Cellular basis of malignancy Flashcards
How do malignant cells invade?
IRREVERSIBLE: mutation, causing loss of e-cadherin or alpha catenin. EMT occurs causing diffuse cells
Assuming a primary cancer (pleomorphic cells, neoplastic), irreversible EMT can occur or reversible EMT occurs, where peripheral cells are exposed to HGF. They focally dissociate and in a new location, MET can occur casusing a new place for a solid cancer.
HGF binds to HGFR which is a transmembrane receptor kinase. This: activates Snail, repressing e cadherin expression; phosphorylates e-cadherin and beta catenin
How can tumour cells invade?
Folliwing HGF binding to HGFR
uPA pathway: uPAR expressed plus serum uPA increases. These together cleave plasminogen to plasmin. Plasmin can cleave: pro-uPA to uPA (+ve feedback); pro-MMPs to MMPs; ECM proteins
MMPs: these are metalloproteinases (Zn2+) that can cleave: ECM to carve out pathway; laminin to promote migration; e-cadherin to lead to EMT
What is the cancer microenvironment?
Often hypoxic regions as tumours outgrow vlood supply
Viable hypoxic cells resist treatment (as radiation needs O2 and chemo targets dividing cells)
Hypoxia will induce p53 to cause apoptosis, however mutated p53 gene cells will selectively survive. Snail is also induced, causing EMT
HIF1alpha will induce VEGF and HGFR in hypoxic conditions
How is angiogenesis induced?
Hypoxic conditions; inflammation; oncogene activation or TSG inactivation
What are the diff types of angiogenesis?
Sprouting: VEGF (produced by hypoxic cells) causes endothelial cells to migrate and invade tumour stroma. eg breast cancer.
Co-option: tumour cells initially grow arounf blood vessles
Intrasusseption: tumours growing against blood vessles force them to split and form new blood vessels
Vasculogensis: angioblasts from bone marrow home in to tumour and differentiate into enothelium.
Mimicry: contribute to blood vessels
What causes angiogenic inhibition?
angiostatin/endostatins
avastin (VEGF) and sorafenib (VEGFR)
