Neoplasia II: Oncogenesis and Pre-Malignancy

• What is oncogenesis?


  Development of cancer
• What are some hallmarks of cancer?

  Limitless replication potential

  
  

  Sustained angiogenesis

  
  

  Evasion of apoptosis

  
  

  Self-sufficiency in growth signals

  
  

  Tissue invasion & metastasis

  
  

  Insensitivity to growth inhibition
• How do cells accumulate these hallmarks of cancer?

  By one oftwomechanisms:

  Activation of oncogenes

  Inactivation of tumour suppression genes
• What is an oncogene?

  A dysregulated proto-oncogene causing cell to grow autonomously
• What is a proto-oncogene?

  A normal gene whose product promotes cell growth
• What is an oncoprotein?


  The product of an oncogene
• How do proto-oncogenes become oncogenes?

  Through mutations, chromosomal rearrangements, & gene amplifications
• How are oncogenes classified?

  They're classified according to where they are in the signalling pathway, so they may act as either:

  Growth factors

  Growth factor receptors

  Signal transducing proteins

  Nuclear proteins

  
• How do oncogenes maintain the self-sufficiency of growth signals?

  They over-express growth factors so that its receptors are constantly stimulated (autocrine activation).

  
  

  Or

  
  

  They can also be self-sufficient through inappropriate activation of the receptor, either through ligand-dependent activation or ligand-independent activation

  
• Give some examples of self-sufficiency of growth signals and which cancer was caused.

  
• What is an example of a signal transduction protein in oncogenesis?

  Ras
• What is Ras bound to in its inactive form?

  GDP

  
• What happens when Ras is activated through upstream signalling?

  It phosphorylates to become bound to GTP and it then induces further donwstream signalling to progress the cell through its cell cycle

  
  

  Ras is then returned to its inactive state

  
• What happens when there are mutations in Ras?

  If it fails to return to its inactive state, it renders this protein to be continuously stimulating downstream proteins, therefore progressing the cell inappropriately through the cell cycle

  
• What are some examples of gene translocations in neoplasia?

  Gene translocation as a mechanism of oncogene activation is relatively common in tumours of the haematopoietic system

  
• Give an example of gene amplification in oncogenesis.

  Amplification of N-myc gene seen in neuroblastomas

  
  

  Over-expression of oncoprotein may result from the duplication of DNA Sequences.

  
• What is the normal function of tumour suppressor genes?

  To regulate cellular proliferation
• How are tumour suppressor genes classified?

  Gatekeeper genes-inhibit proliferation/induce apoptosis of cells with damaged DNA

  Caretaker genes-maintain integrity of genome
• How are tumour suppressor genes inactivated?

  Mutation

  Deletion

  Transcriptional silencing
• What is retinoblastoma?


  Rare, intra-ocular tumour that affects 1 in 20,000 infants

  60% of cases aresporadic(occurs occasionally)

  40% of cases arefamilial(runs in the family, less likely due to chance)

  Knudson’s two hit hypothesis- in tumour suppressor genes, both alleles need to be inactivated before it has a significant impact on tumour progression.

  
• What is the most widely dysregulated tumour suppressor gene in cancer?

  p53 known as the guardian of the genome

  
• What is the role of p53?

  A transcription factor that regulates cell-cycle and DNA repair genes.

  
  

  It is activated in a response to a number of cell/DNA damaging stimuli
• Once P53 is activated, what are the 2 possible pathways that could occur?

  1 - if the stimuli wasn’t damaging enough, there isG1 arrestand repair is initiated.

  2 - If the stimuli was damaging, repair fails and cell undergoes apoptosis

  
• What happens when there is abnormal p53?

  The protein cannot direct the cell following damage to G1 arrest or apoptosis.

  
  

  Any damage that is not lethal will accumulate in the cell.

  
• What are some examples of other tumour suppressor genes that are commonly dysregulated in cancer?

  
• Why are APC mutations significant?

  Beta-catenin needs to translocated to the nucleus as a transcription factor to exert its effects.

  
  

  Because APC usually binds beta-catenin (cell cycle/Tumour promoter).

  
  

  This is to stop it translocating to the nucleus to exert its effects but when there is mutations in APC, it can't do that so beta-catenin is active in inappropriate circumstances

  
• What is BRCA?


  breast cancer (gene) which is usually mutated in 50% of women with breast cancer.

  
  

  Forms a complex with RAD51.

  
  

  Any mutations in BRCA can cause mutant DNA
• What does the regulation of apoptosis depend on?

  Ratio of death antagonists (e.g. bcl-2) to agonists (e.g. bax) determines the cellular response to an apoptotic stimulus

  
• What are 2 additions to the updated hallmarks of cancer?

  Immune evasion:Cancers develop antigens which are recognised by the immune system, particularly cytotoxic T cells. Cancers have developed ways to avoid detection from the immune system.

  altered metabolism: Cancers adapt to a more glyc

  
• What is another important caretaker tumour suppressor gene?

  Xeroderma pigmentosum (XP)

  
  

  Important in nucleotide excision pathway of DNA repair.

  
  

  Any hereditary XP mutations can cause cancers at young ages
• Is cancer a multistep process?

  Yes

  
• What is initiation in oncogenesis?

  The event that induces the genetic alteration that gives the transformed cell its neoplastic potential

  
• What is promotion in oncogenesis?


  Event that stimulates clonal proliferation of initiated cell

  
• Do all carcinomas have an adenoma precursor?

  No

  
  

  But carcinoma have pre-malignant phases, dysplastic