Neoplasia III

Oncogenes

  • Turn up genes that promote growth

RAS

  • Linked with many cancers including colon cancer and lung cancer

BRAF

  • 50% of melanomas

C-KIT

  • GI and stomach cancers

Myc

  • Nuclear transcription factor that promotes growth
  • Common in lymphoma, neuroblastoma, small cell carcinoma of the lung

P13K

  • Most commonly mutated kinase in cancer
  • Limited success in trials - targeted at haematological malignancies

Wnt/APC/beta catenin

  • One of the earliest mutations in colorectal cancer
  • Can occur as a germline mutation causing an inherited condition
    • Familial Adenomatous Polyposis
    • Gardner’s syndrome

Tumour suppressors

  • Stop growth
  • Cells with malignant ambitions must remove them to survive and proliferate
  • Lots of proteins inhibit the cell cycle e.g. p53 and VHL

Hallmarks of malignancy

Unlimited replicative potential

  • In malignancy there is often a mutation that reactivates telomerase (renews length of telomeres)

Avoid apoptosis

  • Bcl-2 binds to Bax/Bak to stop holes being punched in mitochondria

Angiogenesis

  • Formation of new, abnormal blood vessels
  • ‘Successful’ cancers must create their own blood supply - to supply oxygen etc. for growth
  • VEGF is frequently upregulated in some malignancies
    • Useful target for treatment

Repair

  • Nucleotide excision repair (NER): can be damaged by radiation
  • BRCA: associated with breast, ovarian and pancreatic tumours
    • Complex roles in ER and AR regulation
    • DNA repair and cell cycle arrest at G1/S phase
  • Mismatch repair proteins: family of proteins responsible for identifying faults in the code
    • Lynch syndrome: mutation in mismatch repair proteins associated with colorectal carcinomas
    • Faulty protein expression identified using immunohistochemistry - looking for frequency of mismatched segments by analyzing microsatellites

Evasion of the immune system

  • Malignant cells may express ‘foreign’ proteins or expose proteins to the immune system that aren’t normally exposed
  • Patients with cancers with a pronounced inflammatory response have a better prognosis
  • PD-L1: inhibits T cell proliferation (apoptosis)
    • Tumours can overexpress PD-L1 and avoid the immune system

MMPs

  • Malignant cells increase expression of matrix metalloproteinases (MMPs)
  • Means cells can chew their way through surrounding tissues and blood vessels

Subclones

  • Cancer is not clonal - single parent but not all cells are identical
  • Each daughter cell will develop new mutations with each division
  • Chemo and targeted therapies may not work against all clones - some clones may have a survival advantage