Hi. Thanks for the interesting question. I am also interested in E-cadherin in regard to EMT in Crohn's fistulas. To my knowledge, E-cadherin is efficiently repressed via the TGF-beta1-induced transcription factor SNAIL1 during epithelial-mesenchymal transition (EMT). Inhibition of SNAIL1 may prevent E-cadherin repression (antibody, siRNA, ...). In order to allow the epithelial cells to migrate and invade, it is - to my knowledge - essential to repress the intercellular interactions and the connections between the epithelial cells and the underlying membrane. Various factors are able to induce EMT, though.

Best, Sandra

Although loss of E-cadherin is associated with EMT and local invasion which is the first step of metastasis initiation, metastatic lesions in some cancer express epithelial marker like E-cadherin which is associated with mesenchymal epithelial transition (MET). And this MET is essential for efficient metastatic colonization to distant organ. To my mind, stabilization might help in the initial stage but once the cancer cells are disseminated, it can worsen the condition.

In the early transformation to  malignancy the tumor cells begin to produce Matrix Metalloproteinases which destabilizs`e the e-cadherin transforming it to small e-cadherin.  It is the small e-caherein which then interreactis with BRACA and other factors to induce progression to metastasis.  I don't think once malignancy has occurred that the e-cadherin between malignant cells can be stabilized.  It appears in some animal models that the mAb targeting s-e cadherin can cause regression  of the gr owing tumor.  I don't know how this then effects the existing e-cadherin.

Recovery of E-Cadherin definitely slows cell invasion and migration. Typically it is done by removing the repression on the E-Cad gene by targeting SNAI factors, Twists, Zebs which are all transcription factors that repress the E-boxes in the promoter region of E-cad. 

Transcription factors are generally hard to target with small molecules, however, there has been some progress done and a lab recently made a small molecule inhibitor for Twist1. I would suggest looking up the publication.

Some mechanisms are known that restore or up-regulate E-cadherin expression. miRNA-200 acts as a repressor of ZEB1/ZEB2. miR-373 induces E-cadherin expression in acting on a target site in the E-cadherin promoter. AP2 was shown to induce E-cadherin transcription. Similar is true for Wilms tumor protein-1 (WT1). Furthermore, HNF3 together with AML-1 and p300 up-regulates E-cadherin transcription. I think there are reports indicating that E-cadherin is involved in defining the niche where metastatic cells settle down. So impaired E-cadherin function may be important for the initial step to release cells from a primary tumor, but later on E-cadherin expression may be of advantage for the tumor cell. It was shown that E-cadherin expression inhibits apoptosis of tumor cells.