Cancer Biology

• Cancer


  A group of >100 different diseases, often with different causes but some common features. Cancers are cellular diseases characterised by unregulated cell division and cell growth.

  
• Cancer


  • Cancer growth often leads to 'invasion' of cancer cells into adjacent tissues and sometimes spread from their site of origin to other sites within the body – 'metastasis'
  • Cancers are genetic diseases
  • Cancers often interfere with normal body processes (e.g. organ function) and compete with normal tissues for oxygen and nutrients
  • Tumours are a mass of cancer cells (usually derived clonally from one original cancer cell)
  • Some cancers (e.g. leukaemia) don't form tumours

  
• Benign tumour


  Confined to one site
• Malignant tumour


  Cells migrate and invade

  
• Six hallmarks of cancer

  • Growth signal autonomy
  • Evasion of growth inhibitory signals
  • Evasion of apoptosis (programmed cell death)
  • Unlimited replicative potential
  • Angiogenesis (formation of new blood vessels)
  • Invasion and metastasis (not benign tumours)

  
• Emerging hallmarks of cancer

  • Avoiding immune destruction
  • Reprogramming of energy metabolism

  
• Cancer enabling characteristics


  • Genome instability
  • Tumour-promoting inflammation

  
• Transformation


  The process by which normal cells undergo a series of changes to become cancer cells

  
• Cancer cells vs normal cells

  • Lack of 'contact inhibition' and grow in piles or 'foci' rather than a 'monolayer'
  • Ability to grow in low serum medium
  • A round, rather than flat morphology
  • 'Anchorage independence'

  
• Mutation


  Alterations to DNA, including single base/'point' mutations, multiple base insertions or deletions, and large re-arrangements such as deletions, amplifications or chromosome translocations
• Carcinogenesis


  The multi-stage process of cancer formation, where mutations accumulate during the lifetime of a cell/individual

  
• In the UK, more than half of cancer patients are 70+ years old (2012-14), most over 85
• Multi-hit hypothesis of cancer

  The accumulation of multiple mutations over time is usually needed to produce cancer

  
• Colon cancer development


  1. Early polyp: Loss of tumour suppressor gene

  2. Polyp: Mutation of proto-oncogene

  3. Late Polyp: Loss of two additional tumour suppressor genes

  4. Malignant tumor: Inactivation of p53 tumour suppressor

  
• Mutations occurring in germ-line cells (producing gametes; sperm/eggs) can be passed on to offspring and potentially lead to inherited cancer syndromes, but this represents only 1-2% of cancer cases - 98-99% cancers are not inherited

  
• Cancer development and treatment

  • During carcinogenesis, cell behaviour continues to change as more mutations accumulate
  • Different cancer types are treated differently (e.g. primary or metastasis, hormone responsive?)
  • The response of cancers to treatment varies – some are more problematic than others (e.g. breast cancer has much better prognosis than brain tumours)

  
• More than half of new cancer cases in 2016-18 were breast, prostate, lung and bowel

  
• Cancer causes more than 1 in 4 UK deaths (2019)

  
• Rates for successful cancer treatment are improving for most cancers

  
• Cell cycle


  The series of events between each cell division, divided into 4 phases - G1, S, G2 and M
• G0 phase


  A resting phase where most cells are not actively dividing
• Cell cycle regulation


  1. Growth factors or 'mitogens' can induce G0 cells to re-enter G1 phase

  2. Transition between each phase is controlled at 'checkpoints' by pairs of proteins called cyclins and cyclin-dependent kinases (cdks)

  3. Checkpoint protein pairs act as detectors of damage, signal transducers or effectors
• Proto-oncogene


  Positive growth regulators, called oncogenes when hyperactive due to mutations
• Tumour suppressor gene


  Negative growth regulators
• Mutation of proto-oncogenes can lead to increased expression or activity of the oncoprotein, which has a dominant effect (only one allele needs to be mutated)
• G2 checkpoint


  Permits damage repair before mitosis
• M checkpoint


  Ensures correct chromosome arrangement on spindle and correct segregation
• Cyclin/cdks 'checkpoint' proteins


  Control cell cycle
• Disruption of checkpoints


  Can lead to mutation and carcinogenesis
• Groups of genes implicated in cancer

  • Proto-oncogenes
  • Tumor suppressor genes
• Proto-oncogenes


  Positive growth regulators, called oncogenes when hyperactive due to mutations
• Tumor suppressor genes


  Negative growth regulators, mutations are usually recessive but can also be haploinsufficient

  
• p53


  • Mutated in >50% tumours, central role in cell responses to stress (DNA damage, hypoxia), a transcription factor
• Retinoblastoma (Rb) gene


  • Tumor suppressor gene involved in cell cycle regulation, activity regulated by phosphorylation
• Protein kinases


  • Some can act as oncogenes, involved in cell cycle, signal transduction and gene transcription
• Protein phosphatases


  • Some can act as tumor suppressors, e.g. PTEN
• Ras gene family


  • Mutated in 50% some cancers, Ras proteins are G-protein inner membrane-bound signal transducers, mutations can prevent GTP hydrolysis and leave Ras permanently activated
• Factors influencing carcinogenesis


  • Environment
  • Reproductive life
  • Diet
  • Smoking
• Lifestyle changes can reduce cancer risk
• Principles of Cancer Therapies

  1. Surgical excision of tumour mass

  2. Radiotherapy and chemotherapy to cause DNA damage and cell death

  3. Some new drugs target angiogenesis