Pathology and molecular basis of cancer Flashcards
Neoplasm definition?
Lesion resulting from autonomous or near autonomous growth of cells that persists after the initiating stimulus has been removed
RB normal function?
Normally controls G1-S progression; binds to the transcription factor E2F which is needed for the synthesis of replicative enzymes. Ras activation leads to synthesis of g1 cdk-cyclin complex, P* of Rb so cannot bind E2F.
Apaf-1 in cancer?
Lost or downregulated; is key promoter of apoptosis.
Ways of getting sustained proliferative signalling?
Increased receptor expression = hypersensitivity to ambient stimuli, get autocrine growth factor production, reciprocative paracrine signalling with neighbouring stromal cells, and often mutations in key growth promoting pathways such as Ras mutations (downstream of EGFR). Problem with these specific mutations is that the diverse effects of one receptor are “reduced” to single aberrant pathway. H&W (hallmarks of cancer: the next generation) point out that actually excessive oncogene signalling and lead to senescence!
Why hard to identify driver mutations in cancer?
Have widespread genomic instability; even if can study clones cannot tell if a mutation caused a specific clone to become dominant or just coincided with the “real” driver mutation.
Changes in malignant transformation?
Nucleotide changes, epigenetic changes, altered methylation (generally hypomethylated but get hypermethylation of key areas!), gross chromosmal changes e.g. BCR-ABL (9:22). Cells become tumorigenic, anchorage independent (grow in agar), decreased GF requirements and contact inhibition
Proto-oncogenes?
Mediate growth and differentation: Ras, Myc, Raf, EGFR, EGF, apoptosis inhibitors (e.g. BLC-2). Mutated or overexpressed in cancer; activating dominant gain of function mutations. May simply be translocated under new promoters
P53 pathway?
Normally DNA damage causes ATM to P* P53 (the so-called guardian of the genome); this is a TF and transcribes P21; p21 binds to cdk-cyclin complex and thus stops it binding to Rb; this means that cell does not progress. Allows time for repair; if this is not possible then cell apoptoses
Division of labour Rb and P53?
P53 more about endogenous damage; Rb more about responding to external stimuli. Both obviously are important and have key role in G1/s progression.
Ways to identify TS genes?
If function during cell fusion, if LOH seen in their regions, familial e.g. Rb, or if null mice (i.e. no expression of TS gene) get cancer
Three angiogenesis triggers?
VEGF, EGF, FGF!
Why is TGFB oncogene and TS?
Anti-proliferative activity via SMAD signalling; but also promotes EMT and metastasis
Alternative serrated pathway features?
Key is somatic BRAF mutation; serrated pathway so named because defective apoptosis leads to abnormal serrated appearnec of polyps as SSAs (sessile serrated adenomas). Get hypermethylation of MLH1 and CpG islands; overlap with CIMP phenotype and MSI.
E-cadherin loss?
Key to contact inhibition; normally forms homotypical interactions with other E-cad molecules to keep epithelial cells in sheets. If mutated, get loss of contact inhibition, increased cell motility; it is a cardinal feature of the EMT that is recognised as key to facilitating metastasis. Inherited mutation leads to diffuse gastric cancer
Transcription factors relevant to EMT?
Snail, slug, twist. Get increased TGF-B signalling and repression of E-cadherin; may get gain of N-cadherin as become more motile, mesenchymal cells.
