Week 3: Neoplasia II Flashcards
What are exogenous and endogenous elements that can give someone cancer?
Exogenous - chemical, radiation and microbial carcinogens
Endogenous - oncogenes, tumor suppressor genes, failed DNA repair
What genes are common mutagenic targets during oncogenesis?
Proto-oncogenes: genes necessary for cell growth stimulation, mutation that allows it to be constitutively “activated” or hyperactive
Tumor suppressor genes: genes necessary for cell growth inhibition, mutation that inactivates suppressor gene to allow for unregulated tumor growth
What are the different clonal elements of cancer and what kinds of neoplasia do they correspond to?
Neoplastic cells are monoclonal in origin, meaning there was an injury or toxin that mutated the original cell and caused proliferation of that damaged cell into tissue
Non-neoplastic cells are polyclonal in origin, meaning multiple cells or cell types were involved in propagating (i.e. in inflammatory responses with many cell types)
What are common pathways to cancer growth?
Self-sufficiency in growth signals
Insensitivity to inhibitory signals
Defects in DNA repair
Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasize
How mutations arise in proto-oncogenes?
Point mutation
Chromosomal translocation/rearrangement
Increased promoter activation (overexpression)
Gene amplification
What are the basic steps of the oncoprotein signal transduction pathway?
1) Growth factors like TGFa bind to
2) Growth factor recpetors like Her2
3) The intracellular kinase domains of these receptors activate cytoplasmic regulatory proteins like ras and raf
4) Regulatory proteins can further activate nuclear regulatory proteins and transcription factors like C-MYC and cell cycle components like Cyclin D
What is a common example of a point mutation seen in cancer? How does this occur based on the “central dogma” concept or protein expression?
Ras family proteins, which are GTPases. These include:
KRAS, HRAS and NRAS
These proteins are activated/mutated in ~20% of all cancers. A point mutation occurs in the DNA, causing a protein error that might lead to constitutive activity within the cell. Ras is normally activated by GTP binding, and then deactivated by GTP hydrolysis. Inhibition of GTP hydrolysis is blocked in mutated Ras, leading to constitutive activity.
What are the main ways that oncoproteins can become mutated?
1) Point mutations in exons
2) Chromosomal translocation, inversion, or deletion
3) Increased promoter activity
What is an example of how translocation can cause cancer? Why is it relatively easy to target therapeutically?
c-ABL and BCR protein production in chronic myelogenous leukemia involves the production of the ABL protein (a cytoplasmic tyrosine kinase), which is not present in normal cells. ABL + BCR can fuse and cause constitutive activity of cell signaling mechanisms that lead to unrestrained cell proliferation.
These mutated proteins are relatively easy to target since they are not present in normal cells. Imatinib blocks ATP binding to the BCR-ABL fused protein, preventing effector proteins from binding and transducing a signal.
What is an example of increased promoter activity that leads to cancer? How is it linked to IgG production?
Burkitt’s lymphoma (seen in young children) promotes extremely high expression of Myc gene.
In normal cells, the promoter for antibody production is very active. Burkitt’s lymphoma occurs when this promoter gets linked instead to the Myc oncogene, so Myc protein is produced in much higher concentrations than normal.
What is an example of gene amplification that leads to cancer? How does this lead to oncoprotein production?
Breast/ovarian carcinoma is often due to HER2/neu gene amplification, which occurs when the HER2/neu gene is duplicated continually, thus amplifying the production of the HER2/neu oncoprotein.
What are common examples of tumor suppressor genes? Where are they located and what is their normal function?
APC/B-catenin (cytosol) - inhibition of signal transduction
RB (nucleus) - cell cycle regulation
p53 (nucleus) - cell cycle arrest and apoptosis in response to DNA damage
BRCA-1 and BRCA-1 (nucleus) - DNA repair
What are the major, normal functions of tumor suppressor genes (4)? What are examples of each?
1) Inhibit signal transduction (NF1)
2) Inhibit cell cycle (RB)
3) Inhibit transcription (ABC/B-catenin)
4) Lead to apoptosis (p53)
What proteins are involved in cell cycling/proliferation? What inhibits them?
CDK and Cyclin complexes, which are inhibited by p-proteins like p27
How is RB involved in cancer proliferation at the level of cellular expression?
RB (originally found in retinoblastomas) is ubiquitously expressed. Loss of heterozygosity (LOH) allows the allele for RB to become homozygous, creating significantly upregulated protein expression
How is RB involved in cancer proliferation at the level of protein activity and biochemistry?
Phosphorylation of RB releases E2F, a transcription factor of S phase genes. When mutations occur, RB becomes hyperphosphorylated and unbinds from E2F much more easily, allowing for significant upregulation in S phase gene transcription
How do mutations of p53 lead to cancer?
In healthy cells, p53 has a ~20min half life because it is quickly targeted for breakdown. However in damaged cells, PTMs make p53 much more active and it can lead to either apoptosis or cell quiescence (lack of activity). This PREVENTS damaged cells from continuing to proliferate
Mutations in p53 prevent it from signaling apoptotic pathways, meaning damaged cells can continue proliferating/dividing in an unregulated fashion.
Why doen’t chemo/radiation work well on cancers with p53 mutations?
Chemo and radiation induces DNA damage to cancer cells in hopes of causing cell death and apoptosis in those cells specifically. However, if p53 is mutated, the internal cell signal for breakdown/degradation is nonfunctional, so those cells will not undergo apoptotic processes.
What are the two main mechanisms by which HPV can evade programmed cell death?
The viral DNA genome of HPV contains the E6 and E7 genes for two oncoproteins:
E6 causes p53 degradation, as well as telomerase induction to preserve the gene
E7 causes RB degradation, preventing binding to E2F and leading to unregulated transcription and cell proliferation
Why is p16 a good marker for HPV infection?
p53 degradation by the HPV E6 protein causes p16, a cell cycle regulatory protein, to “work overtime” to try to arrest cell proliferation and division. As such, increased levels of p16 is often a signal for HPV infection.
What is the function of B-catenin in cell proliferation? What activates it? What two elements inhibit it? How can deregulation cause cancer?
B-catenin is an activator of proliferative transcription factors including c-Myc, cyclin D, and others.
It is activated by WNTs extracellularly.
Normally, B-catenin is inhibited when bound to E-cadherin, and can also be degraded by APC. However, mutations in APC can cause this regulatory protein to become nonfunctional, leading to increased cell proliferation, especially in colon cancers.
What are the first two major “stages” of B-catenin deregulation? What molecules are involved in the subsequent stages?
Mutation of APC (degrades B-catenin) is the first major step that can lead to cancerous proliferation.
E-cadherin mutation (binds/sequesters B-catenin) is the second major step that can lead to cancer.
Subsequent steps involve K-RAS mutation/upregulation and p53 homozygous loss
How can mismatch repair cause a defect in DNA repair that can cause cancer?
MSI–microsatellite instability–whicih occurs when mismatch repair isn’t working due to mutations in mismatch repair genes MSH2 and MLH1 (which encode MutS and MutL, respectively).
Microsatellites are base pair repeating sequences that accumulate with unfaithful DNA replication
How can cancers evade apoptotic processes (2 mechanisms)?
They can:
1) Inhibit mitochondrial permeability by BCL-2 and BCL-XL proteins, which initiate apoptosis
2) Inhibitors of Apoptosis Proteins (IAPs), which inhibit caspase activity that normally leads to DNA degradation and apoptosis
