Term
| what 3 things activate MMPs for degradation of the basement membrane and stromal matrix? |
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Definition
| EMMPRIN (CD147), plasmin (serine protease), and MMPs themselves |
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Term
| which 2 MMPs play crucial role in neoplastic cell invasion? |
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Definition
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Term
| what 2 substances/enzymes are necessary for malignant tumor cell intravasation? |
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Definition
| MMP9 and plasminogen activator |
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Term
| the first step in malignant tumor cell extravasation (attachment) is mediated by what factor? what are some other possible factors? |
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Definition
| specific alternatively-spliced isoforms of CD44 (i.e. CD44R1) express exons which coney the ability to bind endothelial surface molecules. (breast cancer - CXCR4 receptor and medadherin (MDTH)) |
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Term
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Definition
| surface receptor, binds to ligand HMGB1 --> alterations in developing neurons --> neurite outgrowth. also present on neoplastic cells --> interaction with HMGB1 --> mediates invasion and migration. |
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Term
| in what cancers is RAGE expressed? |
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Definition
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Term
| TWIST expression brings about 3 major changes in embryonic cells and neoplastic cells. what are the changes? |
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Definition
| loss of cellular adhesion, acquisition of motility and acquisition of mesenchymal markers |
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Term
| TWIST expression related to what cancer? what are some related EMT regulators and where do they work? |
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Definition
| breast; snail and SIP-1 overexpressed in gastric carcinomas |
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Term
| what are 2 angiogenic factors? 2 inhibitors of vascular proliferation? |
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Definition
| vascular endothelial growth factor, fibroblast growth factor; endostatin, angiostatin |
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Term
| small cell lung carcinoma is associated with what endocrine syndromes (paraneoplastic syndrome)? |
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Definition
| cushing's syndrome (ectopic secretion of ACTH) and inappropriate ADH (sodium and water retention) |
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Term
| what are the tumors that cause hypercalacemia and what is the mechanism through which this is brought about? |
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Definition
| tumor secretion of parathormone-like peptide; squamous cell lung carinoma, breast and kidney carcinomas; in multiple myeloma and lymphomas related to secretion of osteoclast activating factor |
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Term
| what is another name for migratory thrombophlebitis and with what carcinomas is it assoc? |
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Definition
| trousseau syndrome - pancreatic and lung cancers. small vessels develop in thrombi --> disappear --> reappear somewhere new |
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Term
| what is acanthosis nigricans and in which kind of carcinoma do we see it? |
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Definition
| hyperkeratosis and pigmentation of skin in flexural areas - GI adenocarcinomas |
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Term
| what is hypertrophic osteoarthropathy and with what carcinoma do we associate it? |
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Definition
| periosteal new bone formation (distal long bones, clubbing at ends of fingers) - primary lung carcinomas |
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Term
| how do promoter agents bring about cell divison? |
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Definition
| activation of protein kinase C |
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Term
| do most carcinogens act directly or indirectly? explain. |
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Definition
| some are direct, most are inactive (pro-carcinogens) that are converted to metabolically active derivatives by the MICROSOMAL MONO-OXYGENASE SYSTEM of the cell (whose intent is usually to solubilize and get rid of the reactive substance, but it ends up activating the procarcinogen) |
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Term
| what is the one RNA retrovirus that is linked to human malignancy? |
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Definition
| human T-cell leukemia virus 1 |
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Term
| what is the significance of the proto-oncogene c-ABL? |
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Definition
| encodes a cytoplasmic tyrosine kinase (in CML). as a result of the translocation in CML --> tyrosine kinase fuses with BCR gene --> constitutively active. gleevac binds to the kinase in inactive form and inhibits it from acquiring an activating phosphate. |
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Term
| mutations of c-kit associated with which carcinoma? |
