Metastasis is a major cause of death in cancer patients. According to the inverse relationship between migration and E-cadherin levels in vitro, it has been proposed that invasion and metastasis of the surrounding tissues begin after the loss of the intercellular adhesion protein E-cadherin. However, this hypothesis is inconsistent with the observation that the majority of breast cancers are invasive ductal carcinomas and express E-cadherin in the primary tumor and metastasis.
To address this and other theoretical issues, researchers from Johns Hopkins University (JHU) and other institutions led by Andrew J. Ewald of the JHU School of Medicine tested the genetic requirement for E-cadherin in metastasis using the mouse and human models of luminal and basal invasive ductal carcinoma. The relevant research results were published in Nature recently, entitled “E-cadherin is required for metastasis in multiple models of breast cancer”.
The researchers found that E-cadherin promotes metastasis in multiple invasive ductal carcinoma models. Loss of E-cadherin, while increasing invasion, also decreases the proliferation and survival of cancer cells, the number of circulating tumor cells, the dissemination of cancer cells in distant organs, and the growth of metastases.
Moreover, the researchers pointed out that, at the transcriptional level, E-cadherin was associated with the upregulation of genes involved in transforming growth factor-β (TGFβ), reactive oxygen species, and apoptosis signal pathways. And at the cellular level, sporadic E-cadherin negative cells showed increased SMAD2/3 nuclear enrichment, oxidative stress, and apoptosis. Inhibition of TGFβ receptor signaling, ROS enrichment, or apoptosis reversed colony formation of E-cadherin–negative cells.
The results of this study suggest that E-cadherin acts as a survival factor in the detachment, systemic spread, and seeding processes of invasive ductal carcinoma metastasis by inhibiting reactive oxygen species-mediated apoptosis. Identifying molecular strategies that inhibit E-cadherin-mediated survival of metastatic breast cancer cells may have the potential for the treatment of breast cancer.
Reference
Andrew J. Ewald et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. DOI https：//doi.org/10.1038/s41586-019-1526-3
