TS2 - Cancer Flashcards
(38 cards)
How is rapamycin used to treat cancer? What was its original use?
Rapamycin inhibits mTOR, a protein kinase that regulates cell growth and survival.
It was originally used as an immunosuppressor for organ transplants, but this means it can cause immunosuppression in cancer patients.
How is c-myc associated with cancer development? What is the role of Mxd/Max?
The c-myc oncogene encode a TF that is normally tightly regulated with low levels of expression. This is deregulated in cancer cells, leading to increased proliferation.
In normal cells, Myc forms heterodimers with Max that leads to proliferation. In the absence of Myc, Max binds Mxd to repress transcription. This balance is destroyed in cancer.
How can chronic inflammation cause cancer?
Chronic inflammation can lead to DNA damage, genomic instability, and alterations in cell signaling pathways, all of which can contribute to the development of cancer. Inflammatory cells can secrete cytokines and growth factors that can promote cell proliferation and survival, stimulate angiogenesis, and promote tissue remodeling, all of which can contribute to tumor growth and metastasis.
Definition: tumor suppressor gene
A gene whose loss of function contributes to tumor formation - often acts recessively or in a haploinsufficient manner.
Give an example of a TSG associated with the following functions:
- Linking DNA damage to cell cycle arrest
- DNA repair
- Inhibition of cell cycle
- Antagonist of GF signaling
- p53
- BRCA2
- Rb, INK4
- PTEN
What are the 2 classes of tumor-forming retroviruses? What are their differences? How do they give rise to cancer? Give an example of each.
Class I:
- Rapid formation of tumors
- Tumors arise from multiple founder cells
- Rare
Encode constitutively active versions of proteins involved in GF signaling.
e.g., Avian leukosis virus (ALV) which captured the tyrosine-kinase Src
Class II:
- Slow formation of tumors
- Not all infected get tumors
- Tumors arise from a single founder cell
- Common
Integration of gene next to a cellular gene that’s transcriptionally active.
e.g., MHC leukemia virus
How does angiogenesis relate to cancer cells? What can tumors do to increase this?
Angiogenesis is the process by which new blood vessels are formed from existing vessels.
In cancer, angiogenesis is a necessary step for tumor growth beyond a certain size, as tumors require a blood supply to obtain oxygen and nutrients necessary for their survival and proliferation. Tumors can secrete pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which stimulate the growth of new blood vessels. These new blood vessels can also provide an avenue for tumor cells to spread to other parts of the body through the bloodstream.
How does a primary tumor differ from a secondary tumor?
Primary: benign, restricted to site of origin, often treatable by surgery, requires blood supply.
Secondary: metastatic, able to degrade ECM, invasive.
Give an example of an oncogene at each of the following levels of action:
- Growth factor
- Growth factor receptor
- Transducer of GF responses
- Transcription factors
How are each of these acting in an oncogenic manner?
GF:
- v-sis/c-sis
- overexpression results in autocrine signaling
GFR:
- EGF/PDGF/VEGF receptors
- constitutive activation or overexpression
Transducer:
- Ras (GTPase), Src
- Locked in GTP-bound state; lack of inhibitory domain
TF:
- myc, fos, jun
- overexpression, mutations in inhibitors
Give the domain structure of the p53 protein. Which domain contains the most mutations associated with cancer?
Transactivation domain: binds transcriptional co-activators
SH3 domain: protein-protein interactions
DNA BD: p53-DNA binding
Tetramerization domain
C-terminal regulatory: contains a nuclear localization signal
How does p53 stop the cell cycle?
It induces the expression of a CKI (p21-Kip1).
List the 10 hallmarks of cancer
- Loss of growth factor dependence
- Insensitivity to anti-growth signals
- Evading programmed cell death
- Immortality
- Angiogenesis
- Tissue invasion and metastasis
- Deregulated metabolism
- Evading the immune system
- (Genome instability)
- (Inflammation)
What is the Warburg effect, and how does it help to explain metabolic changes observed in cancer cells?
