1. E cadherin and Metastasis
By Andy Ciesielski

2. CDH1 gene Encodes E Cadherin 16q22.1
Ca2+ Dependent Cell-Cell Adhesion Molecule
16 exons
Genomic organization of the human E-cadherin gene. Positions of exons are shown in color boxes with the base pair number of each exon. The connecting lines are introns.

3. Dynamically Associates with Alpha, Beta, and Gamma Catenins and p120
5 Extracellular Domains containing conserved repeated Amino Acid sequences (cadherin repeats),1 Transmembrane Domain, 1 Intracellular Domain
Forms Homophilic Interactions with Adjacent E cadherins in Lateral Dimerization
Dynamically Associates with Alpha, Beta, and Gamma Catenins and p120
120 kDa
Shematic illustration of E-cadherin in adherens junction. E-cadherin homodimer on the cytoplasmic membranes of adjacent
cells is shown. The juxtamembrane region with the interacting molecules is also shown. CM – cytoplasmic membrane; AJ –
adherens junction; ED – extracellular domain; ID – intracellular domain; AC – actin cytoskeleton; 1-beta-catenin; 2-alpha-catenin;
3-p120.

4. Cellular Roles Adhesion Between Epithelial Cells- Adherens Junctions
Development- Gastrulation, Neurulation, Organogenesis
Adhesion of blastomeres and embryo compaction
Controlled epithelial mesenchymal conversion (loss of epithelial adhesion and polarity)
-/- mutations lethal at blastocyst stage in mice

5. Cellular Roles Signaling Pathways EGFR and MAPK Wnt
Snail, Slug, Twist-
Repressors
of E cadherin
Tumor Suppressor

6. Metastasis
Tumor cells lose adhesion for surrounding cells, undergoing EMT
Spread into blood vessels and other tissues forming new tumors at new sites

7. Loss of E cadherin Leads to Metastatic Tumors
E cadherin functions as a Tumor Suppressor
E cadherin loss enables disaggregation of cancer cells from one another
LOH in CDH1 Correlates with metastasizing malignancies
Over 75% of Metastatic Cancers Exhibit CDH1 Abnormalities
CDH1 mutations involved with several cancers: Breast, Liver, Prostate, Stomach, Endometrium, Ovary, and Lung
Loss of E cadherin Function Correlates with Poor Prognosis

8. E Cadherin Expression in Cancer
Type 1- Preserved Type, Tumor Cells Retain Cadherin Expression
Type 2- Reduced Type, Tumor Cells Show Reduced Cadherin Expression,
Type 3- Complete Loss of Cadherin Function
Type 4- Aggregate Failure

9. E Cadherin Mutations Hypermethylation
Somatic Mutations- Insertions, Deletions, Non-sense Mutations
Diffuse Gastric Tumor Showed In-Frame Mutations
Infiltrative Breast Cancers Showed Out-of-frame Mutations Leading to Truncated E Cadherins
Hereditary Predispositions
Early onset cancers, high penetrance
Silencing or Over Activation of Various Influential Factors
CDH1 promoter
Snail, Slug, Twist – trigger EMT, repress E cadherin
Tyrosine Phosphorylation of accessory proteins, Alpha, Beta, Gamma Catenins interfering with Cadherin Action

10. Down Regulation of E cadherin and Dominant Negative E cadherin Proteins Results in Loss of Typical Morphology- Loss of Cellular Adhesion
The adoption of fibroblastic morphology by shEcad cells typifies a EMT
shEcad cells also showed increases in
Mesenchymal proteins N-Cadherin and
Vimentin compared to control cells

11. Orthotopic and Tail Vein Assays Reveal Metastases in Lungs of Nude Mice
shCntrl
shEcad
DN-Ecad

12. Motility and Apoptosis of Cells Upon Loss of Cell Adhesion
shEcad cells showed increased motility and invasiveness in Boyden
Chamber Assays
shEcad cells showed high levels of cells indicating decreased
apoptosis in the absence of substrate attachment
shEcad cells showed decreased amounts of annexinV indicating
lower rates of apoptosis

13. Summary
E cadherin normally functions to maintain cell adherens junctions in epithelial tissues
E cadherin can be appropriately regulated to trigger EMT during development
Inappropriate regulation or mutations is strongly correlated with a variety of metastatic cancers
E cadherin loss appears sufficient to give metastatic ability HMLER cells.
Loss of extracellular and intracellular domains is necessary for gaining metastatic ability
Loss of E cadherin with additional oncogenic lesions quickens the transition to invasive metastases

14. References
Takeichi, Masatoshi, Cadherins in Cancer: Implications for Invasion and Metastasis. Cell Biology 5 (1993)
T. Onder, P. Gupta, S. Mani, J. Yang, E. Lander, R. Weinberg. Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways. Cancer Research 68 (2008)
Pecina-Slaus, Nives. Tumor Repressor Gene E-Cadherin and its Role in Normal and Malignant Cells. Cancer Cell International 3 (2003) 1-7.