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What are two "normal" cell characteristics.
- Stable genome
- Ability to regulate cell div and growth
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What are extracellular cues for regulating cell division?
- Growth hormones
- Contact inhibition
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What are intracellular cues for regulating cell division?
- Available nutrients/energy
- DNA damaged/need repair?
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Describe senescence and crisis in normal cells.
- Two proliferation barriers
- Senescence - viable but won't replicate
- Crisis - loss of telomeres -> cell death
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What are basic cancer cell characteristics?
- Unstable genome.
- Autocrine signaling of growth factors.
- Anoikis/apoptosis blocked.
- Use of autophagy in hypoxic environments.
- Lack of contact inhibition.
- Ability to migrate/metastasize.
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What causes an unstable genome in cancer cells?
Loss of telomeres, chromsomal breakage, joining with different chromosomes.
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Cancer cells use autophagy until ___.
angiogenesis is activated.
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Cancer cell migration/metastasis is enabled by ___.
E-cadherin turned off and expression of N-cadherin.
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Most cancer cells that enter the blood stream ___.
die
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Describe senescence and crisis in cancer cells.
- Telomerase activity
- - Prevents senescence and crisis
- - Increases breakage-fusion-bridge cycles
- - TERT, telomere subunit, inhibits apoptosis by upping Wnt
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Describe the late stages of cancer development.
- - uncontrolled cell div
- - angiogenesis
- - cell migration/metastasis
- - Inhibition of apoptosis/anoikis
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What are the 6 hallmarks of cancer?
- Sustaining proliferative signaling
- Evading growth supressors
- Activating invasion and metastasis
- Enabling replicative immortality (telomeres)
- Inducing angiogenesis
- Resisting cell death
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In normal cells, what controls proliferative signaling?
Growth factors binding to tyrosine kinase receptors
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What is regulated when growth factors bind to tyrosine kinase receptors?
Cell division, growth, survival, metabolism
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How are growth factors regulated?
- Sequestration in the ECM.
- ECM-degrading enzymes can activate growth factors.
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In cancer cells, what controls proliferative signaling?
- Autocrine signaling (GFs)
- Stimulation of stromal cells (GFs)
- Hyper-responsiveness to GFs
- Ligand-independent GFRs (always on)
- GFR independence (always on downstream)
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What are two other mechanisms leading to unregulated cell div?
- Mutations on PI3 kinase.
- Inhibition of neg feedback loops (e.g. Ras)
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Describe the triggering of senescence/apoptosis in normal cells.
- High levels of Ras (G-protein)
- High levels of Myc, Raf (transcription factors)
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Describe the triggering of senescence in cancer cells.
Disabling of Ras, Myc, Raf pathways even at high levels
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___ and ___ are tumor suppressor proteins.
RB and P53
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RB and p53 have a ___ level of ___.
high, redundancy
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What does RB respond to?
Signals from outside cell.
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What kind of signals does p53 respond to?
- Intracellular signals
- DNA damage
- Metabolic stress
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What are two mechanisms of contact inhibition?
- Merlin protein (NF2 gene product)
- LKB1
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Describe the merlin protein.
- Strengthens cell adhesion by coupling E-cadherin binding to TKRs.
- Kinase is inactivated in normal cells when in contact.
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Describe LKB1.
- Organizes epithelial structure.
- Can suppress Myc's activity.
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When do some cancer cells activate autophagy?
- Hypoxia
- Low nutrient conditions
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During autophagy, what is removed, and how is it done?
- Ribosomes and mitochondria.
- By phagosomes that fuse with lysosome.
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Describe necrosis.
- Not random.
- Release of IL-1a inducing proliferation.
- Release of pro-inflammation signals.
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What induces angiogenesis?
Vascular endothelial growth factor (VEGF)
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VEGF in normal cells is ___ and is used in ___.
- Transient
- Wound healing
- Female reproductive cycle
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VEGF in cancer cells is ___ and is used in ___.
- Upregulated
- Hypoxia
- Oncogene signaling
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___ can also activate tumor angiogenesis.
Fetal growth factor (FGF)
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Describe abnormal blood vessels in tumors.
- Excessive and complex branching.
- Malformed vessels.
- Erratic blood flow/leakiness
- High levels of endothelial apoptosis/cell division.
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Describe anti-angiogenic proteins.
- Endostatin, angiostatin, and 12 others.
- Found in healthy mice and humans.
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Describe angiogenic promoters.
- Facilitate local invasion.
- Prevent chemo drugs from blocking angio.
- Includes innate immune system.
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What immune system components can enhance VEGF?
Macrophages, neuthrophils, mast cells, myeloid precursors
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What are two ways to block angiogenesis?
- Anti-VEGF antibodies.
- Soluble VEGFR1 (competitive inhibitor)
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What is the only angiogenic factor present thruout tumor's lifecycle?
VEGF ligand
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VEGF is thought to be ___ and unsusceptible to ___.
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Metastasis does not occur without ___.
angiogenesis
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During metastasis, there is a loss of ___.
E-cadherin expression
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Describe the metastasis cascade.
- Local invasion (moving, same tissue).
- Intravasation (to blood vessel).
- Transit in blood and lymph vessels.
- Extravasation (exit blood vessel).
- Micrometastasis (still vulnerable).
- Colonization (fairly secure).
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What is EMT?
- Epithelial-mesenchymal-transition.
- Mechanism used by embryonic cells to migrate.
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What happens during EMT?
- Cells change shape from epithelial to fibroblastic.
- Secrete ECM-degrading enzymes.
- Repress E-cadherin.
- Express N-cadherin.
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What activates cell migration?
Twist1 -> RAC1
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How do stromal cells aid metastasis?
Mesenchymal stem cells release CCL5/RANTES to stimulate invasion.
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Why do cancer cells secrete chemoattractants?
Attract macrophages to increase inflammation.
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The release of IL-4 by cancer cells activates ___.
macrophages to release ECM-degrading enzymes.
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Cancer cells can also degrade ___.
ECM
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What are three types of invasion?
- EMT
- Collective invasion
- Amoeboid
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What are the two steps of colonization?
- Movement of cancer cells to distant tissues.
- Adaptation to other tissue microenvironments.
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What are the emerging hallmarks of cancer?
- Avoiding immune destruction.
- Tumor-promoting inflammation.
- Deregulating cellular energetics (glycolysis).
- Genome instability and mutation.
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Describe genome instability.
- Abnormal chromosomal rearrangements (B and T cells).
- Mutation rates increase.
- Increased sensitivity to mutagens.
- Inhibition of DNA repair mechanisms.
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Describe an unusual metabolic change with some cancer cells.
Switch to glycolysis even in the presence of oxygen.
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Some cancer cells secrete TGF-B that ___.
inactivates CTL and Natrual Killer (NK) cells.
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What contributes to tumor-promoting inflammation?
- GFs
- Survival factors
- Pro-angiogenic factors
- EMT-activating signals
- ECM-degrading enzymes
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