Cancer Genetics I and II Flashcards
(42 cards)
Define whether a gene that regulates cell division, immortality, apoptosis, angiogenesis, or metastasis is an oncogene or tumor suppressor gene.
Cell division - Oncogene Immortality - Oncogene Apoptosis - Tumor Suppressor Angiogenesis - Oncogene Metastasis - Oncogen
Explain how oncogenes act in a dominant fashion and tumor repressor genes in a recessive fashion.
Only one mutant oncogene is needed to significantly alter cell cycle activity.
If one tumor suppressor gene is bad, the other one produces enough gene product (p53, etc.). If two tumor suppressor genes are bad, there is no gene product, and that would alter cell cycle activity.
Explain the concept of penetrance.
Even though a dominant mutation has been passed on, the effects may not be passed on to all progeny.
Describe the steps leading to the activation of the caspase cascade in both the death receptor and mitochondrial pathways.
Death receptor:
Death signal binds Fas receptor/ Tnf receptor —> FADD/TRADD —> activation of caspase 8. Caspase 8 can then stimulate tBID as well as the effector caspases.
Cytokine deprivation activates BH3-only proteins—> BH3 only’s inhibit Bcl2, allowing Bax and Bak to form a pore
–>
cytochrome c and SMAC released –> cytochrome c activates Apaf1, which activates caspase 9; SMAC inhibits XIAP, which halts inhibition of caspase 9
List the different processes that may activate the mitochondrial apoptotic pathway.
Cytokine deprivation
Intracellular damage
Oncogene upregulation
Explain a mechanism by which Bcl-2 and Bak/Bax regulate cytochrome C release
from the mitochondria.
Bcl2 inhibits Bak/Bax
BH3-only proteins inhibit Bcl2
Describe the roles of other protein factors released from the mitochondria in addition to cytochrome C.
SMAC inhibits XIAP
How are caspases 8 and 9 activated?
Caspase 9 is activated by the apoptosome (6 cytochrome c’s and apaf1’s in a ring), which cleaves it and allows it to become activated.
Caspase 8 is activated by FADD and TRADD receptor complexes, forming a DISC complex. The caspase is then cleaved and activated.
What is the role of p53 in apoptotic responses?
p53 upregulates the Noxa and other genes that code for BH3 only proteins. An increase in BH3 only proteins means increased inhibition of Bcl2
How do different survival factors inhibit apoptosis?
Transcription regulators increase txn of Bcl2 gene
Survival factor activates Akt kinase, which phosphorylates a BH3-only protein that is inhibiting Bcl2
A survival factor activates MAPk, which phosphorylates (and in doing so, deactivates) Hid. This stops Hid from inhibiting the IAPs (inhibitors of apoptosis)
Distinguish between carcinomas and sarcomas.
Carcinomas form from epithelial cells
Sarcomas form from connective tissues and muscles
Explain the concept of tumor clonality.
Tumors arise from one single mutant cell.
Describe the steps and barriers to the metastatic process (i.e. from the dissociation of a tumor cell from the tumor mass to its growth as a new tumor at a distant site).
Entering the blood/lymph vessel is difficult, as it is hard to escape from the parent tissue.
Flowing through a blood vessel, stopping at a capillary, and exiting the vessel are all easy.
Surviving in a new tissue is difficult.
Explain how changes in telomerase activity lead to genetic
instability and immortality.
As a cell ages, its telomers shorten, and telomerase is usually downregulated. At this point, p53 would normally be upregulated halt any progression toward S phase, and drive the cell into replicative senesence.
Since p53 is shut down, in the absence of telomerase, chromosomes will eventually fuse together and many translocations will be observed in cell progeny. If these mutations don’t kill the cell, telomerase is reactivated, and these configurations are stabilized. Thus, changes in telomerase activity can drive genetic instability and immortality.
List other mechanisms that generate genetic instability in cancers.
The same could be said if the cell maintained or increased telomerase regardless of telomere size.
Understand the concept of the Warburg effect in altered glucose metabolism associated with cancer cells
In cancer cells, 10% of glucose is used to produce building blocks for the cell. Then, following glycolysis, 85% of the pyruvate is converted to lactate. Because so little pyruvate is transferred to oxidative phosphorylation,
the mitochondria can effectively be shut down. This eliminates the mitochondrial apoptotic pathway.
Explain the role of laminin receptors in the three-step mechanism for basement membrane invasion by tumor cells.
A tumor cell must bind laminin receptors in order to start invading a membrane. By binding, the cell can secrete collagenase to digest the basal lamina, and attain motility.
Describe the contribution of EMT to cancer progression and metastasis
EMT allows cancer cells to transition from epithelial cells to mesenchymal cells.
Loss of E-cadherin Loss of cell-cell and cell matrix contacts Increased protease secretions Rounded shape Pluripotent txn factors activated
This transition means that said cells can now invade other tissues (metastasize).
Explain how invasion in angiogenesis by non-transformed endothelial cells has a mechanistic similarity to invasion by metastatic cells.
They are similar in that the cells increase their protease activity, invade the basement membrane, proliferate and go somewhere else.
How do cancer cells signal to epithelial cells to initiate new blood vessel growth?
They secrete growth factors, including VEGF and FGF, to signal the blood vessel endothelial cells to increase protease secretion (collagenase, urokinase plasminogen activator (upa) and decrease protease inhibitor txn.
This allows endothelial cells to invade the vascular basement membrane to proliferate and supply the cancer with nutrients and oxygen.
Define driver and passenger mutations in cancer.
Driver mutations are the mutations that are most commonly found in cancer tissues and “drive” the cancer forward into a later stage, whereas passenger mutations, while found in a significant amount, aren’t found as frequently as driver mutations and likely play a less significant role in cancer progression.
Know the various ways that genes can be made overactive (oncogenes) and the mechanisms for generating second hits in tumor suppressor genes.
Many oncogenes result from increased activity through changes in expression or stacked missense mutations. Tumor suppressor mutations result from loss of activity, either by various nonsense mutations or epigenetic silencing (loss of hetoerozygosity).
Distinguish between genetic and epigenetic mechanisms for generating a cancer phenotype.
Epigenetic mechanisms do not directly involve DNA bases. They consist of methylation of CpG islands on DNA, methylation and acetylation of histone tails, and nucleosome remodeling
Genetic modifications involve changes within the DNA bases. May be heritable.
Explain features of the cancer stem cell phenotype and their function in cancer: its pluripotent potential characterized by a specific group of transition factors, membrane and cytoskeleton changes, slow cell division rate, apoptotic resistance, self-renewal, protease secretion and motility.
Pluripotent potential - it can become many things and exist in many tissues
Membrane and cytoskeleton changes - these changes counteract the usual features of apoptosis, counteracting them
Slow cell division rate - can’t be targeted by anti-cancer drugs
Apoptotic resistance - the cell lives longer and can divide more
Self-renewal - cells are immortal and can continue producing neoplastic cells
Protease secretion - Cell can break through ECM proteins, such as collage n, and invade blood vessels a/o lymphatic ducts
Motility - cell lacks contact inhibition and can move
