Week 25 cell mobility

What is cell motility?

The ability of cells to move and change position

What is cell motility important for?

Development, immune response, wound healing and cancer metastasis

What are the steps of metastasis in order?

• Invasion

• Intravasation

• Circulation

• Adhesion

• Extravasation

What is invasion?

Cells invade into the ECM

What is intravasation?

Cells move from the ECM into the circulation

What happens during circulation?

Cells travel in the bloodstream and have to survive

What is adhesion?

Cells attach to endothelial cells forming the vasculature

What is extravasation?

Cells move across the endothelium into the organ ECM

What is metastasis formation?

A multi-step cascade

What process is implicated and inefficient?

The process of metastasis

What percentage of cancer-related deaths is caused by metastasis?

90% of cancer-related deaths

What are common secondary organs for metastasis?

Brain

lung

liver

bone

Where does metastasis start?

Primary tumour site

Where do cancer cells spread to?

Site of metastasis

What is needed for movement?

• Cell adhesion molecules (CAMs)

• Integrins

What allows cells to invade tissues?

MMPs degrade the ECM

What starts metastasis?

• Loss of E-cadherin

• Epithelial-Mesenchymal Transition (EMT)

What happens next?

• Cells migrate

• Enter bloodstream

• Form secondary tumours

What happens after extravasation at the secondary site?

• Pre-metastatic niche

• Micrometastasis

• Colonization

How does the metastatic cascade start?

Epithelial cells losing E-cadherin expression

What transition is involved in the start of metastasis?

Epithelial-Mesenchymal Transition (EMT)

What happens during EMT?

Epithelial cells acquire the mesenchymal phenotype and lose polarity

What is step 1 of cancer metastasis?

Invasion of cells into the ECM

What is required for invasion?

MMPs metalloproteinase to remodel and degrade the ECM

What are matrix metalloproteases (MMPs)?

Endopeptidases secreted as zymogens, capable of degrading components of basal membrane and ECM

What increases expression or enhanced maturation of MMPs?

Activation of several integrins

Why are MMPs important in invasion?

Most important proteases in terms of invasion

What is found in the active site of the MMP enzyme?

Zinc atom

Which cells can produce MMPs?

• Tumour cells

• Fibroblasts

• Macrophages

What are TIMPs?

Tissue inhibitors of MMPs

What is the function of TIMPs?

Maintain normal levels of MMP activity

What structures are formed at the leading edge of migrating cells?

Lamellipodia and filopodia

What promotes filopodia formation?

Cdc42

What promotes lamellipodia formation?

Rac

What promotes stress fibre formation?

RhoA

What are focal adhesions?

Cell-matrix adhesions mediated by integrins and actin

What happens at the rear of migrating cells?

Adhesions detach

What is needed to move an organelle inside a cell?

ATP, a motor protein and a polarized track

Why is metastasis considered inefficient?

Most circulating tumour cells fail to form secondary tumours

What is colonization?

Growth of metastatic cells into a detectable secondary tumour

What is a pre-metastatic niche?

A favourable environment in a distant organ for tumour cell growth