Cancer cell biology 1 Flashcards
what is the difference between a benign and malignant tumor?
benign= localized growth, grow by expansion, compression, or displacing surrounding normal tissue
malignang = capable of invasion or metastasis, grow by local inflitration, destroying the tissue through which they invade
what do carcinomas, sarcomasl and leukaemias derive from?
- carcinomas= arise from epithelial cells
- sarcomas= arise from mesodermal origin (muscle, bone, fibroblasts)
- lymphoma/leukaemia = develop from circulating cells of blood and lymph systems
what two models exist to account for the heterogeneity and differences in tumour regenerative capacity?
- clonal evolution model = mutant tumour cells with a growth advantage are seleceted and expanded
- cancer stem cell model - refers to a rare subset of tumour cells that have the ability to self-renew and generate diverse tumour cells
*these models aren’t mutually exclusive - cancer stem cells can undergo clonal evolution
describe in detail the cancer stem cell model
- tumours are functionally heterogenous and hierarchical
- tumours composed of cells that can initiate tumours (cancer stem cells) - and cells that arise from these cells, but cannot initiate tumours
- very low frequency of tumour stem cells within the tumour
- this has implications on cancer treatment b/c the old treatment killed anything rapidly proliferating (which would be the cells that arise from stem cells ) but it doesn’t kill the stem cells themselves (which means they can initiate another tumour potentially)
mutations in what three classes of genes can cause cancer?
- proto-oncogenes
- tumour suppressor genes
- care taker genes
what is the normal activity of proto-oncogenes?
normally, they promote cell proliferation
mutant forms = oncogenes
when mutated, they create forms that are excessively active
what is the normal activity of the tumour supressor gene?
they normally inhibit cell proliferation or promote apoptosis - normally for these genes you need to see a mutation in both allels for these genes to be effected
What is the normal function of care-taker genes?
they are the ‘car maintenance check’s = they ensure accurate replication, repair, and segregation of DNA - mutations in these can lead to genomic instability
what are the 6 biological capabilities acquired during the multistep development of human tumours? *the hallmarks of cancer
- sustaining proliferative signaling
- evading growth suppressors
- activating invasion and metastasis
- enabling replicative immorality
- inducing angiogenesis
- resisting cell death
how can tumour suppressor genes be inactivated?
- deletion (loss of functional gene copy leads to loss of heterozygosity)
- point mutation
- methylation of promoter- transcriptional silencing - methylation blocks the transcription factor from binding = silencing mutation
- miRNAs- post transcriptional silencing
what is a ‘nonsense’ mutation
a mutation that indicates an innapropriate ‘stop’ codone
what is a conservative or non-conservative missense mutation?
conservative = codes a different nucleic acid sequence, but ultimately is translated into the same AA
non-conserative= codes for a different nucleic acid sequence and is translated, consequently, into a different AA
give four examples of tumour suppressor genes
- RB
- P53
- APC
- BRCA1
what are the normal functions of the Proto-oncogenes?
- growth factors
- cell surface receptors
- intracellular signal transduction molecules
- DNA binding proteins
- cell cycle proteins - cyclins, cdks, kinase inhibitors, apoptosis inhibitors
what are the three ways proto-oncogenes can be activated?
- point mutation or deletion - Ras , EGFR
- gene amplification - MYCN
- chromosome rearrangement - BCR - ABL
describe the RAS oncogene control system
RAS is mutated in 20-30% of cancers
- “off” RAS is bound to nucleotide guanosine diphosphate
- “on” state RAS is bound to guanosine triphosphate
- mutated RAS revents GTP hydrolysis to GDP so constitutively active
describe the oncogene activation by deletion and EGFR implications?
EGFR requires binding of epidermal growth factor (EGF) to enable kinase activity
the catalytic domain then transfers phosphate groups to target proteins to activate them - leads to translation of proteins involved in mitosis
oncogenic form of EGFR produces a receptor that doesn’t require EGF binding and is furthermore always “active”
the oncogene produce is capable of activating the pro-growth pathway in the absense of pro-growth signals
describe oncogene activation by gene amplification and it’s implications on MYCN in neuroblastoma
MYCN is an oncogenic transcription factor that alters expression of hundreds of genes- MYCN amplification is marker of poor prognosis in patients with neuroblastoma *we use it to determine optimal therapy*
Describe oncogene activation by chromosome rearrangment
translocation of an enhancer to a region that is normally silenced -
what is microsatellite instability?
DNA level instability underlying DNA mismatch repaire defects
what is chromosomal instability?
abnormal karyotypes = extra/missing chromosomes, chromosome rearrangments
what is the relationship between telomerase and cancer?
cancer cells avoid apoptosis or senescence by activating telomerase - which adds repeats back on the ends of chromosomes
