Cancer Pathways- Lecture 56 Flashcards
Describe the components of the Rb pathway.
p16 inhibits Cyclin D1 and Cdk4/Cdk6 which inhibit pRb which is also inhibited by E7 (which is produced by HPV)
pRb inhibits E2F which leads to S phase progression
Describe the flow of the p53 pathway.
ARF inhibits Mdm2 which inhibits p53 which is also inhibited by E6 (from HPV)
the primary function of p53 is to signal for apoptosis or arrest
Describe the flow of the APC pathway.
APC and axin inhibit beta-catenin which activates Cyclin D and Myc
Which parts of the Erk pathway are most commonly mutated in human cancers and which are not known to be associated?
Ras and Raf are normally mutated
ERK and Mek are not known to be associated with cancer
What parts of the Pi3 kinase are normally mutated in human cancers?
AKT and PTEN as well as Pi3 kinase itself
Mutations in growth factors normally _____.
only hit one pathway rather than all of those associated with it.
Describe the pathway of colorectal cancer progression.
normal epithelium –(loss of Apc)–> hyperplastic epithelium –> early adenoma –(activation of K-Ras)–> intermediate adenoma –(loss of Smad4 and other tumor supressors)–> late adenoma –(loss of p53)–> carcinoma –(other unknown alterations)–> invasion and metastasis
Describe how p16 and ARF are related.
ARF contains most of Exon 1b and part of Exon 2
p16 contains most of Exon 1a, all of Exon 2, and the first small piece of Exon 3
they are examples of proteins made via alternative splicing (have separate promoters)
mutations in Exon 2 can be detrimental to both pathways
What is EMT?
epithelial to mesenchymal transition- where cancer cells of epithelial origin loose cell-cell junctions due to loss of E-cadherin expression, loss of cell polarity, and increased migratory behavior
What are the steps of metastasis?
angiogenesis, invasion, intravasion, metastasis, extravasion, secondary growth
What occurs in angiogenesis?
tumor reaches 1-2 mm angiogenesis factors (eg. acidic FGF, basic FGF, and VEGF) are produced that induce blood vessel formation
reduction of inhibitors (eg. thrombospondin)
What occurs in invasion?
tumor cells become attached to sub-endothelial extracellular matrices via cell surface receptors
protease-mediated degradation of matrix
migration via chemotaxis using degradation products or tumor-associated autocrine motility factors
What occurs in intravasion?
tumor cells invade through vascular endothelial cells and sub-endothelial basement membranes and enter the vasculature
What occurs in metastasis?
adhere to endothelial cells of target organ or exposed sub-endothelial extracellular matrix basement membrane
What occurs in extravasion?
extravasate out of the vasculature and into the perivascular stroma
reverse of invasion
