EXAM 2 - Session 20: Cancer Stem Cells (CSC) Flashcards
Describe what cancer stem cells are.
Cells within a tumor that possess capacity to self-renew and give rise to heterogeneous (diverse) populations of cells with different metabolic and mitotic activities & sensitivity to treatment.
What is the possible reason that current anticancer treatments are not 100% effective?
Failure to understand heterogeneity
* when you isolate cells from a tumor –> not all the cells are able to replicate
Describe the tumor cell renewal test and what was interpreted from the data?
null hypothesis: no difference among individual tumor cells in regards to their replication ability
method:
* tumor cells were seperated, counted, added to dish, and covered with nutrients
* individual cells will grow into “islands” or colonies
* compare colony number to seeding number
* examine for any variation in colony size
results:
* colonies varied greatly in size
* colony # < # cells seeded
reasoning:
* heterogeneity - some cells may be most-mitotic; somemay need different nutrients –> lead to cell death
* not all cancer cells can replicate
Are all cancer cells in tumors equal?
No. Cancer tumor cells can differ on several criteria
* variable proteins, mRNA, metabolism, shape, organization, replication pattern (never, very often, or rarely replicate)
What is the association of camptothecin effectiveness and topoisomerase inhibition?
Camptothecin inhibits topoisomerase
* DNA replication must be underway for drug to have effect (drug must be present at the same time as topoisomerase)
* or else infrequently replicating cells “escape” treatment –> lead to tumor recurrence
Tumors are composed of a mix of cells. Describe the cells that make up tumors.
High replication capacity cells (CSCs)
* long cell cycle
* long G1 phase
* yields CSC and TA cells
Transient amplifying (TA) cells
* limited replication capacity
* short cell cycle time
* yield post-mitotic cells
Post-mitotic cells
* TA cells that have loss replication ability
* make up most of tumor
If camptothecin treatment is 4 days long, TA cell cycle = 1 day long and CSC cell cycle = 5 days long, what is your prediction of the treatments efficacy?
The drug treatment does not align with the CSC cell cycle duration. In this example, CSC would have esacaped treatment bc topoisomerase isn’t present at the 4 day mark.
How and when do normal stem cells progess to cancer stem cells?
- mutation in stem cell –> causes loss of cell cycle control; high telomerase expression maintained/regained
- mutation in normal progenitor cell –> causes loss of cell cycle control; high telomerase maintained
- environmental exposure or viral infection in differentiated cell –> causes self-renewal genes to be re-expressed; epigenome changes structure; mutations in promoter region to drive transcription
If CSC progeny cells lead to tumor formation, explain CSC theory.
- predicts clonal marker present during tumor expansion (why/when did the cell become cancerous?)$
- allows for heterogeneity despite shared marker
- read forward and reverse in time for cell identification
- CSC clone with additional mutations in different cells leads to heterogeneity
Explain why identification of the Philadelphia chromosome is significant.
Some cancers are diagnostically marked by chromosome rearrangements - like chronic myelogenous leukemia
* additional mutations may occur but all progeny cells share original marker (Ph c’some)
* Ph chromosome –> BCR-ABL - ends of c’some 9 and 22 are swapped
IF chemo drug only kills off TA cells, then…
Then the tumor will shrink but CSCs will escape treatment and survive.
* CSCs generate more CSC and TA cells
* TA daughter cells replace tumor mass –> regrowth
Describe how targeting over-expressed receptors like EGF-R (epidermal growth factor receptors) would have a therapeutic advantage.
EGF-R receptors: HER1, HER2, HER3, HER4 are associated with different breast cancers
* normal epithelial cells have low level of HER receptors –> normal, infrequent replication –> signals from receptors stimulate DNA synthesis and cell replication
* Cancer stem cell epithelial cells have high HER2 levels –> frequent dimerization/kinase activation = mitosis
Erlotinib and Gefitinib block kinase activity (no signaling) and inhibits DNA synthsis/cell replication
Describe the extracellular targeting of EGF-R HER2 receptors.
Trastuzumab (Herceptin) is a lab-made antibody to HER2 extracellular domain
* blocks dimerization with EGF-R
* antibody binding causes reduced ability to transmit growth signal into cell –> less cell replication –> tumor regression
