Contact inhibition (of proliferation) redux

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It has long been appreciated that proliferation of many cells is inhibited by density, a phenomenon that is often attributed to cell–cell contact. The basic properties of this phenomenon were established in the 1960s, along with the observation that such density-dependence was also lost in transformed cells. The mechanistic basis of contact inhibition of proliferation (CIP) has been slower to reveal itself. Here we discuss recent progress in elucidating the roles that cell–cell adhesion molecules play as receptors for CIP and in characterising the intracellular signaling pathways that mediate adhesion-dependent proliferative inhibition.

Section snippets

Phenomenology: No cell is an island

The concept of CIP was first coined in the 1960s to describe the tendency of tissue culture cells to stop or slow their proliferation as they grew to confluence. This is clearly demonstrated by growth curves that plateau as cultures become confluent accompanied by evidence of cell cycle arrest in G1 [5, 6]. (The earlier literature often described the process as contact inhibition of ‘growth’; however, as ‘growth’ more precisely refers to changes in cell size, we will use the term

Cell–cell adhesion receptors as initiators of CIP

Cell–cell adhesion molecules have long been attractive candidate receptors to initiate CIP: there is an elegant parsimony in having molecular mechanisms that mediate recognition and cell–cell cohesion also serve to regulate proliferation. The realization that these receptors can activate or modulate cell signaling [11] also opened the possibility that they may affect pathways that regulate cell proliferation. Of the several classes of such adhesion receptors that are known, much attention has

Cell–cell adhesion and the Hippo pathway

Over the past decade, the Hippo pathway has emerged as a major conserved growth-regulatory mechanism that can integrate many biological cues and signals to control organ size by regulating both cell proliferation and apoptosis. The molecular details of the pathway have been the subject of many excellent recent reviews (e.g. [25, 26]). For the purposes of our discussion, the Hippo pathway ultimately regulates the action of the transcriptional co-activator, Yes-associated protein (YAP)-1 (in

Contact-dependent inhibition of growth factor receptors

Studies that first recognized the phenomenon of CIP appreciated that as cultured cells reach confluence, the response to serum growth factors is progressively inhibited despite the continuous replenishment of growth factors in the medium [39, 40]. Subsequent work concluded that this was not solely a consequence of growth factor exhaustion and was instead due to the ability of cell–cell adhesion to either directly or indirectly inhibit the response to serum growth factors [41]. These studies

Ideas for the future: adhesion receptors, the cytoskeleton and mechanotransduction in CIP

In summary, we are seeing rapid progress in understanding the molecular bases of CIP. In the process, it is abundantly clear that the cellular phenomenon of contact-induced proliferative inhibition entails the cell's ability to integrate multiple upstream cues, including adhesion receptors, that funnel down to modulate core signaling pathways. In considering the impact of cell–cell adhesion, we would also highlight the importance of adhesive interactions as active, mechanical processes that

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank members of the Yap and McClatchey labs for fruitful discussions. A.I.M. is supported by National Institutes of Health Grants (R01GM087558, R01CA113733) and an MGH Research Scholars Award. A.S.Y. is supported by project grants and a Research Fellowship from the National Health and Medical Research Council of Australia.

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