Pathology

• Cancer


  A collection of diseases with the common feature of an uncontrolled increase in cell number leading to invasion of the surrounding tissues and spread to other parts of the body (metastasis)
• Cancer is a disease where we lose control over our own cells
• Hallmarks of cancer


  • Self-sufficiency in growth signals
  • Limitless replicative potential
  • Insensitivity to antigrowth signals
  • Resistance to apoptosis
  • Angiogenesis
  • Invasion and metastasis
  • Immune avoidance
• Hallmark 1: Self-sufficiency in growth signals


  • Cells receive signals to proliferate
  • In the absence of these signals cells are not able to proliferate
  • These signals are commonly called growth factors
• Hallmark 1: Self-sufficiency in growth signals


  1. In the presence of growth signals, proteins are switched on and become active, starting with the receptor for the growth factor

  2. A sequence of these switches ultimately leads to changes in gene expression leading to cell proliferation

  3. Cell division
• Removing the growth factor signal


  Leads to all the proteins being switched off and cell proliferation stops
• Oncogene


  Genes which, when mutated or overexpressed, can cause cancer
• Mutations in proto-oncogenes lead to a gain of function
• Examples of oncogenes


  • Ras
  • Bcr-Abl
  • myc
  • Src
  • PI3 kinase
• Oncogenes


  • Have increased activity and lead to increased cell proliferation in the absence of specific growth signals (i.e. Self-sufficiency)
• Oncogenes represent an important drug target for future cancer therapies and blocking their function should stop the proliferation of cancer cells
• Hallmark 2: Limitless replicative potential


  • With telomerase (stem cells & cancer)
  • Without telomerase (normal)
• Telomere shortening following cell division limits the number of times a cell divides (40-60 cell divisions)
• Tumour cells are effectively immortal and can rebuild their telomeres using the enzyme telomerase
• Tumour suppressor genes


  Perform the opposite function to oncogenes in that they stop tumours from forming
• In many cases two-hits are required to inactivate a tumour suppressor gene
• Examples of tumour suppressor genes

  • p53
  • BRCA
• Mutations in tumour suppressor genes

  Lead to loss of function
• p53 is the most common mutated gene in cancer - found in 50% of all human cancers
• Hallmark 4: Resistance to apoptosis


  Apoptosis can be triggered in cells by DNA damage and viral infection, two things which can lead to the development of cancer
• Bcl-2 family of proteins

  Controls the sensitivity of the cell to apoptosis
• Pro-survival members of the Bcl-2 family


  Are commonly over-expressed in cancer (gain of function)
• Pro-apoptotic members of the Bcl-2 family


  Are commonly mutated and non-functional in cancer (loss of function)
• With no blood supply, tumour mass is restricted to ~10^6 cells (2 mm diameter)
• 90% of cancer deaths are due to the spread of cancer to distant sites – a process called metastasis
• Malignant cancer cells


  Acquire the ability to move and start to break away from the main tumour
• The most common sites of metastasis are the lung, liver, brain and bone
• New hallmark: Immune avoidance


  • Acquiring the hallmarks of cancer requires lots of mutations
  • Some of these mutations change the structure of the protein to make it look non-self
  • These mutated proteins provoke an immune response leading to destruction of the mutated cancer cells
  • Tumours therefore need to learn how to avoid or inactivate the immune response
• DNA in a typical cell is damaged around 10,000 times per day
• Most of this DNA damage is repaired, but the DNA repair mechanisms are not perfect and some damage is occasionally missed leading to a mutation
• Mutations occur randomly throughout the genome
• Where these mutations occur in key genes such as proto-oncogenes or tumour suppressor genes, they can lead to cancer
• Types of DNA mutation


  • Point mutations
  • Small insertions/deletions
  • Alterations in transcription/splicing
  • Amplifications/deletions of chromosomal regions
  • Chromosomal translocations
  • Gains and losses of whole chromosomes
  • Changes in DNA modification, e.g., DNA methylation
• What causes DNA mutations?


  • UV and other types of radiation
  • Viruses
  • Chemicals (smoking, asbestos, food etc)
  • Free radicals produced during metabolic processes
  • Copying / repair errors (sometimes inherited)
• In cancer accumulated mutations can lead to genome instability and an increased likelihood of further mutations
• A single mutation leading to a single acquired property such as increased proliferation is not enough to lead to cancer
• A single cell has to be able to acquire (usually after multiple mutations) most or all of the hallmarks in order to progress to cancer
• This takes time!
• This study sequenced the genome of lung cancer and compared it with a normal genome to look for mutations and their causes
• Found 23,000 mutations in the lung cancer genome