JM Lecture 56: Cancer Pathways and Tumor Biology Flashcards
Describe the components of the Rb pathway.
p16 inhibits Cyclin D1 and Cdk4/Cdk6
which inhibits pRb (which can also be inhibited by E7 produced by HPV)
pRb inhibits E2F (which allows for progression into S phase)
Describe the flow of the p53 pathway.
ARF inhibits Mdm2
which inhibits p53 (which can also be inhibited by E6 produced by 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 if the Erk pathway are most commonly mutated in human cancers?
Ras and Raf
Erk adn Mek are not known to be associated with cancer
Which parts of the Pi3 kinase pathway are normally mutated in human cancers?
AKT and PTEN as well as Pi3 kinase itself
How do mutations in growth factors normally occur?
normally mutations in growth factors only impact one pathway without impacting other pathways 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 suppressors)–> late adenoma –(loss of p53)–> carcinoma –(other unknown alterations)–> invasion and metastasis
Describe how p16 and ARF are related.
INK4A gene locus:
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 alternate 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, matastasis, extravasion, secondary growth
What occurs in the angiogenesis stage of metastasis?
tumor reaches 1-2 mm
angiogenesis factors (e.g. acidic FGF, basic FGF, and VEGF) are produced to induce blood vessel formation
reduction of inhibitors (e.g. thrombospondin)
What occurs in the invasion stage of metastasis?
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 the intravasion stage of metastasis?
tumor cells invade through vascular endothelial cells and sub-endothelial basement membranes and enter the vasculature
What occurs in the metastasis stage of metastasis?
cancer cells adhere to endothelial cells of target organ or exposed sub-endothelial extracellular matrix basement membrane
What occurs in the extravasion step of metastasis?
cancer cells extravasate out of the vasculature and into the perivascular stroma (reverse of invasion)
