Cancer

• Cancer

  A serious disease, resulting from a malignant growth or tumour, caused by abnormal and uncontrolled cell division
• Cancer

  A disease of DNA change (key genes in cells have been altered), resulting in abnormal signal transduction; signal transduction is the control of various cellular processes, particularly growth, and cancer results in these processes being altered

  
• Mechanism of Cancer

  1. Initiation

  2. Promotion

  3. Progression
• Initiation


  Damage to the DNA (a key gene(s)), which causes a mutation in the genes. The cell is not yet a cancer cell.
• Promotion

  If there's inflammation or something causing cell death, cells will try to grow and divide and fill the need for new cells. Things that promote cell growth can cause the outgrowth of cells which have a growth advantage because of mutations during the initiation stage.
• Progression

  The cells that are going to become cancer cells can acquire other mutations that make them malignant and able to spread around the body.
• Cancer is predominantly a disease of old age, as it takes time for a cell to acquire these multiple mutations that will make it a malignant cancer cell.
• Causes of Cancer

  • Chemicals: diet, job, lifestyle-smoking, alcohol
  • Radiation: UV, gamma rays, radioactivity, e.g. radon
  • Viruses: Epstein-Barr, hepatitis B, human papilloma, Hep C
  • Genetic predisposition: breast cancer BRCA1, BRCA2, retinoblastoma, polyposis coli, repair deficiencies-xeroderma pigmentosum, hereditary non-polyposis coli
  • Immune suppression: EBV lymphomas-transplant patients
  • Cofactors: malaria-Burkitt's lymphoma EBV, hormones, e.g. oestrogen (breast cancer), testosterone (prostate cancer), all of which stimulate cell proliferation
• Proto-oncogenes

  Genes that regulate growth of cells and are naturally present in the genome. If they are mutated, they can be converted to oncogenes, which can then contribute to the multi-hit processes that causes cancer.

  
• Tumour suppressor genes

  Proteins that counteract the effect of oncogenes. As long as they're expressed, the body can counteract the cancer or the development of cancer.
• Metastasis suppressor genes

  Genes that suppress the spread of cancer cells to other parts of the body.
• How Oncogenes and Tumour Suppressor Genes Were Identified

  1. Oncogenic retroviruses and DNA tumour viruses

  2. DNA transfection: human tumour DNA into mouse cells (ras genes)

  3. Chromosome analysis

  4. Human genetic linkage studies

  
• Oncogenes

  Genes that drive cancer. Mutations can affect the structure or expression of proto-oncogenes, converting them into oncogenes that promote cell growth.
• Oncogenes act dominantly

  Only one of the two alleles of the gene present in the human diploid genome needs to be mutated to have the effect.
• Apoptosis

  In-built programmed cell death: all cells are programmed to self-destruct unless circumstance prevents them from doing so. It's a defence mechanism that protects cells from becoming cancer cells.
• Tumour Suppressor Genes

  Genes that limit cancer development by counteracting oncogenes to restrain cell growth. They act recessively - both gene copies must be inactivated for the cancer to evolve.
• RB1

  Cell cycle regulation: can block entry of cells from the G1 phase into the S phase.
• p53

  Transcription factor: acts at G1S, G2M-senses DNA damage. Promotes cell cycle arrest/apoptosis and is called 'guardian of the genome'.
• BRCA1, BRCA2

  DNA repair
• How Cancers Spread (Metastasis)

  1. Primary cancer induces synthesis of blood vessels that bring nutrients into the tumour

  2. Cancer cells can come out of the primary cancer and get into the bloodstream

  3. Tumour cells can crawl through the blood vessels and into the space between them and form a secondary cancer (extravasation)
• Models of Metastasis

  • 'Anatomical' or 'hemodynamic' model - tumour spreads to first organ or tissue connected by lymphatic or blood vessels to primary tumour
  • 'Soil and seed' or 'organ preference' model - some tissues with small fraction of blood supply such as brain, adrenal and bone are involved in metastasis

  
• Cell Communication in Metastasis

  Cancer cells communicate with other cells in their local environment and can get those cells to make digestive enzymes which enable the cancer cell to move and get into the blood.
• Hallmarks of Cancer

  • Unlimited proliferation
  • Sufficiency in growth signals
  • Inactivate growth inhibitory signals
  • Evade apoptosis
  • Sustained angiogenesis
  • Invasion and spread

  
• Diagnosis and Therapy

  • Surgery, radiotherapy: remove or destroy tumour cells
  • Chemotherapy: selectively kill tumour cells
  • Hormone therapy: for prostate and breast cancer
  • Block oncogenic activity: Gleevec (bcr-abl), Iressa, herceptin
  • Stimulate tumour suppressors: mdm2-p53, gene therapy
  • Tweak immune system
  • Block spread: target angiogenesis, which is required for metastasis