Neoplasia Flashcards
Ch. 6 PBVD and Ch. 7 R&C
Which tumors metastasize through lymphatics?
Carcinomas
Which tumors metastasize through blood?
Sarcomas, to liver/lungs
Molecules that cause cachexia?
TNF alpha (cachectin)
IL-1
IL-6
Prostaglandins
What is cell cycle arrest initiated by?
p53
What molecule do senescent cells produce?
beta-galactosidase
Morphologic hallmarks of apoptosis
Margination of chromatin
Condensation and fragmentation of nucleus
Condensation of cell with preservation of organelles
Major cellular inhibitor of autophagy
mTOR kinase
Steps of neoplastic transformation
Initiation- mutagen causes irreversible genetic change
Promotion- proliferation, reversible, benign tumor of initiated cells
Progression- genetic and epigenetic changes that results in malignancy
Two angiogenic factors produced by tumors
VEGF and FGFs
What do vessels produce that stimulate tumor cell proliferation?
IL-1 and PDGF
What do NK cells release to kill tumor cells? Stimulates by?
Perforin, which mediates entry of granzymes
Granzymes (serine proteases), which stimulate apoptosis
Stimulated by IL-2 and binding of stress-induced ligand to NK receptor
How to macrophages kill tumor cells? Stimulated by?
Stimulated by IFN gamma, direct contact and release of ROS, enzymes, NO, and TNF (MHC independent)
How do CD4+ T cells contribute to tumor immunity?
Secrete IL-2 and IFNgamma, which stimulate NK cells, macrophages, and CD8+ T lymphocytes
What immune cell enhances tumor cell survival
Treg cells
How do B cells contribute to tumor cell death?
Produce antibodies, which bind to tumor cells and activate complement and MAC
Also via NK cell or macrophage Antibody dependent cell-mediated cytotoxicity (ADCC) via FC receptors
How do tumors suppress immune system?
Produce TGF-beta
Produce Fas ligand, stimulate T lymphocyte apoptosis
Tregs and tumor associated macrophages
Humoral hypercalcemia of malignancy is caused by (3, in order); mechanism?
AGASACA, lymphoma, multiple myeloma; produces PTHrp
What is associated with space-occupying thoracic lesions?
Hypertrophic osteopathy
What syndrome is observed with mediastinal tumors (ie thymoma); in cats?
Myasthenia gravis; alopecia
What tumor is associated with nodular dermatofibrosis in GSDs?
Bilateral renal cystadenocarcinoma
Methylation profile in cancer
CpG islands are hypermethylated (silenced), body sites are unmethylated (activated); heritable
Prototypical oncogene
RAS (overactivation)
Prototypical tumor suppressor gene; two hit hypothesis?
Guardian of genome- p53 (loss), initiates cell cycle arrest via p21, and induces apoptosis if repair unsuccessful; both alleles must be mutated
Also RB- Governor of proliferation
Prototypical apoptosis regulating genes (3)
p53 mutation
Overexpression of MDM2- degrades p53, so can’t upregulate PUMA (pro-apoptotic), so can’t overwhelm BCL2
BCL2 overexpression- antiapoptotic (stabilizes mitochondrial membrane so cytochrome c can’t leave)
IAP upregulated (inhibits caspase 9)
Prototypical DNA repair gene
How are p53 and RB related?
p53 inhibits progression through cell cycle by producing p16 and p21, which inhibit CDKs, so RB is hypophosphorylated, and E2F is bound and can’t bind DNA to transcribe
Carcinogens vs mutagens
Mutagens cause DNA damage, not always cause cancer
Carcinogens are anything that cause cancer, often are mutagens
Worst UV radiation; mechanism?
UVB; mutagenic and carcinogenic, causes pyrimidine dimers in DNA (covalent cross-linking of pyrimidine bases), distorts DNA
Ionizing radiation- electromagnetic vs particulate; mechanism?
