Cancer & Infectious Disease Flashcards
(43 cards)
1
Q
Carcinoma in situ
A
cells have lost architecture completely and leave normal space to invade other organs
2
Q
Oncogene
A
- gain of function mutation
- ras, Myc
3
Q
Tumor suppressor gene
A
Loss of function promotes tumors
4
Q
Tumor suppressor gene
A
Loss of function promotes tumors
- Inhibits cell prolif or protects genome
ex. p53, pRB
5
Q
Hallmark - self sufficiency in growth signals
A
- Gene expression of receptor over amplified, sometimes more copies of receptor on chromosome
- Oncogenic activation of downstream signalling pathway
6
Q
Hallmark - self sufficiency in growth signals
A
- Gene expression of receptor over amplified, sometimes more copies of receptor on chromosome
- Oncogenic activation of downstream signalling pathway
- Ras, Raf/MAPK, PI3K - Paracrine to autocrine transition
- Blocking of receptor endocytosis
7
Q
HER-2
A
- Human EGF Receptor
- Breast cancer
8
Q
Herceptin
A
- EGFR inhibitor
- Monoclonal Ab that recognizes HER2 extracellular domain
- Doesn’t distinguish b/w normal HER2 (necessary for life) and cancerous HER2, dose dependent
9
Q
Tarceva
A
- EGFR inhibitor
- Approved for late stage pancreatic cancer and non-small cell lung cancer
- Enters cells
- Competes w/ ATP for binding to RTK kinase domain –> blocks kinase activity
10
Q
Hallmark - Insensitivity to anti-growth signals
A
- TGF-beta, via Rb, blocks G1-Cdk and helps keep cells in quiescent state (G0)
- G1 Cdk/cyclin active –> phosphorylate/inactivate Rb –> E2f tx factor active –>S phase entry
- Mut of Rb –> loss of function
- Viral prot inactivates Rb (ex. HPV)
- Down regulate or mutate TGF-beta pathway
11
Q
Hallmark - Evasion of apoptosis
A
- Mutate p53 ‘guardian of genome’ (DNA damage control)
- Allows accumulation of DNA damage
12
Q
Hallmark - Limitless replicative potential
A
- Telomeres: repeated DNA seq at end of chromo that prevent fusions and other instability
- Terminal repeat not replicated during simple DNA replication = shortened w each cell division –> sensed by p53 pathway as DNA damage –> senescence
- Tumor cells express telomerase, prevent telomere loss –> immortalization
13
Q
Hallmark - tissue invasion and metastasis
A
- Invasion requires actin cytoskeleton
- Rho C –> actomyosin contractility
14
Q
Hallmark - Sustained angiogenesis
A
- Hypoxic cells produce VEGF (vascular endothelial growth factor) to recruit new blood vessels
- Most tumors cannot grow until under go ‘angiogenic switch’ to produce VEGF
- Angiogenesis inhibitors –> Avastin
15
Q
Mass effect
A
Tumor growth blocks/compresses vital organ
16
Q
Erosion/ulceration of resident organ
A
- leads to infection of blood vessels –> anemia
- Local interactions b/w tumor and microenvironment
- Invasion, stromal signalling, angiogenesis
17
Q
Paraneoplastic syndromes
A
- Hypercalcemia
- Hypercoaguability,
- Cancer cachexia
- Tumor induced wasting syndrome
- > 50% of cancer patients
- ~20% of cancer deaths
- Tissues and physiology FAR from tumor site are pathologically perturbed by secretion of humoral factors (hormones/cytokines) that promote immune response
18
Q
Passenger and driver mutations
A
- Most are harmless mutations
- Environment can induce additional mutations
- Driver mutations contribute to cell proliferation
- Repair pathway can be mutated, increasing rate of mutations
- Cells can evolve resistance to chemotherapy
19
Q
Chromothripsis
A
- Tens to hundred of genomic rearrangements occur in a one-off cellular crisis
- 2-3% of all cancers
- 255 of bone cancers
20
Q
Mis-segregation
A
Extra chromo can propagate as micronuclei
21
Q
Carcinoma
A
Epithelial cells
-Cover external and internal body surfaces (90%)
22
Q
Sarcoma
A
- Supporting tissue
- Bone, cartilage, fat, connective tissue, pancreas, liver
23
Q
Lymphoma and leukemia
A
-blood and lymphatic tissue
24
Q
Normal cell proliferation
A
- Anchorage dependent
- Density-dependent inhibition
- Limited number of cell divisions
- Telomere shortening
- Proliferation dependent on extracellular signals
- Checkpoints activated at appropriate times
- Apoptosis functional
25
Cancer Cell proliferation
- Anchorage independent
- Can grow on top of each other
- Immortal
- Telomere maintenance
- Constant signal to divide --> independent
- Loss of checkpoint
- Apoptosis inhibited
26
Aneuploidy
Aberrant # chromo
27
genetic basis?
