Lecture 1

• Cancer cells bypass normal regulation to become self-sufficient and overcome the normal requirement for extracellular growth factors
• How cancer cells bypass normal regulation

  1. They produce their own growth factors

  2. They overexpress growth factor receptors

  3. They mutate their signalling pathways to be constantly turned on and to enter the cell cycle at will and proliferate at an uncontrolled manner
• Cancer is caused by mutations in genes which control cell growth
• What is an Oncogene?

  A mutated or abnormally activated proto-oncogene that promotes uncontrolled cell growth and contributes to the development of cancer
• Proto-oncogene


  A normal gene involved in regulating proliferation and survival that can become an oncogene due to mutations or abnormal activation
• What do Proto-oncogenes do?

  • They typically encode proteins involved in cell growth, proliferation, or differentiation
  • When mutated or activated inappropriately, they can promote uncontrolled cell growth and contribute to the development of cancer
• Tumour suppressor genes


  Genes that inhibit cell proliferation, promote apoptosis (programmed cell death), and repair damaged DNA. Mutations or loss of function in these genes can lead to unchecked cell growth and an increased risk of cancer development.
• Oncogenes derive from proto-oncogenes
• Oncogenes were first discovered through ancient Egyptian drawings and the discovery in the 1900s that chickens could get cancer as a result of a viral infection
• The epidemiology of human cancer was not consistent with an infection, with most cancers not containing any viruses, only a few cancers are caused by viral infection
• Cancers caused by viral infections

  • Cervical carcinomas
  • Liver carcinomas
• Apart from age, carcinogens increase the risk of cancer
• When did techniques to test the theory that carcinogens increase cancer risk became available

  1970s
• Experiments proving carcinogens increase cancer risk and cancer is of genetic origin


  1. They added chemical carcinogens to mouse or human cells

  2. Cancer growth was seen after a few weeks

  3. To prove the genetic origin, the DNA alone was isolated from these transformed/cancerous cells and transfected into normal cells

  4. After a few weeks, these normal cells became cancerous

  5. These cells were then injected into a mouse, which eventually grew a tumour proving their cancer-forming ability
• Mechanisms for oncogene activation

  • Gene amplification
  • Regulatory mutation
  • Deletion or point mutation in coding sequence
  • Chromosome rearrangement
• List the 7 different Proto-oncogenes

  • Growth Factors
  • Growth Factor receptors (e.g. Receptor Tyrosine Kinases)
  • G proteins
  • Intracellular serine/threonine kinases
  • Intracellular tyrosine kinases
  • Transcription factors
  • Negative regulators of apoptosis
• What do Growth Factors bind too? what does it lead too?

  Bind to growth factor receptors and send signals to intracellular proteins, leading to transcription factor changes, like MYC
• Signalling by Growth Factors

  Endocrine or paracrine signalling = external signalling
• Signalling by cancer cells

  Autocrine signalling = they produce their own growth factors which bind to their own receptors
• Autocrine growth factor in cancer

  • TGF-alpha
• TGF-alpha


  Binds to Epidermal growth factor receptor (EGFR)
• Cancers that produce TGF-alpha


  • Prostate, lung, pancreatic, mesothelioma, breast
• Other ligands and receptors used in cancer

  • VEGF-A (VEGF-R)
  • NRG (HER2/3)
• What happens when Tyrosine Kinase receptors bind to a ligand

  The receptor dimerises, leading to initiation of cell signalling cascades
• How cancer cells increase Growth Factor signalling

  1. Mutations affecting the EGFR structure within the cytosolic domain can cause dimerization and firing without a ligand/growth factor present

  2. Overexpression of EGFR leading to molecular crowding and ligand-independent firing
• Cancer with Growth Factor receptor dysregulation


  • Breast adenocarcinomas - Receptor: HER2 (Oncogene), Ligand: NRG, Cancer Mutation: Overexpression
• Effect of HER2 overexpression in breast cancer

  Cells with many copies of HER2 have a poorer prognosis as they aggressively grow
• Southern blotting can detect DNA overamplification, Northern blotting can detect RNA, and dysregulation of transcription leading to overexpression
• G proteins


  A large family of proteins which are activated by binding GTP
• Example of a G protein


  • RAS
• RAS activation cycle


  1. When GDP is bound, RAS is inactive

  2. Upstream signalling causes GDP to be released and GTP to bind to RAS, activating RAS

  3. RAS is blocked by oncogenic mutation

  4. GTP is turned into GDP and a phosphate molecule
• Guanine nucleotide exchange factors (GEF)


  Activate RAS by converting GDP to GTP
• GTPase activating proteins (GAPs)


  Inactivate RAS by converting GTP to GDP
• There are 4 RAS isoforms
• RAS isoforms


  • NRAS
  • HRAS
  • KRAS4A
  • KRAS4B
• RAS isoforms are 21kDa in size
• The most common RAS isoform is KRAS
• Cancers with different RAS isoforms


  • NRAS - Skin, thyroid
  • KRAS - Pancreatic, Colorectal, Biliary Tract
  • HRAS - Head and Neck cancers, Cervical
• How adaptor proteins link Receptor Tyrosine Kinase to RAS


  1. Once a growth factor ligand binds, it modifies the side domains of the receptor tyrosine kinase

  2. This side domain phosphorylates the intermediate molecule Grb2, which is bound to GEF

  3. GEF becomes activated by binding to the cytosolic domain of the receptor, encouraging the exchange of GDP to GTP on RAS
• Oncogenes often have hotspot mutations, not many mutation positions, but many cancers are formed by them