Week 9-molecular cell biology of cancer Flashcards
Define neoplasia
- Abnormal growth of cells which persists after initiating stimulus has been removed
- cell growth escaped from normal regulatory mechanims
- two types –> benign vs malignant
Define benign neoplasia and malignant
Benign –> cells grow as compact mass and remain at site of origin
malignant –> invasion and metastases
What types of cell are neoplastic cell?
what have they acquired?
Neoplastic cells = transformed cells
they have acquired a series of changes that permit them to form tumours
What underlies cellular transformation in neoplastic cells?
genetic and epigentic changes underlie this transformation
there has to be a change to DNA or gene expression
change must be non lethal and passed onto daughter cells
what happens during invasion and metastasis?
cell- cell interactions disrupted
cell -stromal interactions disrupted
interactions are important for cell and tissue differentiation, embryogenesis and growth regulation (cell signalling disruption)
abnormalities allow invasiveness and metastases
Describe cell cycle checkpoints
- G1 –> S phase –> G2 –> mitosis –> two daughter cells
- G1 checkpoint (prior to S phase) –> halted if DNA is damaged, also are conditions favourable, correct EC signals? Once cell has passed G1 checkpoint, this is the last point at which EC signals have any impact.
- G2 checkpoint (prior to G2 and Mitosis) –> Is all DNA replicated? Is the cell correct size to divide?
- M phase checkpoint –> are chromosomes attatched to spindle? Aligned at metaphase at equator?
Describe the proteins involved in cell cycle regulation
- Cyclins are proteins that show cyclical variation in levels during the cell cycle
- Cyclin - dependent kinases (CDK’s) = constant levels throughout the cycle but are only active with specific cyclins
- CDK’s phosphorylate target proteins to drive forward the cell cycle
- CDK inhibitor proteins can delay/ pause progression through the cell cycle
What is cancer?
What are the six hallmarks?
Cancer = genetic disease at cellular level
Six hallmarks:
- Growth signal autonomy
- evasion of growth inhibitory signals
- evasion of apoptosis
- unlimited replicative potential
- angiogenesis (formation of new blood vessels)
- invasion and metastasis
What are some potential other hallmarks of cancer?
- dysregulation of metabolism
- avoiding immune destruction
- tumour promotion by inflammation
- genomic instability and mutation
What are the cellular factors involved in sustained proliferation?
- Oncogenes (mutated form of proto oncogene) –> e.g. gene encoding GF, or GF receptors, signal transduction proteins within the cell, transcription factors
- Every stage of signalling:
- GF’s
- receptors
- signal transduction proteins
- transcription factors
- Cell cycle entry proteins
What are examples of proteins invovled in growth suppression?
Normally protiens physiologically curb cell growth, loss of function –> tumour growth
Examples = Rb (retinoblastoma) and p53
How is telomerase involved in cancer biology?
Telomerase expression keeps chromosome length –> telomere remains long enough for cell to keep dividing
avoid senscence
seen in stem cells and cancer cells
How is genomic instability involved in MB of cancer?
- Genomic instability caused by defects in DNA repair mechanism –> e.g. mutation in protein involved in DNA repair –> leads to more muations
- often seen in inherited syndromes, sporadic cancer
- DNA remains susceptible to genetic damage
- DNA repair defects
How is clonality involved in MB of cancer?
- Tumours develop from a single cell – >form a monoclonal population arising from single cell
- if clonality can be proved , strong evidence for neoplasia
- further mutations lead to other charactersitics of neoplasia
- mutations passed from cell to cell; all progeny have mutation and accumulation of these mutations leads to adaptation of developing tumour
What DNA alterations may be involved in cancer?
- Genetic mutations:
- point
- insertion
- deletion
- large chromosomal aberrations (abnormal) – >deletions/ chromosomal translocations/ copy numbers
- Epigenetics –> DNA methylations and acetylation of histone
How do mutations arise?
- germline mutation (inherited)
- spontaneous copy errors during DNA replication
- carcinogens (e.g. UV light, viral infection).
- Leads to DNA repair –> outcome can be 1) apoptosis 2) Normal division 3) division with mutated gene to daughter cells
- Now cell w mutated/ Damaged DNA –> more mutations (3 to 7 more)
- Targeted by immune system (may be removed)
- or could be exposed to carcinogen and risk factors (age, diet etc..)
- leads to clonal expansion of mutated cell –> cancer
How can UV light lead to DNA damage?
- UV light leads to development of cyclobutane pyrimidine dimer
- DNA polymerase now recognises two cysteines as a TT –> then adds AA
- subsequent rounds of DNA replication –> leads to further mutations with knock on effects
Describe normal gene structure
- exons = coding regions of gene –> encodes protein –> mutation within these genes could have no effect, protein with changed function or truncated protein/ no protein
- (intron spliced out)
- Promoter sequences –> mutation here could have no effect, or increase or decrease expression
Which genes are involved in cancer development?
- Positive (accelerators) = oncogenes
- singlas from outside cell (growth factors)
- receptors (EGFR/HER2)
- coupling molecules –> RAS, BRAF –> Ras only active when GTP bound, can mutate to become active in abscence of GTP
- phosphorylation reactions -> CDK’s, cyclin complexes
- Negative (tumour suppressor geners)
- singlas outside the cell (loss of growth inhibitor)
- cyclin kinase inhibitors
- checkpoint (loss of proteins invovled)
What is a key tumour suppressor protein?
what are its roles?
p53 = Master guardian of the genome
roles:
1) Detect DNA damage
2) abbertant
What is a retinoblastoma?
Copare the differences between the sporadic and familial condition and how they occur
