Transcript Document 241673

E cadherin and Metastasis
By Andy Ciesielski
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.
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-alphacatenin;
3-p120.
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
Cellular Roles
Signaling Pathways

EGFR and MAPK

Wnt

Snail, Slug, TwistRepressors
of E cadherin
Tumor Suppressor
Metastasis
Tumor cells lose adhesion for surrounding cells, undergoing EMT
Spread into blood vessels and other tissues forming new tumors at
new sites
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
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
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
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
Orthotopic and Tail Vein Assays Reveal Metastases in
Lungs of Nude Mice
shCntrl
shEcad
DN-Ecad
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
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
References
Takeichi, Masatoshi, Cadherins in Cancer: Implications for Invasion
and Metastasis. Cell Biology 5 (1993) 806-811.
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) 3645-3654.
Pecina-Slaus, Nives. Tumor Repressor Gene E-Cadherin and its
Role in Normal and Malignant Cells. Cancer Cell International 3
(2003) 1-7.