BOD L16 Tumour progression and metastasis Flashcards
Learning outcomes: Understand the biological basis of tumour progression and metastasis. To develop a critical awareness and understand of the cellular and molecular features of tumour progression. Critical understanding of the importance of host-tumour interactions.
What four general processes occur during tumour development
Transformation.
Growth of transformed cells.
Invasion of tumour cells into surrounding tissue.
Metastasis of tumour cells to distant sites.
Out of the six hallmarks, which is the most devastating to patient health?
Metastasis.
What four ways can cancer cells acquire self-sufficiency in growth signals?
Generate their own (eg. PDGF or TGFalpha)
Upregulate GF receptors (e.g. EGF-R)
Switching ECM receptors (e.g integrins that activate Ras-Raf-MAP kinase mitogenic pathway)
Heterotypic signals between different cells - stromal support, fibroblast, endothelial cells, inflammatory cells etc
What percentage of colon cancers occur without family history?
90%.
Sporadic with ‘unknown causes’ (food)
What three molecular groups are disrupted in cancer?
Chromosomal instable group - mutations in specific oncogenes and tumour suppressors.
Microsatellite instable group - mutations in DNA repair genes that leads to genetic hypermutability.
CpG Island methylation phenotype - hypermethylation (epigenetic) changes
How does colon cancer progress? (adenoma from carcenoma)
Hyperplasia - cells acquire mutations that allow rapid division, but still appear normal.
Small adenoma - mass of cells that emerge on colon tissue.
intermediate to large adenoma - larger masses, end up with polys that obstruct lumen of colon.
invasive carcenoma - tumour has become invasive
What is the APC gene?
Adenomatous polyposis coli gene.
Tumour suppressor gene. Associated with chromosomal deletions seen in for e.g. in FAP and thus with dev. of adenomas.
What associated diseases are seen with APC?
APC mutations, large risk of FAP, or FP forms of colorectal cancer.
APC mutations associated with >90% of large-bowel carcinomas.
Also seen in other adult cancers such as brain, pancreatic, thyroid.
What is FAP and how is it caused?
Famililal adenomatous polyposis.
Inherited mutation in adenomatous polyposis coli (APC) gene. FAP is linked to deletions in chromosome 5q.
One allele is missing.
What is tumour heterogeneity?
Many different cells within a tumour, that interact with one another.
What factors increase likelihood of metastasis?
Tumour size.
Age of tumour.
Differentiation of tumour.
Marker cell types , e.g. sarcomas more likely.
What two mediums can cancers disseminate around the body?
Via lympatics, or haematogenous.
Describe the major steps in metastasis
Invasion of surrounding tissue.
Release cancerous cells.
Ability to survive (EMT)
Invasion of capillary beds of distant organs.
Growth of cells to new tumour.
What is the ECM?
A complex protein structure surrounding and supporting cells. Referred to as connective tissue.
Structural proteins such as collagen and elastin. Proteins such as fibrillin, fibronectin and laminin, and proteoglycans (GAGs).
What do MMPs do?
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases that are secreted by migrating cells to degrade ECM components
What principles does a matrigel invasion assay work by?
Porous membrane sepaerates two chambers of cell culture media.
Cells in top chamber, and chemoattractant in bottom layer.
Cells cannot pass through membrane unless they are invasive as too small for regular cells to pass.