- Cancerous state = clonally inherited
- Tumor induction via viruses in animals
- Mutagen induction
- Some WBC cancers associated w chromo abnormalities
28
Rous sarcoma virus
- 1st tumor inducing virus
- gag = capsid protein of virus
- pol = reverse transcriptase
- env = viral envelope protein
- v-src = prot kinase
- Inserts into PM of infected cells
- Oncogene that is resp for virus' ability to induce abnormal cell growth
29
Knudson's 2 Hit Hypothesis
- When tumor suppressor genes are mutated, a predisposition to develop cancer often follow a dominant pattern of inheritance
- Mut is usually a loss-of-function mut in tumor suppressor gene
- Cancer develops only if second mut in somatic cell KO func of WT allele
30
Somatic mutation
- Basis for development and progression of all types of cancer
- As mut accumulate and cells become unregulated, genetic instability incr likelihood that the cells will develop the hallmarks of cancer
31
HIV genome
- gag= encodes structural proteins for viral core
- pol= encodes reverse transcriptase, integrase, protease
- env= encodes coat proteins for virus exterior
32
HIV entry
- Invasion initiated when HIV binds to cell surface receptor CD4 + CCR5/CXCR4(co-receptors)
- Macrophages (early) and Th cells (later)
- CCR5 delta32 homozygotes are immune to HIV infection
33
HIV mem fusion
- gp120 (from env) binds to receptors
- gp41 (from env) is uncovered and inserts into PM
- Fusion protein merges two separate lipid bilayers into a single continuous bilayer, allowing viral core access to cellular cytoplasm
- Excludes H2O and destabilizes target membrane
- Crystal structure (6 alpha helicies) v similar to SNARE (4 alpha helicies)
34
Tuberculosis internalization survival
- Tb containing phagosomes do not incorporate the v-ATPase and maintain a higher pH
- Survive in phagolysosome
35
Red Queen Hypothesis
- Due to competition against other species, species have to constantly evolve to stay alive
- Ex. Host-pathogen "arms race"
36
Law of constant extinction
The probability of extinction for a species is not dependent upon how long it has already existed
37
CCR5-delta32
- Confers HIV resistance
| - Seen in europe and west Russia
38
trypanosomes and renal disease
- Incidence of late-onset kidney disease v high in African Americans
- GWAS found 2 genes under v strong natural selection
- Within haplotype is ApoL1, serum factor that lyses trypanosomes
- Evolution --> Red Queen
- Trypanosome evolves ability to evade human APOL1
- Humans evolve G1 and G2 alleles of APOL1 to evade trypanosomes
39
pfcrt and pfama-1
Genes known to confer anti-malarial drug resistance
40
Norovirus
- highly contagious
| - needs H antigen on cell surface to enter
41
H antigen
- Sugar presented on epithelial intestinal cells
- Enzyme FUT1/FUT2 required for H antigen production
- FUT2 is responsible for H antigen in epithelial cells
- 428G-->A
- Must be homozygous recessive to be immune
42
MHC
- Composed of many HLA genes found on chromo 6
- Loci are massively polymorphic
- Vary among populations
- Mutations creating new HLA alleles can reduce response to some pathogens, but also provide defense against pathogens that have evolved to evade common HLA alleles
- Genes in MHC are linked
43
Genetics of infectious agents
- Generation time much faster
- Rapid accumulation of mutations to avoid immune surveillance
- Mutations confined to exposed parts of proteins
- Vaccines that target side of proteins are longer lasting bc lower mut rate
