104:
largely responsible for inhibiting cell growth in mammals. This pathway consists primarily of a phosphorylation cascade involving serine kinases and is mediated by regulatory proteins, which regulate cell growth by binding to growth-controlling genes. The serine/threonine kinase Hippo (Mst1/Mst2 encoded by the STK4 and STK3 genes respectively in mammals) activates a secondary kinase (Lats1/Lats2), which phosphorylates YAP, a transcriptional activator of growth genes. The phosphorylation of YAP serves to export it from the nucleus and prevent it from activating growth-promoting genes; this is how the Hippo-YAP pathway inhibits cell growth. More importantly, the Hippo-YAP pathway uses upstream elements to act in response to cell-cell contact and controls density-dependent inhibition of proliferation. For example, cadherins are transmembrane proteins that form cellular junctions via homophilic binding and thus act as detectors for cell-cell contact. Cadherin-mediated activation of the inhibitory pathway involves the transmembrane E-cadherin forming a homophilic bond in order to activate α- and β-catenin, which then stimulate downstream components of the Hippo-YAP pathway to ultimately downregulate cell growth. This is consistent with the finding that E-cadherin overexpression hinders metastasis and tumorigenesis. Because YAP is shown to be associated with mitogenic growth factor signaling and thus cell proliferation, it is likely that future studies will focus on the Hippo-YAP pathway's role in cancer cells.
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proliferation may be viewed as a reversible form of cell cycle arrest. Furthermore, to transition from cell cycle arrest to senescence, contact-inhibited cells must activate growth-activating pathways such as mTOR. Once cells in high-density cultures become confluent enough such that the cell area falls below a critical value, the adhesion formations trigger pathways that downregulate mitogen signaling and cell proliferation. The growth-promoting mTOR pathway is therefore inhibited, and consequently the contact-inhibited cells cannot transition from cell cycle arrest to senescence. This has crucial implications in cancer therapy; even though cancer cells are not contact-inhibited, confluent cancer cell cultures still suppress their senescence machinery. Therefore, this may be a plausible explanation why senescence-inducing cancer therapy drugs are ineffective.
82:
Thus, it may be reasonably concluded that cell-cell contact is an essential condition for contact inhibition of proliferation, but is by itself insufficient for mitotic inhibition. In addition to making contact with other cells, the contact-inhibited cells must also be forced to reduce its cell area under the mechanical stress and constraints imposed by surrounding cells. Indeed, it has been suggested that mechanical tension acts as an inhibitory signal for mitosis. Moreover, it is important to note that such an inhibition of mitotic activity is a local phenomenon; it occurs between a select few cells in a likely heterogeneous culture.
138:
cells in different directions in an effort to alleviate the elastic tension. A possible alternate event that also leads to the assembly dissociation is that upon stress fiber alignment, the cells' leading edges repolarize away from the contiguous lamellae. This produces significant elastic tension across the entire cell bodies,
100:, a species in which cancer has never observed, show hypersensitivity to contact inhibition. This finding may provide a clue to cancer resistance. Furthermore, recent studies have further revealed some mechanisms of contact inhibition of proliferation and its potential implications in cancer therapy.
90:
Untransformed human cells exhibit normal cellular behavior and mediate their growth and proliferation via interplay between environmental nutrients, growth factor signaling, and cell density. As cell density increases and the culture becomes confluent, they initiate cell cycle arrest and downregulate
150:
Furthermore, as replication increases the amount of cells, the number of directions those cells can move without touching another is decreased. Cells will also attempt to move away from another cell because they stick better to the area around them, a structure called the substratum, than on other
69:
Contact inhibition is a regulatory mechanism that functions to keep cells growing into a layer one cell thick (a monolayer). If a cell has plenty of available substrate space, it replicates rapidly and moves freely. This process continues until the cells occupy the entire substratum. At this point,
137:
to form and align with each other in both colliding partners. The alignment of these stress fibers locally accumulates elastic tension in the lamellae. Eventually, the tension buildup becomes too great, and the cell adhesion complex dissociates, collapses the lamellae protrusions, and releases the
116:
In most cases, when two cells collide they attempt to move in a different direction to avoid future collisions; this behavior is known as contact inhibition of locomotion. As the two cells come into contact, their locomotive process is paralyzed. This is accomplished via a multistep, multi-faceted
103:
Furthermore, it has been shown that cell-cell adhesion formation not only restricts growth and proliferation by imposing physical constraints such as cell area, but also by triggering signaling pathways that downregulate proliferation. One such pathway is the Hippo-YAP signaling pathway, which is
81:
activity over time. Exponential growth has been shown to occur between colonies in contact for numerous days, with the inhibition of mitotic activity occurring far later. This delay between cell-cell contact and onset of proliferation inhibition is shortened as the culture becomes more confluent.
