The structural and mechanical complexity of cell-growth control

Abstract

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.

Connecting signaling and cell cycle progression in growth factor-stimulated cells

“…Cell cycle progression is also controlled by cell shape and cytoskeletal tension (Huang and Ingber, 1999). Under conditions where the growth factor and total cell-ECM contact is kept constant, cell shape determines whether the cells do or do not move into S phase (Chen et al, 1997;Huang et al, 1998).…”

“…The shape of the cell and cytoskeletal tension are also important variables and p27 Kip1 is at least one of the points at which they interface with the cell cycle program. The cells shape and tractional force variables may be particularly relevant to in vivo settings as compared with tissue culture systems that are usually used to study regulation of cell proliferation (Huang and Ingber, 1999).…”

Gene expression profiles of bladder cancers: evidence for a striking effect of in vitro cell models on gene patterns

“…There are several possible explanations for the dramatic impact of in vitro cellular models. First, cell -cell interactions markedly differ between these three in vitro models, leading to changes in cellular geometry which could modify gene expression through mechanical forces or cell distortion (Huang and Ingber, 1999;Huang, 2000). Furthermore, variations in cell growth rates under the different culture conditions (data not shown) may participate in this phenomenon.…”

“…Moreover, it is noteworthy that in vitro experiments traditionally use a 1-D or 2-D tumour cell model, whereas solid cancer cells display a 3-D geometry in vivo. Despite the fact that these basic parameters were not frequently taken into account, they have been demonstrated to have dramatic impact on biological responses of cells to differing stimuli (Mansbridge et al, 1994;Dangles et al, 1997;Huang and Ingber, 1999;Lang et al, 2001).…”

“…They are also physical entities with geometric dimensions and are therefore governed by the laws of macroscopic mechanics (Huang, 2000). Indeed, an individual normal cell, within the same biochemical milieu, will divide, differentiate or undergo apoptosis simply because of its external shape (Huang and Ingber, 1999).…”