Invasion and Metastasis

Question 1

What is the sequence of invasion and metastasis?

Answer 1

• Detachment and invasion into surrounding tissues, neo-vascularisation= secrete matrix proteolyzing enzymes
• Penetration of body cavities and vessels- lymph/blood
• Release of tumour cells for transport to other sites in vessels
• Evasion of host defences, avoid immune destruction
• Adherence and reinvasion, or extraversion at site of arrest
• Manipulation of new environment to promote tumour cell survival, vascularisation and growth in new site (metastasis- rate limiting step)

Question 2

What is invasion?

Answer 2

Cells move through 3D space, destruction of tissue matrix or widening of tissue spaces by oedema

Question 3

What does invasion require?

Answer 3

• Change and/or loss in cell-cell/ cell-matrix adhesion (motility)
• Focal proteolysis of matrix
• Movement to occupy space

Question 4

What are cadherins?

Answer 4

Central to adhesion, establish cell polarity and cell-cell differentiation

Question 5

What does experiments and clinical observations show about cadherins?

Answer 5

Invasion can be inhibited by E-cadherin expression (animal models)
Role in adenoma to carcinoma transition
In carcinomas, cadherins, beta catenin and APC are lost/extensively mutated so loss of adhesion

Question 6

What are integrins?

Answer 6

Cell matrix adhesion and signalling for cell survival and proliferation

Question 7

What is the difference between stationary normal cells and motile malignant cells in cell adhesion?

Answer 7

Normal= Int receptors in clusters at base, assembled matrix
Malignant= Int receptors dispersed reduced in expression, secreted matrix
Tumour cells lose apoptotic response to changes in matrix signals after changing distribution and stability of Int receptors

Question 8

What occurs during matrix proteolysis in cancer cells?

Answer 8

• Switch on synthesis and secretion of matrix proteases
• Signal to stromal fibroblasts to turn on secretion of matrix proteases
• Proteases= Matrix Metallo-Proteases (MMPs), collagenases, hyaluronidases
• Downregulate expression of Tissue Inhibitors of Metallo-Proteases (TIMPs)

Question 9

What is tumour angiogenesis?

Answer 9

Need new blood vessels for growth- outgrow blood supply= necrosis in middle of nodule
Avascular tumour nodule can only be formed without

Question 10

What are the mechanisms of tumour angiogenesis?

Answer 10

• Cancer cells secrete angiogenic factors (VEGF) and permeability factors (leaky capillaries)
• Tumour macrophages secrete angiogenic factors
• Breakdown of matrix by proteolysis releases sequestered growth factors such as Fibroblast growth factor
• Tumours elaborate on abnormal matrix leading to abnormal vessel formation (convoluted, leaky)
• High levels of angiogenic factors vs normal balance between pro and anti
• Abnormally structed dilated vessels, poor gas exchange, necrosis. reduced effect of cytotoxic drugs (require oxygen)

Question 11

How does anatomy influence metastasis?

Answer 11

Nature of lymphatic and venous drainage (breast cancer to nodes, colorectal cancer to liver due to portal venal drainage of large bowel)
Liver, lung, bone, brain

Question 12

How does organ specificity influence metastasis?

Answer 12

Some cancer cells express; adhesion molecules that permit preferential attachment to different capillary beds/ chemokine receptors to chemokines highly expressed on different capillary beds

Question 13

What are cancer stem cells?

Answer 13

Self renew/ proliferate indefinitely/ can reproduce the cancer through serial transplantation in mice
Acute myeloid leukaemia

Question 14

How do cancer stem cells arise?

Answer 14

Mutation in stem cell, mutation in transit amplifying cell (acquire stem cell properties)
Must escape niche control or manipulate the niche