Flashcards in Pfeffer Rao and Weir Stuff Deck (48):
What is vasculogenesis ?
earliest morphogenetic process of vascular development that takes place exclusively in embryonic development. Consists of differentiation of angioblasts into blood islands, which then fuse to form primitive capillary plexuses.
What is angiogenesis ?
a process by which new capillary blood vessels sprout from a preexisting blood vessel. Any developing new network of endothelial tubes (sprouting capillaries) that is not surrounded by mural cells is fragile and prone to rupture, remains susceptible to hypoxic regulation, fails to become remodeled, and is unable to sustain proper circulation; it cannot adapt to changes in physiological demands of blood supply.
What growth factor mediates angiogenesis ?
Vascular endothelial growth factor family is the major regulator of angiogenesis. Endothelial cells, tumor cells, fibroblasts and many other cells, produce VEGF.
What are the stimuli of angiogenesis ?
The major stimuli of angiogenesis are VEGF, hypoxia, PDGF, angiopoietins and histamine.
What does VEGF do ?
Direct actions of VEGF include:
- Stimulation of endothelial mitogenesis
- Promotion of endothelial survival by an Akt-dependent pathway
- Control of vascular permeability; VEGF is 50,000 times more potent in inducing vascular leakage than histamine. The mechanism of this effect appears to be fenestration of the endothelium of small venules and capillaries through a Src kinase-dependent mechanism.
What are the 6 steps of angiogenesis ?
1.) Angiogenic signals are present
2.) Endothelial cells degrade the vascular membrane by releaseing MMPs
3.) Endothelial cells migrate, forming tip cells, toward the stimulus.
4.) Non-tip endothelial cells, stalk cells, proliferate and form a lumen
5.) Lumen extends toward the angiogenic signal through endothelial cell division and tip cell migration
6.) Two sprouts fuse their lumens to provide a route for blood flow
What immune cell is involved in angiogenesis ?
Mast cells are typically found at sites of neovascularization and are important mediators of the process because they release histamine. Histamine increases vascular permeability, causes vasodilation and stimulates angiogenesis.
What is arterogenesis ?
rapid proliferation of pre-existing collateral arteries. One of the main functions of arteriogenesis is to alleviate an occlusion in a major artery. Normally, less major arterioles are recruited, which must undergo significant vascular remodeling to thicken vascular walls and increase luminal diameter. This process is thought to be mediated by the pressure of the blood flow.
How do you inhibit angiogenesis ?
There are two agents currently used to inhibit pathologic angiogenesis: Anti-VEGF antibodies and tyrosine kinase inhibitors (TKI). There is more about this in the study questions.
How can angiogenesis be used as a cancer target ?
Angiogenesis is now being used as and anti-cancer target. Anti-angiogenic agents are used to starve the tumor and avoid intravasation of metastatic cells. Anti-lymphangiogenic agents are used to maintain chemotherapeutic levels and prevent metastases.
How can you control angiogenesis with transcriptional controls ?
HIF is molecule that regulates transcription and VEGF and EPO. HIF is only activated in hypoxic environments and can efficiently control the synthesis of the pro-angiogenic molecules so that they are only generated when they are needed. The other transcriptional regulators act in a similar fashion.
* EPO = erythropoietin: glycoprotein hormone that controls RBC production
How does hypoxes induce angiogenesis ?
Hypoxia inducible factor is stabilized by hypoxic conditions and upregulates several genes to promote survival in low-oxygen conditions. Gene products that result are glycolytic enzymes, VEGF and EPO. When oxygen becomes available again, HIF becomes inactive.
How can VEGEF therapy be refractory ?
Using and anti-VEGF therapy can result in remnants of the newly formed vasculature (“scaffolds of empty sleeves”) and pericytes. If the tumor develops different metabolic pathways and starts producing other pro-angiogenic molecules, the remnants can be re-activated and start growing again.
What are the guidance signals in angiogenesis ?
Tip cells extend the length of the growing capillary and are directed toward guidance signals (pro-angiogenic factors).
What do heparin and heparin sulfate do in angiogenesis ?
1.) Facilitates the binding of growth factors and growth factor receptors
2.) Increases the half-life of the growth factor.
What are angiopoietens ?
The angiopoietins are protein growth factors that promote angiogenesis.
What is the evidance for angiogenesis as a tumor target ?
1.) VEGF, mRNA and protein of VEGF are all up-regulated in tumor cells. An experiment mentioned in one of the readings demonstrated that when you alter the VEGF levels, tumor growth rates also changed.
What is bevacizumab ?
Bevacizumab is an angiogenesis inhibitor. Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A).
Why is HIF inhibition difficult to determine ?
Because all tissues, not just cancerous tissues, utilize HIF when they become hypoxic. If you use therapies that block this mechanism it might be detrimental to other organs.
What is the paradox of vascular normalization that may make a combination therapy of VEGF blockade and chemotherapy more effective?
Anti-VEGF treatment was originally used to stop tumor angiogenesis; however, it can be used with other chemotherapeutic agents so that the drug can take a more direct route to the tumor and it doesn’t just diffuse out of the leaky neovasculature.
What is resistance/refractoriness to angiogenesis inhibition?
The tumor can alter its metabolic pathways to use other compounds to make new blood vessels to sustain its own growth.
Why are TKIs second-line therapies?
