Normal cells grown in culture are inhibited or restricted from migration and/or proliferation by adhering to neighboring cells creating monolayers in culture (1
). This phenomenon, known as contact inhibition (CI), was first observed in cells taken from chick embryo ventricles in 1953 (2
). As early as 1957, it was recognized that cells derived from tumor tissue did not contact inhibit (3
). CI of migration (CIM) describes the cessation of cell movement when a cell comes into contact with another cell. CI of proliferation (CIP) is a separate phenomenon that describes the cessation of cell division following cell-cell contact (1
). The observation that tumor-derived cells do not contact inhibit (neither CIP nor CIM) led to the hypothesis that one step in tumor progression is the loss of cell-cell adhesion. Since loss of CI is one of the first observable steps in cancer progression, it is likely to be a key event. In the years since these observations, a number of proteins involved in promoting cell adhesion, known as cell adhesion molecules (CAMs; ref. 1
) have been identified.
CAMs are subdivided into four superfamilies: cadherin, immunoglobulin (Ig), integrin, and selectin. Members of all CAM superfamilies can mediate cell-cell interactions, while integrins alone mediate cell-matrix interactions. CAMs bind to either the exact same proteins, known as homophilic binding, or different proteins, called heterophilic binding.
Many CAMs, including E-cadherin, cell-cell adhesion molecule 1 (C-CAM1) and deleted in colorectal cancer (DCC) are putative tumor suppressor genes (4
). Genetic loss or DNA hypermethylation results in reduced CAM expression, and is one possible explanation for the loss of CI in cancer (4
Post-translational changes of CAMs, such as proteolysis, has been observed and may also result in the loss of CI observed in cancer. Cleavage of many CAMs resembles that of the Notch receptor following ligand binding (5
). Three cleavage events occur in the processing of Notch, identified as S1, S2, and S3 (). S1 cleavage is attributed to a furin-like convertase in the trans
-Golgi. S2 occurs in response to ligand binding and is mediated by a disintegrin and metalloprotease (ADAM). ADAM cleavage results in the shedding of the extracellular domain (ECD) of the Notch receptor. S3 is mediated by the γ-secretase complex and cleaves Notch within its transmembrane domain, thereby releasing its cytoplasmic fragment to translocate to the nucleus (5
). γ-secretase consists of four proteins at any one time: the protease, either presenilin-1 (PS-1) or presenilin-2 (PS-2), and three other essential members of the complex, nicastrin, Aph-1, and Pen-2 (5
). This same cleavage paradigm has been observed for other transmembrane proteins, including cell-cell CAMs (6
Figure 1 Notch cleavage. The Notch receptor is cleaved in three-step process to yield a functional signaling protein. S1 cleavage occurs in the Golgi by a furin-like protease. S2, or α-secretase, cleavage by ADAM17, occurs on the extracellular face of (more ...)
We suggest four potential mechanisms whereby cleavage of CAMs could alter their biological function and result in the loss of CI. First, the cleavage and shedding of the ectodomain (ECD) of cell-cell CAMs can reduce cell-cell adhesion and promote proliferation and/or migration due to its release from the plasma membrane, potentially antagonizing cell-cell adhesion by “occupying” the transmembrane receptor (7
). Second, the shed fragment may associate with integrins and/or components of the extracellular matrix and form a new molecular substrate for cell migration (8
). Third, the shed ECD may bind to different receptors on other cells and activate distinct signals that regulate either proliferation or migration (9
). Finally, the released cytoplasmic fragment (ICD) may not associate with its normal signaling partners and may instead activate novel signals that regulate either proliferation or migration or potentiate normal signals when not anchored to the plasma membrane (11
We propose a new theory to explain the loss of CI in tumor progression, in which cleavage of homophilic cell-cell CAMs deregulates CI by interfering with stable cell-cell adhesion and/or activating signals that promote cell proliferation and/or migration. We only consider homophilic cell-cell CAMs in this Perspective since cell-extracellular matrix CAMs are not involved in mediating inhibition of growth and migration initiated by cell-cell contact. We will review the four best examples of homophilic cell-cell CAM cleavage in cancer, E-cadherin, N-cadherin, EpCAM and PTPμ-subfamily receptor protein tyrosine phosphatases (RPTPs). lists what is known about the cleavage and shedding of other homophilic cell-cell CAMs that may also disrupt CI. When considered altogether, there is a large body of evidence that supports our theory that disruption of stable cell-cell adhesion and adhesive signaling through homophilic cell-cell CAM proteolysis may be the key to explaining the loss of CI observed in cancer.
Summary of Cell-Cell CAM Cleavage in Cancer