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