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44 Cards in this Set

  • Front
  • Back
characteristics of epithelial neoplasms
lobulated
central necrosis
umbilicated
scirrhous
ulcerated
pigment
characteristics of mesenchymal neoplasms
fleshy or firm
pigment
lymphoma: may be very soft & semi-fluid or rubbery & cream colored
round cell sarcomas may be infiltrative & enlarge organ w/out forming discrete nodules
immunohistochemistry to ID anaplastic tumors
cytokeratin: epithelial cells
desmin: muscle cells
vimentin: all mesenchymal cells
actin: some forms are specific to certain cell types (ex. smooth vs. skeletal m.)
grading tumors
attempt to quantify characteristics of tumor for px

degree of differentiation, mitotic index
staging tumors
done according to progression of tumor based on size of primary tumor, lymph node involvement, presence of metastasis
epidemilogic factors influencing cancer development
age
breed
species
coat color
nutriton
cell populations based on growth characteristics
continuously dividing cells: epi surfaces of skin, repro tract, urinary tract, GI tract, bone marrow (old cells replaced by stem cells)
stable (quiescent) cells: remain in G0 until stimulated (ex. hepatocytes, other glands, mesenchymal tissues (bone, cartilage, fibroblasts, etc.))
nondividing cells: neurons, cardiac & skeletal m.
cell cycle: G1/S checkpoint
checks integrity of DNA before replication
cyclin D synthesis ↑ during G1 & forms complex w/ a CDK
activated CDK phosphorylates RB
phosphorylated RB releases E2F
E2F binds to specific site on DNA & drives expression of genes that lead to movement into S phase
cell cycle: G2/M checkpoint
checks DNA after replication & monitors whether cell can safely enter mitosis
macromolecules of the extracellular matrix
fibrous structural proteins (collagens, elastins)
adhesive glycoproteins (cadherins, integrins, selectins)
proteoglycans & hyaluronic acid
hallmarks of cancer
nonlethal genetic damage (ex. mutations) is a key feature of tumors
virtually all tumors are of monoclonal origin: arise from a single cell
most tumors arise from stem cells rather than from adult cells
acquired capabilities of cancer cells
1. self sufficiency in growth signals
2. insensitivity to anti-growth signals
3. evasion of apoptosis
4. defects in DNA repair
5. limitless replicative potential
6. sustained angiogenesis
7. tissue invasion & metastasis
oncogene
gene that promotes autonomous cell growth in cancer cells

able to promote cell growth in absence of normal mitogenic signals
proto-oncogene
normal cellular counterpart of oncogenes

physiologic regulators of cell proliferation & differentiation
oncoprotein
product of oncogene

resemble normal products of proto-oncogenes except they are devoid of important regulatory elements
how tumor cells proliferate without external stimuli
cancer cells acquire ability to make growth factors
onocogenes encode abnormal growth factor receptors --> continuous mitogenic signals to cell
tumor cells drive normal cells to release growth factors (ex. inflammatory cells)
overexpression of normal forms of growth factor receptors
2 mechanisms of anti-growth factors
move cells out of cell cycle to G0
PERMANENTLY move cells into a post-mitotic pool
tumor suppressor gene
encodes proteins that apply brakes to cell proliferation

loss of function of these genes is key event in most/all tumors
role of p53 in DNA damage
DNA damage --> phosphorylation of p53 --> causes cell cycle arrest thru transcription of CDK inhibitor p21 & induces DNA repair genes --> if DNA cannot be repaired --> p53 signals cell to undergo apoptosis
components of apoptosis
Fas receptor and TNF-α receptor: sensors that trigger apoptosis
Fas receptor + Fas ligand --> “death signal” sent to cell (non-functional Fas receptor protects cell from normal death signal)

bcl-2: protects cells from apoptosis by mitochondrial pathway (overexpression common in B cell lymphoma)
caspases 8 & 9: activate cascade of effector caspases that execute death program
lack of p53 --> ↓ transcription of pro-apoptotic gene BAX --> ↓ apoptosis
how tumor cells have limitless replicative potential
assoc. w/ maintenance of telomere length & function

cancer cells can restore telomerase activity to maintain telomere length & replicative potential
methods of angiogenesis in tumor cells
endothelial precursor cells (EPCs) stored in bone marrow

migration of pre-existing vessels
regulation of angiogenesis
integrins: critical for formation & maintenance of new vessels
matricellular proteins: destabilize cell-matrix interactions & thus promote angiogenesis
proteinases (ex. matrix metalloproteinases): important in tissue remodeling during endothelial invasion
tumor vessels are more leaky than normal vessels d/t ↑ production of VEGF
role of VEGF (vascular endothelial growth factor) in angiogenesis
stimulates mobilization of endothelial cell precursors from bone marrow & enhances proliferation & differentiation of these cells at sites of angiogenesis

stimulates proliferation & motility of endo cells, thus initiating sprouting of new caps
anti-angiogenic factors
may be produced by tumor (ex. thrombospondin-1) or in response to tumor (ex. angiostatin, endostatin, tumstatin from cleavage of collagen, plasminogen, etc.)
stages of metastasis
invasion of ECM
vascular dissemination
homing & arrest
extravasation
angiogenesis & growth
invasion of ECM by tumor cells
detachment of tumor cells from each other

