The structural and mechanical complexity of cell-growth control
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78 as well as growth that is free of anchorage, but not of serum 79 . review NATURE
CELL BIOLOGY | VOL 1 | SEPTEMBER 1999 | cellbio.nature.com E135
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review The structural and mechanical complexity of cell-growth control Sui Huang* and Donald E. Ingber*† *Departments of Pathology and Surgery, Children’s Hospital and Harvard Medical School, Boston, Massachussetts 02115, USA †e-mail: ingber@a1.tch.harvard.edu Tight control of cell proliferation is required to ensure normal tissue patterning and prevent cancer formation. The analysis of cultured cells has led to an explosion in our understanding of the molecules that trigger growth and mediate cell-cycle progression. However, the mechanism by which the local growth differentials that drive morphogenesis are established and maintained still remains unknown. Here we review recent work that reveals the importance of cell binding to the extracellular matrix, and associated changes in cell shape and cytoskeletal tension, to the spatial control of cell-cycle progression. These findings change the paradigm of cell-growth control, by placing our understanding of molecular signalling cascades in the context of the structural and mechanical complexity of living tissues. ver the past decade, enormous advances have been made in a our understanding of the molecules that mediate the control Oof cell proliferation. Soluble mitogens, insoluble extracellular matrix (ECM) molecules, cell-surface growth-factor receptors, integrins, signal-transducing molecules and proteins that form the central core of the cell-cycle machinery have all been identified, iso- lated and sequenced, and their encoding genes cloned. With the rapid progress of the Human Genome Project, more growth activa- tors and inhibitors will no doubt be uncovered in the near future. However, the questions that are central to studies of both morpho- genesis and cancer formation are not just how cell growth is turned on and off, but also where and when this happens. A more thorough understanding of the intricate workings of the molecular cascades that mediate cell-cycle progression inside individual cells will not answer this question of spatial control. In this review, we focus on recent work that reveals the importance of cellular adhesion to the ECM, cell shape and mechanical tension in the cytoskeleton for b local control of cell-cycle progression. These results provide new insight into morphogenetic regulation and emphasize the need to develop new approaches to confront the structural complexity of biological systems. Back to basics The three-dimensional forms of specialized tissues, such as branch- ing capillary networks and multilobular secretory epithelia, result from the establishment of local growth differentials over distances that sometimes extend across just a few cell diameters (Fig. 1a)1,2. Reiteration of this simple building rule over time and space causes similar localized sites of growth acceleration to be established along the sides of newly formed buds or branches, thereby creating the fractalized forms that are exhibited by almost all living tissues (Fig. 1b). Localized production of growth factors, such as members of Figure 1 How local growth differentials drive normal tissue patterning during the fibroblast growth factor (FGF) family, has been shown to pro- epithelial morphogenesis and angiogenesis. Epithelial morphogenesis is shown mote tissue expansion and to guide branching in certain developing at the top of each panel, and angiogenesis at the bottom. a, A higher magnification tissues3. However, although localized production of soluble chem- view showing how growth is constrained to small groups of cells (red) under which oattractants and mitogens may determine the general position at lie regions of the basement membrane (green) that have become thin as a result of which future tissue branches form, they do not explain how these accelerated rates of ECM turnover. Outward budding and branching result from branches are created. For example, the existence of soluble gradi- mesenchymal influences and because neighbouring cells along the same basement ents of mitogens alone cannot explain how the sharp growth differ- membrane remain quiescent (white cel s). b, A lower magnification view showing how entials that determine tissue patterning can be established on the reiteration of this simple building rule over time and space results in creation of micrometre scale (for example, between adjacent cells). Localized complex tissue architecture with characteristic fractal-like forms. growth differentials are also observed in microenvironments that are known to be saturated with numerous soluble mitogens, such as during wound healing or angiogenesis as well as in in vitro morpho- living embryos reveals that growing sprouts, quiescent differenti- genesis models. In fact, careful analysis of capillary development in ated tubes and regressing capillaries can all co-exist in the same NATURE CELL BIOLOGY | VOL 1 | SEPTEMBER 1999 | cellbio.nature.c© 1999 Macmillan Ma om gazines Ltd E131
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