X-rays, gamma rays vs alpha, beta particles, protons, neutrons; chromosome breakage, translocations
Viruses that utilize host-derived oncogenes
feLV
Viruses that utilize their own oncogenes; examples
Papillomavirus;
E6, which inhibits p53 and stimulates TERT (telomerase expression)
E7, which inhibits pRB and p21
E5 activates PDGF beta receptor- fibroblast growth and loss of contact inhibition
What is insertional mutagenesis; example
Virus inserts itself in a host cell oncogene promoter region; avian leukosis virus
What is the hit and run mechanism? example?
Transient infection of cells initiates carcinogenesis; bovine papillomavirus
What indirect mechanisms can viruses use to induce oncogenesis? Examples
Suppress immune system, stimulate target cell proliferation
Marek’s disease- t cell lymphoma because can’t eliminate transformed cells
Rabbit poxvirus- encodes EGF gene
Oncoprotein inhibition- What applies brakes to RAS activation? What inhibits PI3K pathway?
GAP; PTEN
What is the warburg effect?
Shift from oxidative phosphorylation to aerobic glycolysis
How does cellular metabolism change in growth (in response to GF activating RTK)
Glucose transporters (GLUT1) upregulated via PI3K-Akt, so increased glucose uptake
Glutamine utilization increased via MYC
Glycolysis
What drives Warburg effect?
Hypoxia–>HIF1alpha not hydroxylated, not broken down by VHL, so target genes turned on
RAS activation
Most important apoptotic pathway in cancer cells
Intrinsic
What prevents replicative immortality?
RB and p53
What allows for replicative immortality?
Telomerase (via TERT)
Transcription factors that control epithelial to mesenchymal transition; change in markers in EMT
SNAIL and TWIST; downregulation of e-cadherin and upregulation of vimentin and SMA
Which enzyme breaks down type IV collagen in BM?
MMP9
What stimulates motility of neoplastic cells when invading?
Hepatocyte growth factor (HGF) aka scatter factor from stroma binds RTK MET on tumor cells
Two enabling characteristics for tumors
Genomic instability
Tumor promoting inflammation
How do tumor associated macrophages help tumor cells? What type of macs are they?
Prevent anoikis; M2
Order of cell cycle
Gknot–>G1–>G1/S checkpoint–>S–>G2–>G2/M checkpoint–>M
What causes checkpoints to occur?
p53
What causes G1 to S transition
Cyclin D/CDK 4 and 6
Cyclin E/CDK 2
What causes S to G2 transition
Cyclin A/CDK 1 and 2
What causes G2 to M transition
Cyclin B/CDK 1
What inhibits G1 to S transition; how?
p16, p15, p18, p19 aka CDKN2A,B,C,D; inhibits Cyclin D/CDK 4 and 6
What inhibits the cycle broadly?
p21, p27, p57 aka CDKN1A,B,C
What’s another name for p16
INK4a
Six effects of transcription factor p53
Growth arrest
p21 and p16
DNA damage repair via GADD45
MDM2 production (negative feedback on p53)
Activates BAX and PUMA–>apoptosis
Senescence
TGF beta effect on cell cycle
Increases production of CDKIs through serine-threonine kinase receptor–>phosphorylation of SMADs–>enter nucleus, bind SMAD4–>CDKI gene transcription (p21 and p15)
Most important transcription factor in cancer; effects (5)
MYC
D cyclin production
Protein synthesis
Warburg effect
Telomerase activity
Stem cell transition
What stimulates MYC production?
RAS, Notch, Wnt, hedgehog
Important factor for canine neoplasia
NFkappaB (see article)
What does CDKN2A encode?
p16- inhibits CDK complex
p14- inhibits MDM2
How do tumor cells inhibit T-cell activation?
Upregulate CTLA-4 on T cells, which removes B7 ligands from APCs (preventing binding of CD28 for second signal)
Upregulate PD-L1 and L2, which activate programmed death-1 receptor on T cells
What T cell type does BCL-6 suppress?
TFH
