Mechanisms of tumour progression, invasion and metastasis

Question 1

What are the 3 main characteristics of malignant tumours?

Answer 1

• Growth - unlimited growth as long as adequate blood supply
• Invasiveness - migration of tumour cells into surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs
• Metastasis - spread of tumour cells from primary site to form secondary tumours

Question 2

What is the classical progression in colorectla cancer?

Answer 2

• Normal epithelium -> hyper-proliferating epithelium -> adenoma -> carcinoma -> metastasis

Question 3

What are the 4 things that help tumour progression?

Answer 3

• Acquisition of specific mutations
• Clonal expansion
• Genomic instability
• Epigenetic changes

Question 4

What genomic instability is there in colorectal cancer?

Answer 4

• Chromosomal instability (CIN) - metaphase checkpoint failure -> aneuploidy and non-disjunction (LOH)
• Microsatellie instability (MIN) - mismatch repair gene mutations -> increased mutability

Question 5

What happens if TSG promoters are methylated?

Answer 5

• Gene is switched off -> no production of TSG

Question 6

What are the steps involved in cancer dissemination?

Answer 6

• Primary tumour forms - needs to develop a blood supply to grow
• If it can invade the local blood stream, it can move around the body
• Eventually will arrest in microvessels of various organs
• Can then start growing there and developing a new blood supply

Question 7

What triggers angiogenesis?

Answer 7

• Hypoxia can trigger activation of angiogenic factors

- Tumours wont grow more than 2mm without own supply

Question 8

What are angiogenic factors?

Answer 8

• Stimulate directional growth of endothelial cells
• eg VEGF, FGF-2, TGF-b, HGF/SF
• mainly stored bound and inactive to ECM, may be released by MMPs

Question 9

What are the 3 mechanisms of tumour cell invasion?

Answer 9

• Increased mechanical pressure cause by rapid cellular proliferation
• Increased motility of the malignant cells (epithelial to mesenchymal transition)
• Increased production of degradative enzymes by tumour cells and stromal cells

Question 10

What happens during epithelial-mesenchymal transition?

Answer 10

• loss of epithelial shape and cell polarity, cytokeratin intermediate filament expression and E-cadherin
• Acquire - fibroblast-like shape and motility, invasiveness, vimentin expression, mesenchymal gene expression and MMP-2/9 secretion

Question 11

What are E-cadherins?

Answer 11

• Adhesion of cells with the same cadherin
• Calcium-dependent
• Inhibits invasiveness
• Binds beta-catenin

Question 12

What are integrins?

Answer 12

• heterodimers (alpha and beta subunits)
• Hetreotypic adhesion molecule
• Adhesion to ECM (via collagen, fibronectin, laminin etc)
• Cell migration

Question 13

How do stromal cells contribute to tumour progression?

Answer 13

• Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, GFs, cytokines and proteases
• eg. uPA, activated by tumour cells -> plasmin production -> MMPs -> ECM breakdown -> invasion and release of matrix bound angiogenic factors

Question 14

How is proteolytic activity regulated?

Answer 14

• Depends on relative amounts of proteinase and inhibitoes of proteinases
• Most tissues have large amounts of TIMPS (tissue inhibitor of MMPs)
• Some tumours eg pancreatic tumours have decreased levels of TIMPs

Question 15

What determines the pattern of tumour spread?

Answer 15

• Mechanical hypothesis = what is the first vessel bed that tumour is likely to arrive and arrest at?
• Seed and soil hypothesis - specific adhesions between tumour cells and endothelial cells in the target organ