cancer

• cancer is a disease caused by the uncontrolled division of abnormal cells in a part of the body
• cancer cells are abnormal because:

  • they multiply indefinitely
  • they invade underlying tissue
  • they migrate to other sites in the body and multiply there
• cancer cells cause death because the crowd out healthy cells and cause disruption to normal cell function

  • cancer is a neoplastic disease
  • a neoplasm is an overgrowth of cells that serve no useful purpose e.g. tumour
• tumours can be classified as:

  1. benign - small, slow growing, non-invasive, stay localised
  2. malignant - large, fast growing, invasive, metastisise
• cancers are usually described by:

  1. location in body
  2. type of cell they originate from
• invasion is when cancer cells spread from a primary site to another part of the body

  • complex process involving change of cell to a migratory phenotype and secretion of enzymes to break down surrounding extracellular fluid
• metastisis: cancer cells reinvade new tissue and grow at new location

  • declines prognosis significantly
• as the tumour enlarges, it requires oxygen and nutrients and the centre of the tumour may not receive enough, causing a necrotic core

  • cancers can secrete signalling molecules to promote angiogenesis towards them
  • can be stopped by anti-angiogenic therapy to limit tumours blood supply
• in cancer cells, mutations remove controls that monitor cell division once DNA is damaged, and allows cells to continually divide and grow out of control

  • they may not detect neighbouring cells
  • they may produce their own growth hormone
  • they may not produce tumour suppressor proteins
  • they may ignore normal apoptotic signals
• many genetic changes must occur for full development of cancer

  • often results in gradual changes such as hyperplasia (increased cell growth) and dysplasia (disorderly growth)
• transformation of normal cells into cancer cells is referred to as oncogenesis, carcinogenesis or tumourigenesis

  • it is a multistep process, entailing changes in the expression of many genes
  • commonly mutated genes include tumour suppressors (work to reduce development of cancer) and oncogenes (genes that promote cancer and mutations)
• cancer risk increases with age, and there are 2 theories that currently exist to explain this:

  1. conventional oncogenesis
  2. adaptive oncogenesis
• 1. conventional oncogenesis

  • aging facilitates the accumulation of oncogenic mutations, including activating mutations in oncogenes or genetic / epigenetic inactivation of tumour suppressor genes
• 2. adaptive oncogenesis

  • the ability of an oncogene to induce cancer is context specific
  • in a healthy population, the ability of cells to effectively compete for niche space is high due to optimal progenitor cell fitness, so competition is inherently tumour suppressive
  • however, as cells age, cellular fitness decreases and the acquisition of an oncogenic mutation could be adaptive due to its ability to correct or circumvent defective cellular function
• carcinomas - cells that cover internal and external body surfaces

  leukaemia - blood cells

  lymphoma - lymph nodes and tissues

  sarcomas - cells in supportive tissues e.g. bones and muscles

  teratoma - tumour of mixed cell components

  melanoma - malignant tumour of melanocytes

  nevus - benign tumour of melanocytes (mole)
• skin cancer is usually keratinocyte or melanocyte based tumours that can be divided into melanoma and non-melanoma

  • signs of melanoma include asymmetry, ragged or irregular borders, variable colour and large diameter
• example of skin cancer: basal cell carcinoma

  • normally found on head, neck, arms, hands and face
  • 75% of all skin cancers
  • highly treatable as it grows slowly
  • starts in the basal cell layer of skin
  • presents as a small shiny bump on skin, mainly at areas with high exposure to sun
• example of skin cancer: squamous cell carcinoma

  • normally found on face, ears, lips and mouth
  • 20% of all skin cancers
  • more aggressive than basal, but still highly treatable
  • presents as nodules or red, scaly patches on the skin that spread throughout the body
• example of skin cancer: malignant melanoma

  • less common but the most deadly
  • begins as a mole that turns cancerous
• lung cancer is the most common cause of cancer deaths

  • it can arise from any part of the lung, but 90% are from epithelial cells
  • can be either small-cell lung cancer (15% - caused by smoking) or non-small-cell lung cancer (85%)
• examples of non-small-cell lung cancer:

  1. adenocarcinoma (40%) - arises from cells lining the alveoli in non-smokers
  2. squamous cell carcinoma (30%) - arises from cells that line the inside of airways in smokers
  3. large cell carcinoma (15%) - arises from any part of the lung, but grows and spreads quickly
• blood cancer example : leukaemia

  • found in blood and bone marrow
  • caused by the rapid production of abnormal WBCs
  • theses impair the ability to produce RBCs and platelets
• blood cancer example : lymphoma

  • affects lymphatic system
  • abnormal lymphocytes become lymphoma cells which collect in lymph nodes and impair immune system
• blood cancer example : myeloma

  • targets plasma cells
  • myeloma cells prevent the normal production of antibodies
• the most common form of breast cancer is ductal carcinoma, which begins in the cells of the ducts

  • it is highly treatable and be diagnosed by physical exam and history, biopsy, clinical breast exam, ultrasound, MRI, blood study or mammography
  • cancer growth is driven by oestrogen
  • BRCA1 and BRCA2 incraeses risk
• risk factors for prostate cancer include age, genetics, race and diet

  • prostate cancer often spreads to pelvic bone
• risk factors for cancer development:

  • lifestyle : smoking, diet, lack of exercise, obesity, UV exposure
  • environment : viral, 2nd hand smoke inhalation, air pollution, chemical exposure
  • family history
• biological mutagens are a cause of cancer, and can be viral or bacterial

  • viral - HPV (cervical cancer), hepatitis B (liver cancer)
  • bacterial - helicobactor pylori (stomach cancer)
• chemical mutagens also cause cancer, as the foreign molecules bind to DNA resulting in misreading of DNA

  examples:

  • benzopyrene in cigarette smoke
  • vinyl chloride in plastics industry
  • aflatoxin in certain moulds
• physical mutagens are another cause of cancer

  • physical mutation results from ionising radiation (punches holes in DNA and breaks correct genetic sequence), UV radiation (causes DNA to remain bound together) and by mineral fibres (directly damage DNA)
• DNA is continuously bombarded by damaging forces

  • exogenous - originate outside of the cell e.g. cigarette smoke
  • endogenous - originate inside cell e.g. free radicals
• damage to DNA results in:

  • loss of normal gene function
  • inability to replicate chromosomes
  • death of cell
  • development of cancer

  while the cell has enzymes to counteract this, they can fail and cause a mutation, resulting in a permanent alteration of the nucleotide sequence
• there are two types of gene mutation:

  1. inherited - passed from parents to child and present in every cell
  2. acquired - occurs in one cell and present in their offspring
• DNA damage can occur in replicating cells (e.g. stem cells) or non-replicating cells (e.g. brain)

  • replicating -> cancer
  • non-replicating -> aging
• DNA lesions are sites of damage in the base-pairing or structure of DNA and there are 6 major types:

  • abasic site
  • mismatch
  • modified bases
  • single stranded breaks
  • double stranded breaks
  • crosslinks
• ABASIC SITE

  • a base is missing from the DNA
  • occurs due to a rise in temperature, drop in pH or alkylations on the base
• MISMATCH

  • caused by replication errors e.g. tautomerisation
• MODIFIED BASES

  • caused by changes to the bases themselves

  e.g. UV-induced creation of thymine dimers
• SINGLE STRANDED BREAKS

  • nick in sugar phosphate backbone of one strand
  • this is caused by oxygen radicals, ionising radiation or peroxides
• DOUBLE STRANDED BREAKS

  • most lethal type of lesions
  • both strand backbones are broken
  • caused by ionising radiation