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
How can cancer use telomerases to become “immortal”?
Cancer cells activate telomerases, which are normally only active in stem cells, that add telomeres to the end of DNA. Telomeres prevent DNA degradation, so the presence of telomerases means the DNA of dividing cells will not be shortened and, eventually, degraded, so cancer cells become essentially “immortal”
What are the major molecules that mediate carcinogenic angiogenesis?
bFGF and VEGF (seen in normal cells’ hypoxic response) are produced in high amounts by cancer cells, stimulating nearby blood vessels to extend branches of vessels out to tumor cells. These vessels are leaky/abnormal due to haphazard growth and disordered cells in the tumor.
What are three principal ways in which cancer cells can more easily invade/metastasize into other tissues?
Cancer cells have downregulated cadherins, making them less “sticky” to each other
Malignant tumors overexpress collagenase, allowing them to detach from collagen meshwork and move to other locations
Tumors use ameboid migration to get into vasculature/lymphatics
What are the stages of carcinoma progression?
In-situ carcinoma: confined to epithelium without penetration of basement membrane
Microinvasion: invasion through basement membrane
Local invasion: direct, contiguous extension within organ
Local metastasis: discontiguous spread within organ AND to neighboring lymph nodes
Distant metastasis: spread to distant organs/lymph nodes
What is clinically observed in local invasions and distant metastases?
Local: obstruction, bleeding, organ failure
Distant: organ failure i.e. liver failure
What are cancer patients subject to as far as clinical issues?
Infections (sepsis, multi-organ failure)
Bleeding/thrombosis (blood volume loss, pulmonary embolism)
Paraneoplastic syndromes (endocrinopathies, cachexia, etc.)
What are the clinical outcomes and treatment options of brain metastases?
10-20% of all cancers will metastasize to the brain. Median survival is 1-2 months without treatment, 3-6 months with whole brain radiation, 6-12 months with multimodality treatment
Treatment options: resection, radiation, a few systemic therapies
What cancers metastasize to bone most commonly?
Breast, prostate, lungh, thyroid, and renal. Can cause spinal cord progression, and usually moves to axial rather than appendicular skeleton.
How can bony metastases be managed clinically?
Pain control with NSAIDs, narcotics
Bisphosphonates to reduce new metastases and fractures
Radiation to area if pain is not well controlled
Surgery for at-risk hips/femurs
How can cancer-related infections arise? What factors govern the likelihood of infection?
Infections can arise normally but are particularly effective at spreading due to lack of proper immune function
Neutropenia from chemo/radiation, type of underlying cancer, history infections, overall immune function
What are common para-neoplastic syndromes?
Symptoms associated with cancer that are not explained by tumor spread. These include:
Endocrinopathies
Hypercoagulability
Immunologically-mediated
What is a common endocrinopathy that is observed in cancer? What is it’s etiology?
Cushing’s syndrome results from ectopic production of ACTH (adrenocorticotropic hormone), causing hypertension, muscle wasting, hyopkalemia, and dark skin striae
Common causes are small cell lung cancer, pancreatic neuroendocrine tumors
Paraneoplastic hypercalcemia results from release of parathyroid hormone related peptide (PTHrp), mobilizing Ca2+ from bones into the blood. This is commonly caused by squamous cell lung carcinomas and breast carcinoma
Syndrome of Inappropriate ADH secretion (SIADH) occurs due to ectopic ADH production, and causes hypo-osmolar hyponatremia (irritability, confusion, weakness, seizures can occur)
What are common hypercoagulability issues seen in cancer?
DIC–disseminated intravascular coagulation, sytemically activates coagulative elements including factors and platelets, producing bleeding, vascular occlusion and tissue hypoxia. (Both thrombotic AND bleeding effects are seen).
Migratory thrombophlebitis (Trousseau Syndrome)–production of procoagulant factors by tumors, causing venous thrombosis, then resolution, then formation of another thrombus in another site
What are common immunological neoplastic syndromes seen in cancer?
Paraneoplastic myasthenia gravis and Lambert-Eaton syndromes occur when antibodies against tumor cell antigens cross-react with neuronal cell antigens like ACh receptors. Turmor cell antigens mimic neural cell antigens, so the body labels them as foreign and then attacks normal neural cell antigens like ACh receptors.
This produces neuromuscular symptoms, muscle fatigue/weakness, etc.
What is the pathology of cachexia?
Progressive loss of fat and skeletal muscle even with adequate nutrient intake. Elevated metabolic rate accompanied by weakness and anemia.
TNFa, IL-6/1 cause systemic inflammation in the muscles, liver metabolism, and causes fat use/depletion
