Cancer II: molecular changes and cancer hallmarks Flashcards
(34 cards)
Cancer
Abnormal grwoth – cells continue to proliferate forming a mass (tumour)
Collection of hundreds of disease with the common features of uncontrolled growht
Acquisition of genetic alterations resulting in uncontrolled proliferation
Namethe types of tumours and how their masses behave
Benign – growth remains a single mass.
Malignant – cells gain the ability to invade surrounding tissue: Metastasis
Describe how cells become malignant and how this allows them to eventually metasatisize.
Cells gradually become malignant through progressive alterations at a genetic level.
Selection for growth advantage and survival, eventually invasion and metastasis.
Metastasis:what makes cancer cells undergo metastasis?
Complex, multistep process responsible for >90% of cancer-related deaths. In addition to geentic and external envrionmental factors, the physical interactions of cancer cells wth their microenvironment and their moulation( mechanical stimuli influencing cancer cell behaviour) by mechanical forces are key determinants of the metastatic process
Angiogenesis
Angiogenesis (the growth of new blood vessels): important for tumour growth and metastasis.
VEGF (vascular endothelial growth factor): key molecule involved in the production of new blood vessels.
In tumours with low oxygen (hypoxia) HIF stabilised and can transcriptionally activate VEGF
Hallmarks of Cancer
Biological capabilities acquired during the development of human tumours.
Cancer cells acquire these capabilities as they develop/evolve.
Why are molecular changes important in personalised medicine?
Understanding changes at molecular/genetic levels allow targeted therapies: every tumour could be unique and ultimately this allows for personalised medicine.
What causes Unregulated cell growth role in tumour development
Cell proliferation results in increased cell numbers (cell division cycles)
Cancer cells defined by their uncontrolled proliferation and ability to overcome cl death mechanisms
Tumour development is a balance between growth and cell death (increased cell division and decreased apoptosis)
Cell division cycle controls cell number
Cyclins and cyclin dependent kinases
- Cyclins bind to and regulate activity of the CDKs.
- Cyclin dependent kinases (CDKs): Family of serine/theronine kinases that can modify various protein substrates involved in cell cycle progression
- CDKs require presence ofcyclinsto become active.
- Cyclins : family of proteins that have no enzymatic activity of their own but activate CDKs by binding to them.
- CDKs must also be in a particular phosphorylation state — with some sites phosphorylated and others dephosphorylated — in order for activation to occur. Correct phosphorylation depends on: action of other kinases and a second class of phosphatases that are responsible for removing phosphate groups from proteins.
- CDK1 and CDK2 bind to multiple cyclins (cyclin types A, B, D and E),
CDK4 and CDK6 only partner D-type cyclins.
D-type cyclins and CDK4 or CDK6 regulate events in early G1 phase, cyclin E-CDK2 triggers S phase, cyclin A-CDK2 and cyclin A-CDK1 regulate the completion of S phase, and CDK1-cyclin B is responsible for mitosis.**
Oncogenes vs Tumour suppressor
Oncogene: gene with the potential to cause cancer. are often mutated or expressed at high levels in tumour cells. (Accelerator)
Tumour suppresor is a gene that normally can prevent / repress cancer. (Brake)
Two main types of oncogenes
Viral oncogene: gene from the virus itself; E6/E7, E1a/b, large T
(i.e., no cellular homologue).
Cellular oncogene: gene derived from the host cell genes that
normally are in an ‘inactive’ form.
Proto-oncogene
Normal form of the cellular gene under normal regulation.
Can be converted into oncogenic forms through mutation/alteration that leads to enhanced activity/expression.
Functions of oncogenes
Numerous oncogenes identified with a wide variety of specific functions - ultimately they are all growth promoting.
Growth factors: epidermal growth factor (EGF) and platelet derived growth factor (PDGF).
Growth factor receptors: PDGF and EGF receptors (e.g. HER2 in BC).
Signal transduction: Ras, Raf, Src.
Transcription factors: Myc, Jun, Fos, Elk-1.
Anti-apoptotic: Bcl-2.
Cell cycle regulation: Cyclin D1.
Function of Ras
Functions as a molecular switch: active when GTP is bound and inactive when GDP is bound.
Two classes of signalling protein regulate Ras activity
Ras-GEFs and Ras-GAPs
GEF: Guanine nucleotide exchange factors. Ras-activating protein whereby Ras exchanges GDP for GTP.
GAP: GTPase-accelerating proteins. Ras inactivating protein by increasing the rate of hydrolysis of Ras-GTP
Oncogenes: Ras. What does it do?
Mutation results in a constantly active Ras: Consitutive activation.
Ras activation drives signalling cascades from the plasma to the nuceluspromoting cellular proliferation and tumour survival
TSGs (Tumour Supressor Genes)
Regulate diverse cellular activities including cell cycle regulation, DNA repair, apoptosis, ubiquitination and protein stability, differentiation, migration and angiogenes.
Some tumour suppressors normally restrict the cell
Tumour suppressor genes (TSG): normally act as brakes for the cell cycle to suppress cell proliferation.
p53, Rb (checkpoints) : p53 controls checkpoints throughout the cell cycle from G1 phase to cytokinesis whereas the classical model associates RB only with cell cycle control during G1 and at the G1/S transition
Retinoblastoma (retinal cancer)types and inheritance
Rare childhood tumour of the eye
Most cases (60-70%) are sporadic (not inherited) and present in children 1-4 years of age
remaining 30-40% have hereditary form of retinoblastoma and thus inherited germline cancer predisposing mutation - tend to have tumours earlier and are more likely to have multiple tumours in one (unilateral) or both (bilateral) eyes.
Knudson Two-hit hypothesis. How is retinoblasma inherited?
- illustrate how inherited and somatic genetic changes might contribute to cancer.
- Demonstrates recessive nature of some tumour suppressors
- basis for our understanding of how TSGs drive cancer.
- Inherited retinoblastoma: One defective copy of Rb is genetically transmitted - loss of single Rb copy is sufficient for tumour development, but retinoblastoma develops as a result of second somatic mutation at the Rb allele (this explaining dominant pattern of inheritance)
Noninherited retinoblastoma - rare, development requires two independent somatic mutations to inativate both normal copies of Rb in the same cell.
What is Rb and what does it do?
What inhibits Rb?
Rb negatively regulates cell cycle progression through binding to and inactivating E2F - preventing G1/S progression
Rb: 110 kDa nuclear phopshoprotein: a key cyclin/Cdk target. Rb phosphorylation by Cdk/cyclin pervents binding to E2F prallowing E2F to activate cell cycle progression through G1/S.
p53 - how was its role as a tumour suppressor confirmed
p53 (TP53) - mutated in over half of all human cancers.
p53 confirmed as a tumour supressor in 1990 by finding that patients with Li-Faumeni syndrome (which predisposes to diverse tumour types) had inherited TP53 mutations. Further confirmed in 1992 by experiments showing thatTrp53(which encodes mouse p53) knockout mice are prone to tumours.
70% of families inherit mutation in p53
p53- Role
- Orchestrates cell fate during the stress response.
- Most well characterised role of p53 is as a nuclear transcriptional activator.
- p53 mutated in 50% of cancers - other half thought to have mutationsin pathways impacting on P53 function.
p53: the guardian of the genome
Different stressors result in increased p53 levels and this helps to prevent damage/repair damage/kill cells that are too damaged.
Two key p53 target genes
p21:Cdk inhibitor which causes cell cycle arrest (G1). Has a P53 promoter region so activated by p53- time to repair damage
Bax: prop-apoptotic - if cell damage is too great then Bax can lead to apoptotic cell death stopping tumour growth