48:
when in contact with one another. In most cases, when two cells contact each other, they attempt to alter their locomotion in a different direction to avoid future collision. When collision is unavoidable, a different phenomenon occurs whereby growth of the cells of the culture itself eventually
52:
Both types of contact inhibition are well-known properties of normal cells and contribute to the regulation of proper tissue growth, differentiation, and development. Both types of regulation are normally negated and overcome during organogenesis during embryonic development and tissue and wound
107:
However, it is important to note that contact-inhibited cells undergo cell cycle arrest, but do not senesce. In fact, it has been shown that contact-inhibited cells resume normal proliferation and mitogen signaling upon being replated in a less confluent culture. Thus, contact inhibition of
95:
cells typically lose this property and thus divide and grow over each other in an uncontrolled manner even when in contact with neighbouring cells. This results in the invasion of surrounding tissues, their metastasis to nearby organs, and eventually tumorigenesis. Cells of
91:
proliferation and mitogen signaling pathways regardless of external factors or cellular metabolism. This property is known as contact inhibition of proliferation and is essential to proper embryonic development, as well as tissue repair, differentiation, and morphogenesis.
132:
exhibit high retrograde flow. A cellular adhesion forms between the lamellae, reducing the actins' retrograde flow rate in the area immediately surrounding the adhesion. Consequently, the cells' velocity and motility are reduced. This then allows actin stress fibers and
146:
collapse, complex disassembly, and the cells' dispersion. Though this hypothetical tension has been characterized and visualized, how tension builds in lamellae and how cell repolarization contributes to tension buildup remain open to investigation.
1142:
Abercombie, M.; Heaysman, J. (1953). "Observations on the social behaviour of cells in tissue culture: I. Speed of movement of chick heart fibroblasts in relation to their mutual contacts".
532:
Seluanov, Andrei; Hine, Christopher; Azpurua, Jorge; Feigenson, Marina; Bozzella, Michael; Mao, Zhiyong; Catania, Kenneth C.; Gorbunova, Vera (26 October 2009).
848:"DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence"
117:
mechanism that involves the formation of a cell-cell adhesion complex upon collision. The disassembly of this complex is thought to be driven largely by
1226:
Weiser, R.J.; Doris
Renauer (1985). "Involvement of plasma membrane glycoproteins in the contact-dependent inhibition of growth of human fibroblasts".
158:, despite being able to proliferate indefinitely, still experience contact inhibition, though generally to a lesser extent than normal cell lines.
1009:"Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence progra"
142:, and likewise causes the adhesion complex's disassembly. Elastic tension has been thought to be the primary driving force of the
691:"The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex"
799:"E-Cadherin Suppresses Cellular Transformation by Inhibiting β-Catenin Signaling in an Adhesion-Independent Manner"
151:
cells. When the two cells colliding are different types of cells, one or both may respond to the collision.
334:"Contact Inhibition of Growth of Human Diploid Fibroblasts by Immobilized Plasma Membrane Glycoproteins"
475:"Contact Inhibition, Macromolecular Synthesis, and Polyribosomes in Cultured Human Diploid Fibroblasts"
1066:
Bell, P. (February 1978). "Contact inhibition of movements in transformed and nontransformed cells".
740:"E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components"
167:
53:
healing. However, contact inhibition of locomotion and proliferation are both aberrantly absent in
383:"Cell-cell signaling by direct contact increases cell proliferation via a PI3K-dependent signal"
534:"Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat"
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in the cells and ultimately results in the colliding cells' changing directions.
1194:
956:
Stoker, M.G. (1967). "Density dependent inhibition of cell growth in culture".
230:
Stoker, M.G. (1967). "Density dependent inhibition of cell growth in culture".
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Abercrombie, M. (27 September 1979). "Contact inhibition and malignancy".
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985:
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724:
499:
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259:
208:
187:
Abercrombie, M. (September 1970). "Contact inhibition in tissue culture".
