithelial cells, primarily through induction of a ϳ120-kDa gelatinase. This Id-1-regulated invasive phenotype could contribute to involution of the mammary gland and possibly to the development of invasive breast cancer.The epithelial cells of the mammary gland undergo coordinate changes in growth, differentiation, and invasion of the surrounding ECM during embryonic development and puberty, and throughout much of adulthood during each menstrual cycle. Particularly striking changes occur during pregnancy, lactation, and involution. The molecular mechanisms that control the growth and functional differentiation of mammary epithelial cells are slowly being elucidated, but far less is known about the transient invasive behavior of normal breast epithelial cells.Normal breast epithelial cells proliferate and invade the surrounding ECM during the fetal and postnatal development of the gland, and then more vigorously at puberty as the branches of the mammary epithelial tree are formed. After puberty, there are minor waves of mammary epithelial-cell proliferation during each estrous cycle (16,46). The most striking activity of mammary epithelial-cell proliferation and invasion occurs during pregnancy,...
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