oncogenes

oncogenes

• Oncogenicity of driver genes and passenger genes 

  • Increased proliferation leads to greater tumour growth 

• Driver genes are genes whose mutations actively contribute to cancer development or progression 

  • 2 types, oncogenes and tumour suppressor genes 

• Passenger genes acquire mutations that do not provide a significant selective advantage to the cancer cell 

  • Carried along as the tumour expands 

  • Can arise as cancer cells have genome instability and thus accumulate many mutations 

• A gene that has the potential to cause cancer 

• Tend to affect cell proliferation either directly through the cell cycle or through signal transduction which ultimately feed into cell proliferation 

• Activated proto-oncogenes 

• Utilise phases of cancer process 

  • Have a replicative immortality 

  • Become overactive 

    • Cell growth 

    • Cell division 

    • Cell survival development 

• We don't have cancer genes 

  • Other genes are hijacked 

cancers are complex tissues

• Multiple cell types 

  • Contain genetically different cancer cells (subclones) 

  • Contain normal cells as well (e.g. fibroblasts) 

• Tumour microenvironment 

  • Interact continuously with the extracellular matric  

  • Interactions can influence tumour growth, invasion and survival 

• Cell to cell communication 

  • Cells release signalling molecules such as growth factors, cytokines and chemokines 

  • These signals can alter the behaviour of both cancerous and non-cancerous cells 

• Blood supply 

  • Tumours need nutrients and oxygen 

  • Cancer cells can stimulate angiogenesis, causing new blood vessels to form 

• Immune interactions 

  • Immune cells can recognise and attack cancer cells 

  • Tumours can alter their environment to suppress or evade immune responses 

• Heterogeneity 

  • Different cancer cells within the same tumour can have different mutations and behaviours 

previously asked questions

• Is cancer a contagious disease 

  • Some viruses cause cancer 

• Is it a genetic disease 

  • Might have a previous disposition towards cancer 

• Is it an environmental/lifestyle disease 

  • Actions can effect epigenetics, increasing cancer likelihood 

Rous’ protocol for inducing sarcomas in chickens

• Transferred tumour material between chickens and found that the tumour could be reproduced in other chickens 

• Produced a cell-free filtrate from the tumour 

  • Could still induce sarcomas 

  • Showed that the cancer could be caused by a filterable infectious agent, RSV (Rous sarcoma virus) 

• RSV is a retrovirus 

  • Carry reverse transcriptase, which allows viral RNA to be converted into DNA 

  • The viral DNA can then integrate into the host-cell genome 

  • Provided a mechanism by which a virus could produce long-lasting changes in cell behaviour 

• src 

  • In RSV 

  • Encodes tyrosine kinase 

  • Abnormal activation promotes processes such as cell proliferation and transformation 

• Sarcomas are cancers of connective and non-epithelilal tissues 

• Viruses go through the filer due to their small size (compared to bacteria and other microorganisms) 

• More viruses could be recovered in the sarcoma tumour growth compared to what had been injected 

transformed cells forming foci

• Used the RSV particle from chicken sarcoma 

• Infects cells and introduces the viral src oncogene into them 

• Alters normal signalling controlling cell growth and behaviour 

• Cells continue proliferating and piling up on top of each other, forming a foci 

RSV exploits a kindapped cellular gene to transform cells

• The viral transforming gene of RSV (v-src) is closely related to another gene called c-src which is found in normal chickens 

  • This is a proto-oncogene 

• The virus produces a viral version, v-src 

  • The viral version becomes deregulated or altered compared to normal c-src 

• Normal c-src activity is controlled whilst v-src is constitutively active 

  • Its kinase activity is switched on continuously 

the cellular origin of oncogenes

• Most types of human cancer do not spread from one individual to another. 

• Attempts in the 1970s to isolate viruses from most types of human tumors were unsuccessful. 

• Only a handful of tumor types can be linked to viral causative agents. 

  • Human Papilloma Virus causes cervical cancer 

  • Epstein-Barr Virus causes lymphoma and stomach cancer 

  • Hepatitis B and C virus causes liver cancer 

  • Human herpes virus 8 causes sarcoma 

  • Human T-cell leukemia virus causes T-cell leukemia/lymphoma.  

• Proto-oncogenes were not noxious cancer genes lying in wait until stirred into action by a carcinogen, but were part of the genetic machinery of normal cells and carried out a function vital for the developing cell. 

• Oncogenes are found in cells that showed no sign of viral infection, meaning that they had not been deposited in the germ line by a virus at some distant point in the past, but rather originated in healthy cells and were later introduced in modified, oncogenic form into the genome of an evolving retrovirus.  

• Proto-oncogenes survived through many stages of evolution also indicated that they must perform a vital function, most likely in directing the growth and development of cells 

• A proto-oncogene is a gene with normal function and which has the potential to become oncogenic and to drive tumorigenesis. 

tumour formation

• Normal cell 

• Genetic changes occur 

• Abnormal cell proliferation 

• Clonal expansion 

• Tumour develops 

protoncogene to oncogene

• Due to a genetic alteration causing it to become abnormally active 

• For example 

  • Point mutation 

  • Gene amplification 

  • Chromosomal translocation leading to fusion events 

  • Insertational mutagenesis 

  • Chromosomal rearrangements 

examples

• Point mutations and ras signalling 

  • Abnormal amount of ras and GTP binding factor 

  • Leads to the Ras/Raf/Mek pathway 

  • More transcription 

  • Some mutations can lead to cancers 

• Gene amplification (breast cancer) 

  • High expression of HER2 

  • More proteins 

  • Non-random amplifications and deletions of chromosomal regions 

    • Chromosomes break and when put back together can either amplify or delete 

• Insertional mutagenesis 

  • RNA virus inserts into genome 

  • Can activate cancer 

    • If it interacts in certain regions 

• Chromosomal rearrangements 

  • e.g. burkitt's lymphoma 

  • Translocation of the immunoglobin gene on chromosome 14 to the c-myc oncogene locus on chromosome 8 

• Translocation leading to fusion events 

  • Creates a new gene and thus a new protein 

  • Can make a cancer causing oncogene