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44 Cards in this Set
- Front
- Back
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characteristics of epithelial neoplasms
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lobulated
central necrosis umbilicated scirrhous ulcerated pigment |
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characteristics of mesenchymal neoplasms
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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 |
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immunohistochemistry to ID anaplastic tumors
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cytokeratin: epithelial cells
desmin: muscle cells vimentin: all mesenchymal cells actin: some forms are specific to certain cell types (ex. smooth vs. skeletal m.) |
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grading tumors
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attempt to quantify characteristics of tumor for px
degree of differentiation, mitotic index |
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staging tumors
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done according to progression of tumor based on size of primary tumor, lymph node involvement, presence of metastasis
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epidemilogic factors influencing cancer development
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age
breed species coat color nutriton |
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cell populations based on growth characteristics
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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. |
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cell cycle: G1/S checkpoint
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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 |
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cell cycle: G2/M checkpoint
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checks DNA after replication & monitors whether cell can safely enter mitosis
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macromolecules of the extracellular matrix
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fibrous structural proteins (collagens, elastins)
adhesive glycoproteins (cadherins, integrins, selectins) proteoglycans & hyaluronic acid |
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hallmarks of cancer
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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 |
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acquired capabilities of cancer cells
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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 |
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oncogene
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gene that promotes autonomous cell growth in cancer cells
able to promote cell growth in absence of normal mitogenic signals |
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proto-oncogene
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normal cellular counterpart of oncogenes
physiologic regulators of cell proliferation & differentiation |
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oncoprotein
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product of oncogene
resemble normal products of proto-oncogenes except they are devoid of important regulatory elements |
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how tumor cells proliferate without external stimuli
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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 |
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2 mechanisms of anti-growth factors
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move cells out of cell cycle to G0
PERMANENTLY move cells into a post-mitotic pool |
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tumor suppressor gene
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encodes proteins that apply brakes to cell proliferation
loss of function of these genes is key event in most/all tumors |
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role of p53 in DNA damage
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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
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components of apoptosis
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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 |
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how tumor cells have limitless replicative potential
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assoc. w/ maintenance of telomere length & function
cancer cells can restore telomerase activity to maintain telomere length & replicative potential |
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methods of angiogenesis in tumor cells
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endothelial precursor cells (EPCs) stored in bone marrow
migration of pre-existing vessels |
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regulation of angiogenesis
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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 |
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role of VEGF (vascular endothelial growth factor) in angiogenesis
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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 |
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anti-angiogenic factors
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may be produced by tumor (ex. thrombospondin-1) or in response to tumor (ex. angiostatin, endostatin, tumstatin from cleavage of collagen, plasminogen, etc.)
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stages of metastasis
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invasion of ECM
vascular dissemination homing & arrest extravasation angiogenesis & growth |
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invasion of ECM by tumor cells
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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) |
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vascular dissemination of tumor cells
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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) |
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homing & arrest of tumor cells that metastasize
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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.) |
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metastasis
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generation of cells w/in a mass w/ ability to disseminate & form new foci of growth at noncontiguous sites
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pathways of metastasis
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hematogenous: sarcomas
-ex. thyroid carcinoma lymphatic: carcinomas -ex. mammary carcinoma seeding body cavities -ex. GI carcinoma (carcinomatosis) |
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activation of oncogenes
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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 |
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types of oncoproteins
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growth factors (ex. sis)
growth factor receptors (ex. erbB) signal transducing proteins (ex. raf, ras) transcription factors (ex. myc) cyclins (ex. cyclin D) |
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RB
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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 |
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p53
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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) |
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carcinogenic agents
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chemical
radiation hormonal oncogenic viruses & bacteria miscellaneous |
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2 types of chemical carcinogens
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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) |
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procarcinogen method of action
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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 |
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examples of procarcinogens
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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 |
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chemical carcinogenesis: initiation
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change produced in cell by sufficient single exposure to carcinogen (usually permanent)
alone not sufficient to produce neoplasia usually requires short exposure periods |
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chemical carcinogenesis: promotion
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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) |
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complete carcinogen
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can both initiate & promote if given in sufficient dosages over sufficient periods of time (ex. aflatoxin)
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co-carcinogenesis
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synergism b’twn 2 carcinogens such as UV radiation & chemical carcinogens
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Ames assay
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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 |
