Cellular Basis of Malignancy Flashcards
What is EMT?
Epithelial to mesenchymal transistion
What holds a normal polarised cell together?
Adherens junction made up of a calcium dependent connection between cells. Contains E-cadherin, beta catenin and alpha catenin all connected to an actin cytokskeleton
What is the difference between irreversible EMT and reversible EMT?
Irreversible causes diffuse types of cancers by loss of E-cadherin and loss of alpha catenin expression
Reversible causes focal dissociation by phosphorylation of E-cadherin or beta catenin due to HGF
What does hepatocyte growth factor do?
Activates Ras oncoprotein and induces proteins like Snail which repress E-cadherin gene
Phosphorylates E-cadherin and beta catenin
Why is HGFR excessively active in cancer?
Over expression due to altered regulation
Gene amplification
Missense point mutation
Coexpression with HGF in same cells causing autocrine self activation loops
What is the name given to the proteolytic molecules on tumour surface protrusions and what stimulates them?
Podosomes/invadopodia
Stimulated by growth factors
How does urokinase-type plasminogen activator (uPA) break down connective tissue?
pro-uPA binds to uPAR
This then cleaves plasminogen to plasmin
Plamin cleaves pro-uPA to uPA, pro-MMPs to MMPs and ECM proteins
What do matrix metalloproteinases do to promote tumour invasion?
Breaks down ECM to carve a path for cell migration
Releases growth factors in the ECM and from binding proteins
Activates laminin 5 which promotes migration
Suppresses E-cadherin so less endothelial cell adhesion
How do integrins also support invasions?
Releases focal adhesion kinase (FAK) and Ras causing proliferation, invasion and pro-uPA production
Why do cancers often have areas of necrosis?
They outgrow their blood supply and become hypoxic
What challenges do hypoxic tumours present?
Hypoxic cells are resistant to chemotherapy and radiotherapy
Hypoxic cells lead to activation of HIFalpha and vascular endothelial growth factor (VEGF)
Selects for aggressive tumours via p53 mutants
Hypoxia increases risk of metastases via snail (induces EMT) and HIFIalpha (induces HFGR)
Which three things trigger angiogenesis?
Metabolic stress
Inflammation
Activation of oncogenes or loss of tumour suppressor genes that usually control angiogenesis
What is angiogenic sprouting?
Tumours express VEGF which draws enothelial cells away from an existing blood vessel to form a new one supplying the tumour
What is co-option of existing blood vessels?
Tumours initially grow around existing blood vessels and use that blood supply
What is intussusception?
Tumour grows into a vessel and splits it into two
