L13 Neoplasia Introduction

• Cancer is an overgrowth disease caused by genetic mutations that perturb cell division
• Oncogenes


  Genes that drive proliferation
• Tumour suppressor genes


  Genes that normally arrest or repair damaged cells
• Neoplasia


  Formation of new tissue
• Benign neoplasm


  Well differentiated, usually encapsulated, slow growing tumour that does not metastasise
• Malignant neoplasm (cancer)


  Abnormal proliferation, increased mitotic rate, lack of differentiation, do not resemble adjacent tissue, have abnormal nuclei, increased nuclear to cytoplasmic ratio, form tumours, undergo metastasis and angiogenesis
• Invasion and metastasis


  1. Detachment from primary site

  2. Penetration of basement membrane

  3. Degradation of extracellular matrix
• Routes of metastasis


  • Haematogenous (via blood, often to liver and lungs)
  • Lymphatic system
  • Direct organ to organ contact
  • Perineural (via nerve sheath)
• Metastasis


  Spread of cancer from primary site to another organ/site
• Metastasis is not a random event, it is determined by factors like appropriate growth factors, compatible adhesion sites, and selective chemotaxis
• Atypia


  Structural abnormality
• Hyperchromatic


  Darkly staining (histologically)
• Pleomorphic


  Variability in size and shape
• Differentiation


  Developmentally from a less specialised cell to a specialised cell
• Hyperplasia


  Increased number of cells
• Metaplasia


  Disordered growth, pleomorphic, hyperchromatic nuclei
• Dysplasia


  Disordered growth, pleomorphic, hyperchromatic nuclei
• Anaplasia


  Lack of differentiation
• Metaplasia increases the risk of progression to dysplasia
• Grade


  If a tumour is 5cm it is high grade
• Stage


  More useful if there are metastases
• Hallmarks of cancer


  • Self-sufficiency with respect to growth signals
  • Insensitivity to growth-inhibitory signals
  • Evasion of apoptosis
  • Limitless replicative potential
  • Sustained angiogenesis
  • Ability to invade and metastasise
  • Reprogramming of energy metabolism
  • Avoidance of detection and destruction by immune cells
• Malignant transformation of cells requires normal cells to have a fixed lifespan, but then proliferate by mitosis to replace damaged or senescent cells
• Normal cell proliferation


  1. Growth factors

  2. Growth factor receptors (tyrosine kinase intracellular domains)

  3. Signal-transducing proteins

  4. Nuclear transcription factors
• Checkpoints control the cell cycle, and mutations can occur during normal replication that are not repaired, leading to cancer
• Cancer is an overgrowth disease where normal cell proliferation is perturbed by genetic mutations that dysregulate the cell cycle
• Neurons


  For life
• Normal cells


  Proliferate (increase in number) by mitosis to replace damaged or senescent cells
• Normal cell division


  1. Normal proliferation occurs via the cell cycle

  2. Mitosis

  3. DNA synthesis
• Processes involved in normal cell proliferation

  • Growth factors (GF)
  • Growth factor receptors – tyrosine kinase (TK) intracellular domains
  • Signal-transducing proteins
  • Nuclear transcription factors
• Growth factors


  Entry to cell cycle
• Checkpoints


  Control cell cycle
• Mutations can occur during normal replication
• Some mutations are repaired. If repair is NOT possible, the cell is prevented from replicating : "checkpoint control"
• Cancer


  An over-growth disease
• Cancer in prehistoric animals

  • Gorgosaurus – extraskeletal osteosarcoma (77 million years ago)
  • Hadrosaurs – metastatic sarcoma (66 million years ago)
• Cancer


  An overgrowth disease where normal cell proliferation is perturbed
• Cancer development


  1. Genetic mutations in specific cells lead to dysregulation of the cell cycle

  2. These cells are said to be TRANSFORMED
• DNA repair system


  Corrects mutations during replication
• Mutations in repair genes

  Prevent repair