Tyrosine kinase inhibitors are used as selective EGFR inhibitors that block the downstream effects of growth factors binding to EGFR. This is a second-line therapy used in cases when anti-VEGF therapies fail. Also, it isn’t used as a first-line therapy because it can have more serious systemic side effects.
What is the basis of cell cycle control ?
Cyclicallly-activated protein kinases are the basis of cell cycle control, which is a series of counterbalances: synthesis/degradation and phosphorylation/dephosphorylation. Checkpoints are highly conserved and can halt the cycle in unfavorable conditions. Some common checkpoints are in the picture below:
What are Rao and Johnsons Experimental conclusions ?
1.) S phase nucleus releases something that drives G1 nucleus into S
2.) G2 nucleus is resistant to S phase promoting factor
3.) G1 and G2 do not influence each other
4.) Mitotic nuclei release mitosis-promoting factor that affects all interphase nuclei to become mitotic
Describe the lifespan of a cell
Cells have limited lifespans that are inversely related to age of individuals. Normal aging is called senescence and premature aging is called progeria. Telomeres play a role in aging of cells. In fact, overexpression of telomerase immortalizes cells.
What is MPF ?
Maturation (mitosis)-promoting factor (MPF) is a heterodimeric protein composed of cyclin B and cyclin-dependent kinase (Cdc2 kinase) that stimulates the mitotic and meiotic phases of the cell cycle. MPF promotes the entrance into mitosis from the G2 phase by phosphorylating multiple proteins needed during mitosis.
How is MPF activated ?
MPF is activated at the end of G2 by a phosphatase, which removes an inhibitory phosphate group added previously. MPF activity oscillates in association with cyclin concentration; however, MPF concentration is usually constant and cyclin concentration oscillates. MPF must be activated in order for the cell to transition from G2 to M phase.
What are the targets of MPF ?
- Condensins, which enable chromatin condensation
- Various microtubule-associated proteins involved in mitotic spindle formation
- Lamins, interaction contributing to degradation of the nuclear envelope
- Histones, H1 and H3
- Golgi matrix, to cause fragmentation
How is MPF deactivated ?
MPF is disassembled when anaphase-promoting complex (APC) polyubiquitinates cyclin B, marking it for degradation in a negative feedback loop. In intact cells, cyclin degradation begins shortly after the onset of anaphase (late anaphase), the period of mitosis when sister chromatids are separated and pulled toward opposite spindle poles. As the concentration of Cyclin B/CDK1 increases, the heterodimer promotes APC to polyubiquitinate Cyclin B/CDK1.
What does MPF actually do ?
- Triggers the formation of mitotic spindle through microtubule instability.
- Promotes mitosis i.e. chromatin condensation through phosphorylation of condensins.
- Causes nuclear envelope breakdown by phosphorylating the lamins that form an intermediate filament-type network (nuclear lamina) underlying the inner nuclear membrane
What are the phases of the cell cycle ?
The cell cycle consists of G1 phase, S phase, G2 phase and mitosis. G1/G2 phases provide time to monitor the signals and prepare for the next phase.
What happens in G1 ?
G1 phase: rate of proliferation of most mammalian cells is regulated through G1 transit. If the cell is not ready to go through the cycle, cells go into a resting phase (G0)
What happens in S ?
S phase: initiation of DNA synthesis with euchromatin first and then heterochromoatin. During this time, synthesis of histones, enzymes for DNA replication and other enzymes is completed.
What happens in G2 ?
G2 phase: synthesis of proteins for mitosis
What happens in M ?
What causes malignancies ?
( define Oncogene and Tumro Supressor )
Pncogenes- mutations give rise to a gain of function or an enhanced level of function. Drives toward Proliferation
Tumor Supressor Genes- Tumor Supressors usually encode negative regulators of growth and proliferation that protect cells from malignancy
What are common disorders that will predispose to malignancies ?
Li Faumeni Syndrome and Cowden Syndrome
How does Li Faimeni Syndrome Work
A syndrome that predisposes you to a number of cancers. Results in a loss of P53 function.
How does Cowden Syndrome work ?
A mutated P 10 can not halt proliferation
What does cKit oncogene cause ?
Gi Stromal tumor caused by constant activation of RAS pathway and PIK3 pathway which result in the proliferation of B cantenin
What do mutations in EGFR ?
EFGR Kinase mutations are activating mutations present in 5% smokers 15% non smokers and 50% never smokers with adenocarcinoma
Describe the progression to a neoplasm
Multiple mutations ( non hereditary cancer ) that are acquired over time that will lead to malignant transformation of a cell
What is an important target to treat breast cancer ?
You can block HER-2 cross talk
You can inhibit mTOR pathways
What is an important target to treat prostate cancer ?
Although low grade prostate cancer is unlikely to cause death. Androgen receptor blockades can specifically target this tumor by 1. Binding AR-DHT, Blocking its progression through the cytosol, and blocking its binding to DNA
Describe targeted therapies ?
Drugs that can target a specific receptor, pathway, or DNA segment that has sustained a mutation that has lead to cancer.
Are targeted therapies curative ?
Very Rarely, The cancer can develop new mutations to overcome the effects of the targeted therapy
How can tumors overcome therapeutic effects of targeted therapies ?
The cell can alter its pathways to overcome the targeted therapy