attachment to matrix components
- neoplastic cells often have more adhesion mols than normal cells

degradation of ECM
- tumor cells secrete proteases or induce host cells to secrete proteases
- cleavage products of matrix components have growth-promoting, angiogenic, & chemotactic activities

migration of tumor cells
- mobility of tumor cells influenced by cytokines & growth factors
- some cleavage products from ECM have chemotactic, growth promoting, & angiogenic functions (ex. VEGF, bFGF)
vascular dissemination of tumor cells
vascular penetration: tumor cells are particularly vulnerable to host defenses once in circulation (NK cells)

aggregation: tumors cells tend to aggregate w/ each other or w/ platelets in blood stream (may mask antigenic sites of tumor cells)
homing & arrest of tumor cells that metastasize
site at which circulating tumor cells leaves caps to form secondary deposits is related, in part, to anatomic location of primary tumor

endothelial address theory: tumor cells may have adhesion mols whose ligands are expressed preferentially on endothelial cells of target organ

chemo-attraction theory: chemokines play role in determining site of metastasis (tumor cells sense certain chemokines on target organ surface)

fertile soil theory: target tissue may be unfavorable environ for growth of tumor seedlings b/c of lack of appropriate growth factors (ex. skeletal m.)
metastasis
generation of cells w/in a mass w/ ability to disseminate & form new foci of growth at noncontiguous sites
pathways of metastasis
hematogenous: sarcomas
-ex. thyroid carcinoma
lymphatic: carcinomas
-ex. mammary carcinoma
seeding body cavities
-ex. GI carcinoma (carcinomatosis)
activation of oncogenes
alterations of gene expression:
- enhancer/promoter insertion
(promoters: stimulate adj. genes, must be upstream of gene to facilitate expression, enhancers: stimulate promoter activity (orientation independent))
- chromosomal alterations (translocation & exchange)

alterations of gene structure:
mutation of individual nucleotides (point mutations)
translocation of chromosomes
types of oncoproteins
growth factors (ex. sis)
growth factor receptors (ex. erbB)
signal transducing proteins (ex. raf, ras)
transcription factors (ex. myc)
cyclins (ex. cyclin D)
RB
tumor suppressor gene
plays key role in regulating cell cycle
exists in all cell types
exists in a normal nonphosphorylated state & binds E2F transcription factors
entry into S phase is regulated by cyclins that phosphorylate RB & free E2F to stimulate cell replication
loss of functional RB --> uncontrolled cell replication
p53
tumor suppressor gene
functions: regulates entry of cells into S phase of cell cycle, involved in induction of apoptosis
genetic damage --> p53 half life ↑ & accumulates in nucleus --> cells arrest at G1 checkpoint --> DNA damage repaired if possible OR initiation of apoptosis
cells w/ mutated p53 genes don’t arrest before entering S phase --> less likely to undergo apoptosis
lymphoid tumors: ↑ expression of bcl-2 (blocks apoptosis)
carcinogenic agents
chemical
radiation
hormonal
oncogenic viruses & bacteria
miscellaneous
2 types of chemical carcinogens
direct acting: capable of causing cancer w/o metabolic conversion by body (ex. cyclophosphamide, beta-propiolactone)

procarcinogens: requires metabolic conversion to ultimate carcinogen (most common category)
procarcinogen method of action
metabolized in liver by monooxygenases in SER (cytochromes p450 & p448)
1. bioactivation: metabolic pathway yields a more toxic or carcinogenic by-product
2. conjugation: compound forms covalent bonds w/ macromols (DNA) --> mutations; not all adducts are equal
3. excretion/transport
examples of procarcinogens
polycyclic aromatic hydrocarbons: very potent, form epoxides, cause neoplasia in variety of tissues, in tobacco smoke, well cooked meats

aromatic amines & azo dyes: cause cancer at site of metabolic activation

naturally occurring compounds: aflatoxins, nitrosamines, bracken fern (bovine)

misc: asbestos, vinyl chloride, insecticides, PCBs
chemical carcinogenesis: initiation
change produced in cell by sufficient single exposure to carcinogen (usually permanent)

alone not sufficient to produce neoplasia

usually requires short exposure periods
chemical carcinogenesis: promotion
enhancement of tumor development by exposure of initiated cells to noncarcinogenic substances or environments (ex. saccharin, hormones)

usually requires long exposure periods

tumors develop only when promoter is applied AFTER initiation (must not be too much time b’twn episodes of promotion to cause tumor formation)
complete carcinogen
can both initiate & promote if given in sufficient dosages over sufficient periods of time (ex. aflatoxin)
co-carcinogenesis
synergism b’twn 2 carcinogens such as UV radiation & chemical carcinogens
Ames assay
test that measure production of mutations by test chemicals in a specific strain of Salmonella typhimurium, which cannot synthesize histidine

bacteria grown on histidine deficient medium --> only bacteria that have mutated grow
# of bacterial colonies growing indicates mutational potency of test compound
60-90% of carcinogens are mutagens