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41:
897:"Collective and single cell behavior in epithelial contact inhibition"
1297:
977:
251:
1179:"Inter-cellular forces orchestrate contact inhibition of locomotion"
913:
642:"The Hippo-YAP signaling pathway and contact inhibition of growth"
78:
92:
54:
424:"Mechanical feedback as a possible regulator of tissue growth"
1263:
The
Dictionary of Cell & Molecular Biology, Third Edition
129:
58:
531:
124:
First, motile cells collide and touch via their respective
57:
cells, and the absence of this regulation contributes to
24:
refers to two different but closely related phenomena:
845:
40:). CIL refers to the avoidance behavior exhibited by
1225:
1141:
1006:
894:
846:Leontieva, O.; Blagosklonny, M. (December 2010).
688:
1325:
1013:Proceedings of the National Academy of Sciences
901:Proceedings of the National Academy of Sciences
744:Proceedings of the National Academy of Sciences
593:"The Hippo pathway: regulators and regulations"
538:Proceedings of the National Academy of Sciences
479:Proceedings of the National Academy of Sciences
428:Proceedings of the National Academy of Sciences
280:
77:cultures, they exhibit decreased mobility and
1092:
895:Puliafito, A.; Hufnagel, L. (November 2011).
1176:
796:
689:Gumbiner, B.; Stevenson, B. (October 1988).
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281:Hanahan, D.; Weinberg, R. (7 January 2000).
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737:
639:
331:
186:
1095:"Forcing contact inhibition of locomotion"
1007:Leontieva, O.; Demidenko, Z. (June 2014).
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473:Levine, E.; Becker, Y. (February 1965).
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1177:Davis, J.R.; Luchici, A. (April 2015).
381:Nelson, C.M.; Chen, C.S. (March 2002).
332:Wieser, R.J.; Oesch, F. (August 1986).
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955:
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1093:Roycroft, A.; Mayor, R. (July 2015).
1068:Birth Defects Original Article Series
140:not only at the local site of contact
73:As motile cells come into contact in
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70:normal cells will stop replicating.
797:Gottardi, C.; Wong, E. (May 2001).
738:Nam-Gyun, K.; Koh, E. (July 2011).
34:contact inhibition of proliferation
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1228:Experimental Cell Research
1195:10.1016/j.cell.2015.02.015
422:Shraiman, B. (July 2004).
1111:10.1016/j.tcb.2015.05.001
591:Yu, F.; Guan, K. (2013).
283:"The Hallmarks of Cancer"
168:Hyaluronic acid synthase
1034:10.1073/pnas.1405723111
924:10.1073/pnas.1007809109
803:Journal of Cell Biology
765:10.1073/pnas.1103345108
695:Journal of Cell Biology
646:Journal of Cell Science
597:Genes & Development
559:10.1073/pnas.0905252106
441:10.1073/pnas.0404782102
338:Journal of Cell Biology
156:immortalised cell lines
1099:Trends in Cell Biology
815:10.1083/jcb.153.5.1049
707:10.1083/jcb.107.4.1575
609:10.1101/gad.210773.112
864:10.18632/aging.100265
500:10.1073/pnas.53.2.350
350:10.1083/jcb.103.2.361
1290:1979Natur.281..259A
1025:2014PNAS..111.8832L
970:1967Natur.215..171S
756:2011PNAS..10811930K
750:(29): 11930–11935.
550:2009PNAS..10619352S
544:(46): 19352–19357.
491:1965PNAS...53..350L
244:1967Natur.215..171S
658:10.1242/jcs.140103
201:10.1007/BF02616114
22:contact inhibition
1284:(5729): 259–262.
1265:. Academic Press.
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317:11 November
1328:Categories
174:References
144:protrusion
42:fibroblast
914:1112.0465
93:Cancerous
75:confluent
65:Mechanism
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312:10647931
217:11554527
189:In Vitro
162:See also
128:, whose
126:lamellae
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1286:Bibcode
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1021:Bibcode
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546:Bibcode
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368:3733871
359:2113841
268:4150783
260:6049107
240:Bibcode
209:4943054
119:tension
79:mitotic
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55:cancer
44:-like
32:) and
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990:S2CID
909:arXiv
852:Aging
286:(PDF)
264:S2CID
213:S2CID
154:Some
130:actin
46:cells
1302:PMID
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