The Warburg effect is the reliance of cancer cells on aerobic glycolysis to generate energy, rather than oxidative phosphorylation. This increases glucose metabolism.
Perhaps this is because aerobic glycolysis generates an excess of metabolic intermediates that can be diverted into other pathways to make other molecules needed for growth.
List 4 mutation types by which an oncogenes can be activated. Give an example for each.
- Point mutation e.g., Ras
- Gene amplification/overexpression e.g., HER2
- Chromosomal translocation e.g., bcr-abl
- Association with viruses e.g., SV40 T antigen
What are nutlins? What other methods can be used to target p53 to treat cancer?
Small molecule inhibitors that target and inhibit the interaction between p53 and MDM2, hence promoting p53-induced apoptosis of cancer cells.
Other:
- reactivate WT p53
- restore binding of mutant p53
- targeting p53 downstream effectors e.g., BCL-2 inhibitors
How is p53 activated by the following:
- oncogenes
- DNA damage
- metabolic stress
Oncogenes:
p19ARF binds MDM2 and prevents it from destabilizing p53.
DNA damage:
phosphorylated by ATM protein kinase in response to double-stranded breaks
Metabolic stress:
glucose depletion activates AMPK which phosphorylates p53 to promote survival in the absence of glucose
How might avian leukosis virus have picked up the Src gene?
ALV undergoes reverse transcription and integrates into the host genome, sometimes near genes like src. This led to transcription of a fusion RNA containing v-src, which was packaged into viral particles.
When these altered virions infect new cells, v-src is overexpressed due to strong viral promoters. The gene rapidly accumulates activating mutations, which are selected for, resulting in progressive expression of an activated Src protein and increasingly aggressive cancer phenotypes.
How do p53 and pRB interact with one another?
- p53-dependent G1/S arrest via p21 involves the inhibition of pRB phosphorylation from CDKs.
- Deregulated E2F activity induces p19ARF and p53-dependent apoptosis (pRB is a negative regulator of E2F)
- p16IN4A and p19ARF are encoded by alternative reading frames at the same locus:
p16INK4A = blocks pRB phosphorylation
p19ARF stabilizes p53
Define: oncogene.
What are the two categories of oncogenes?
A gene containing a gain of function mutation or a mutation that acts in a dominant manner to contribute towards tumor formation.
- c-onc (mutated chromosome)
- v-onc (virally encoded)
What is the role of mTORC1 in autophagy?
mTORC1 integrates multiple cellular signals to inhibit autophagy. mTORC1 is inhibited during nutrient deprivation or other forms of cellular stress.
List the ways a tumor suppressor gene can be identified.
- Identify genes in families with a propensity for certain tumor types.
- Clone genes that reverse cell transformation.
- Identify proteins that interact with immortalizing oncogenes.
Give examples of genes regulated by p53 that are involved in cell cycle inhibition and apoptosis.
CCI:
1. p21 - inhibitor of G1 CDKs
2. 14.3.3.o - this binds and sequesters CDC25
Apoptosis:
1. Genes that generate ROS for mitochondrial degradation
2. PUMA and NoxA (requires acetylation of p53)
[PUMA inhibited BCL2 and NoxA activates Bax and Bak to form holins]
What are the requirements for mammalian cell proliferation?
- Nutrients e.g., amino acids
- Macromolecular nutrients e.g., insulin
- Attachment molecules (sometimes) e.g., fibronectin
- Serum i.e., PDGF, EGF
Explain Imatinib’s mechanism of action. How is it specific?
Imatinib inhibits Bcr-Abl, acting as a kinase inhibitor. Crystal structures suggest it locks the kinase in an inactive conformation.
Bcr-Abl is unique to cancer cells, so Imatinib will only inhibit the fusion protein and not the WT proteins in normal cells.