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Definition
| gastrointestinal stromal tumors |
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Term
| what are the 2 ways chromosomal translocations can lead to neoplasms? |
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Definition
| 1. can lead to dysregulation of oncogenes by their approximation to active promotor sequences (as in burkitts. c-MYC gene close to Ig heavy chain locus). 2. translocation in CML --> chimeric oncoprotein (tyrosine kinase activity of c-ABL gene is unmasked by fusion to BCR seq) |
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Term
| whats the name of the syndrome where there is an inherited germline mutation in p53? |
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Definition
| li-fraumeni syndrome (multiple malignancies at a young age) |
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Term
| what is the significance of ATM kinase? (p14) |
|
Definition
| it is a sensor peptide which, when it detects cellular stress (dna damage, uv radiation, abn growth signals) stabilizes the p53 protein and keep it from being degraded --> increased amts of p53 --> activation of p53 peptides --> cell cycle halt, assist in dna repair, or trigger apoptosis |
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Term
| how does p53 arrest the cell cycle? |
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Definition
| activates transcription of p21, which inhibits ALL of the G1 CDKs (prevents progression into S phase); activates transcription of miRNA34, which prevents the translation of mRNAs for cyclins. |
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|
Term
| how does p53 trigger apoptosis? |
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Definition
| activates transcription of the pro-apoptotic proteins bax, noxa and puma. |
|
|
Term
| how does p53 trigger DNA repair? |
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Definition
| activates transcription of GADD45, functions in DNA repair |
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Term
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Definition
| prevent MDM2 from binding to p53 --> prevent p53 degradation |
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Term
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Definition
| restore the DNA-binding capacity of mutant p53 protein |
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|
Term
| how does p16 assert its tumor-suppressing function? |
|
Definition
| protein inhibits CDK4/6 --> block formation of cyclin-CDK complexes --> prevents cell from entering S phase. |
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Term
|
Definition
| hypermethylation of upstream promotor (epigenic silencing) |
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|
Term
| how does PTEN act as a tumor suppressor? |
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Definition
| removes a phosphate from PIP-3 --> inhibits growth and survival effets of the AKT pathway (normally leads to cell proliferation and inhibition of apoptosis) |
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Term
| describe the WNT pathway and its significance. |
|
Definition
| APC gene (tumor suppressor) encodes a peptide which is a part of the WNT pathway. APC protein binds to and degrades B-catenin. when APC protein is altered (or absent) --> B catenin is free to move into the nucleus --> activation of other genes (c-MYC) --> proliferation. this is the first step in COLON cancer |
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Term
| the caretaker pathway involves 3 types of DNA repair that have the potential to be altered/mutated and contribute to neoplasm. what are the 3 mechanisms of DNA repair. |
|
Definition
| 1. mismatch repair (human MutS and MutL homologues) 2. nucleotide excision repair 3. double-stranded break repairs (ATM, BRCA1, BRCA2 which are involved in regulation of DNA repair) |
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Term
| what do microRNAs do and when are they a problem? |
|
Definition
| negatively regulate gene expression. overexpression --> decreased expression of tumor suppressor gene; underexpression --> increased expression of an oncogene |
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|
Term
| what is the warburg effect? |
|
Definition
| cancer cells, even in presene of oxygen, preferentially metabolize glucose thru glycolosis |
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|
Term
| what are the 3 BCL-2 subfamilies? |
|
Definition
| antiapoptotic = BCL2, BCLx, BCLw (share 4 regions of homology); proapoptotic = bax, bak (3 similar sequences of homology with BCL-2); proapoptotic = bim, bid, puma, noxa (BH3 is only shared region of homology) |
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Term
| how is apoptosis triggered by BCL-2 proteins? |
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Definition
| free bax and bak join into oligomers --> form channels in outer mitochondrial membrane --> release cytochrome C --> binds to apaf-1 --> promotes caspase cascade --> executes apoptosis |
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Term
| what do BCL2, BCLx and BCLw do? |
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Definition
| bind to bax and bak and keep them from inducing apoptosis |
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Term
| what do the "BH3-only" proteins bim, bid, puma, noxa do? |
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Definition
| activate bax and bak directly; engaging and neutralizing bcl2 bclx bclw --> freeing bax and bak |
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