Invasion and metastasis, ECM

 Invasion and metastasis are biologic hallmarks of malignant tumors

• For tumor cells to break loose from a primary mass, enter blood vessels or lymphatics, and produce a secondary growth at a distant site,

they must go through a series of step (the

metastatic cascade):

Divided into two phases: 

1. Invasion of the extracellular matrix (ECM)

2. Vascular dissemination, homing of tumor cells,

and colonization.

Invasion of Extracellular Matrix

Two types of ECM: 

1. Basement membrane (BM) and 

2. Interstitial connective tissue

Composition: ECM is made up of collagens, glycoproteins,

and proteoglycans

1. A carcinoma must first breach the underlying BM

2. Then traverse the interstitial connective tissue, and 

3. Gain access to the circulation by penetrating the

vascular BM

This process is repeated in reverse when tumor cell emboli

extravasate at a distant site

Invasion of Extracellular Matrix

Invasion of the ECM initiates the metastatic cascade and is an active process that

can be resolved into several steps 

1. Changes (“loosening up”) of tumor cellcell interactions 

2. Degradation of ECM 

3. Attachment to novel ECM components 

4. Migration of tumor cells. 

Sequence of events in the invasion

of epithelial basement membranes

by tumor cells: 

Tumor cells detach from each other because of reduced adhesiveness,

then secrete proteolytic enzymes, degrading the basement membrane. 

Binding to proteolytically generated binding sites

and 

tumor cell migration follow.

Dissociation of cells from one

another

1(“loosening up”) of tumor cell-cell interactions

As a result of alterations in intercellularadhesion molecules.

Normal cells are bound together

by adhesion molecules

• Cell-cell interactions are mediated by the

cadherin family of transmembrane

glycoproteins 

• Intracellularly the E-cadherins are

connected to β-catenin and the actin cytoskeleton.