Mechanisms behind signet ring cell carcinoma formation

Signet ring cell carcinomas are highly malignant dedifferentiated adenocarcinomas. There are no cell-cell interactions between these round-shaped cells. They contain huge numbers of vacuoles, filled with mucins, which are secreted from the cells. The mechanism behind this phenotype has recently begun to be elucidated. In highly differentiated adenocarcinomas the ErbB2/ErbB3 complex is activated, which is followed by phosphatidylinositol 3-kinase (PI3K) activation. p38 MAP kinase is activated downstream of PI3K and adherens junctions are disrupted via Rac1 activation. Loss of adherens junctions leads to the disappearance of tight junctions, which results in a loss of cell-cell interactions. Secretion of mucin is enhanced by activation of PI3K. One of the mucins - Muc4 - can activate ErbB2. Under normal conditions Muc4 and ErbB2 are separated by adherens and tight junctions, however in signet ring cells they are able to interact, since these junctions have been lost. Therefore, an activation loop is formed, consisting of ERbB2/ErbB3-Muc4-ErbB2/ErbB3. As a result, the ErbB2/ErbB3 signaling pathway becomes constitutively activated, cell-cell interactions are lost, and signet ring carcinomas are formed. As a result of constitutive activation of the ErbB2/ErbB3 complex, cell growth is continuously enhanced. Some signet ring cell carcinomas have been found to have mutations in the E-cadherin gene, which fits the above hypothesis. (C) 2014 Elsevier Inc. All rights rights reserved.