Tumours with up & down regulation

 Tumors with down-regulated

E-cadherin expression

Seen in several epithelial tumors, including adenocarcinomas of the colon and breast 

• This down-regulation reduces the ability of cells

to adhere to each other and facilitates their

detachment from the primary tumor

• The normal function of E-cadherin is dependent

on its linkage to catenins

• In some tumors E-cadherin is normal, but its expression is reduced because of mutations in

the gene for α catenin

2-Local degradation of the basement membrane and interstitial connective tissue

Elaboration of proteases by

– Tumor cells themselves or

– Stromal cells [induced by tumor cells]

Many different families of proteases

– Matrix metalloproteinases (MMPs) 

– Cathepsin D  & 

– Urokinase plasminogen activator.

MMPs

Tumors either elaborate large quantities of MMPs or they

may reduce the concentrations of MMP-inhibitors

They regulate tumor invasion by:

• Dissolving components of the BM & interstitial matrix 

• Releasing ECM-sequestered growth factors

– Cleavage products of collagen and proteoglycans also havechemotactic, angiogenic, and growth-promoting effects

• epithelial and vascular basement membrane and also stimulatesEg: release of VEGF from ECM-sequestered pools

MMP9 is a gelatinase that cleaves type IV collagen of the

Eg: Benign tumors of the breast, colon, and stomach show

little type IV collagenase activity, whereas their

malignant counterparts overexpress this enzyme.

3 - Attachment to novel ECM components

• Normal epithelial cells have receptors, such as integrins,

for basement membrane laminin and collagens that are polarized at their basal surface

– These receptors help to maintain the cells in a resting,

differentiated state

• Loss of adhesion in normal cells leads to induction of apoptosis [tumor cells are resistant to this form of cell death]

• The matrix itself is modified in ways that promote

invasion and metastasis

– Eg: cleavage of the basement membrane proteins collagen IV

and laminin by MMP2 or MMP9 generates novel sites that bind

to receptors on tumor cells and stimulate migration.