Cancer

Cancer

Introduction
1. Carcinogenesis (Cancer Development)
  1. initiation -> promotion -> progression
    1. initiation is difficult to define in human cancers outside the lab
    2. Progression describes the changes after a cancer has formed
2. Altered DNA bases are the basis of cellular changes that cause cancer
3. Several mutations are required for carcinogenesis
4. a cancer in one cell can be generated by multiple pathways
5. Different cancers have different aetiologies although they may have some common features
6. Cancers have a clonal origin (they arise in single cells)
7. Cancers detected by clinical means are at an advanced stage of their natural history
8. Concept: all the cells in the cancer, arise by proliferation of one abnormal cell; that is, cancers are monoclonal in origin
9. Terminology
  1. Neoplasia
    1. In most cases these cells produce a solid mass of tissue - a tumour (exception: leukaemia)
      1. New growth - abnormal and continued growth of cells which are no longer subject to homeostatic controls typical of normal tissue
  2. Growth Regulation depends upon
    1. - growth factor dependency
      1. - density dependent inhibition of growth
        - anchorage dependence
        - contact inhibition of movement
        - adhesiveness
  3. Tumour growth rate:
    1. rate of new cells versus rate of old cells lost
      1. influenced by:
        blood supply, hormone presence
  4. Benign
    1. if mutations lead to neoplasms that grow in a restricted space = benign tumour
      1. cells grow, metabolise, reproduce and mature normally
    2. rarely lifethreatening
      1. may cause: nerve damage, ischemia, necrosis or organ damage
      2. Acoustic Neuroma / vestibular Schwannoma like what George got =(
  5. Malignancy
    1. undifferentiated and cannot perform functions
    2. infinite proliferatation
    3. uncontrolled & disorderly metabolism
    4. high nutrient demand
    5. invasisveness, initially of same cell type
  6. Metastasis
    1. break away and travel in blood or lymph
10. there are causative events in cancer development
11. geographical differences in cancer incidence indicate the importance of diet & solar radiation
12. influence of diet is complex and involves fat, vitamins, fibre, etc
13. smoking, diet, sex hormones, age, family history alter risk
14. most cancers are preventable
15. molecular epidemiology can identify people at risk and causative agents
Diet and Cancer
1. fruit & veg contain: vit C, carotenoids, folate, phytochemicals (glucosinolates, dithiolthiones, indoles, chlorophyll, flavonoids, allylsulphides and phyytoetrogens)
2. 80-100g of F/G halves the risk of oral cancer, 20% r in squamous cell carcinoma of the oesophagus, 30% r in stomach cancer
3. evidence that carotenoid protect against prostate and gastric cancer & selenium protects against prostate, lung cancer and bowel adenoma
4. high folate = breast cancer in heavy drinkers & fibre in bowel cancer for red meat eaters
5. fibre fermination produces short-chain fatty acids (anti-cancer properties)
6. red meat increases risk of bowel cancer
7. it is thought the nitrosamines in red meat make the body make more and they are carcinogenic
8. high salt intake i stomach cancer risk
  1. possibly by i-ing the sensitivity of the stomach lining to carcinogens
    1. may also directly cause mucosal damage and inflammtion
Oncogenesis
1. oncogenes code for proteins that, in their abnormal form or number, induce malignant growth by speeding up or switching on cell division
  1. antioncogenes (TSG) have the opposite effect
    1. one of the most commonly defective is the gene Tp53
  2. type of TSG called caretaker genes also recognised
2. >300/20-20,000 genes are known to play a role in carcinogenesis
  1. mutations in genes may be inherited or occur over a person lifetime
  2. oncogenes cause normal cells to grow out of control and become cancerous; they are mutated protooncogenes
    1. proto- oncogenes normally control cell division
      1. they normally mutate into oncogenes by amplification, translocation or point mutation and becomes permanently active
        cells divide too quickly and can lead to cancer
        only one alleles in a proto- oncogene needs to be overactive
    2. BCR-ABL is an oncogene
      1. it is the result of translocated chromosome 9 (ABL) and 22 (BCR)
        This is now the Philadelpia chromosome. The resulting BCR-ABL protein that is formed interferes with signalling pathways in the cell
        This causes WBC to be overproduced --> Chronic Myloid Leukaemia.
      2. possible target for treatment
3. TSG encode proteins that normally slow down cell division, repair DNA mistakes and trigger apoptosis eg. Tp53
  1. inactive TSG mean cells can grow out of control -> cancer?
    1. inactivation may be from point mutations, deletion or epigenetic mechanisms and these mutations may be inherited
4. caretaker genes
  1. as this class of TSG do not regulate cell division, their inactivation does not directly cause cell division
  2. aka stability genes: recognise & repair DNA damage
  3. inactive caretaker genes cause genetic instability
    1. increased mutation rate in all genes including oncogenes and TSG
5. Multi-step process and cancer
  1. development of cancer requires the accumulation of mutations in key genes
    1. different tissue and cell types need different gene mutations to become cancerous
      1. breast and colon cancer studies found that while they had an average of 90 mutations, only a few were responsible for the cancer
        others are considered bystander or passenger genes; they do not effect growth are most common where caretaker genes are mutated
    2. sporadic development of cancer may be the result of a genetic abbaration in a single cell; this is not repared, passed to a daughter cell and the daughter cell mutates also resulting in two mutations. this is then passed on too.
      1. if this is repeated, increasingly abnormal cells develop possibly leading to a cancer, capable of invasion and spread
        It is believed that this process originates in stem cells
Initiation & Progression
1. Coal tar derivatives onto the skin of mice -> skin cancer
  1. 1st stage initiation: mutagenic effects of tar on skinstem cells; no evidence of tumour
    1. 2nd stage promotion: induced by agents (not necessarily carcinogenic) - benign skin tumours develop by increased cell proliferation - redness of the skin
2. Progression
  1. tumours, once formed progress by differentiation, increasingly autonomous growth and aggressive behaviour
    1. comes from multiple changes in growth regulatory mechanisms
  2. 2 common features
    1. altered cell proliferation
    2. angiogenesis
      1. tumours directly release angiogenic growth factors
      2. well developed vasculature in a tumour is illustrated by proliferation being faster near blood vessels and slower away from the vessles
Immune Tolerance
1. Tolerance Definition: A type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but response to other antigens normally
  1. Tolerogens Definition: Antigens that induce tolerence
    1. Normal individuals are tolerant of their own antigens (self-antigens) --> self-tolerance
      1. Foreign antigens may be administered in ways that preferentialy inhibit immune response by inducing tolerance in specific lymphocytes- antigen induction
2. During neonatal stage of life, or when immune system is developing, all antigens present are recognised as self
3. Tolerence is achieved by clonal deletion - cells which come across self-Ag undergo apoptosis
4. Tolerance is antigen specific and results from recognition of antigens by specific lymphocytes
5. Mechanisms of Immune Tolerance
  1. central tolerance
    1. in the central lymphoid organs as consequences of immature self-reactive lymphocytes recognising ubiquitous self-antigens
      1. clonal deletion (apoptotic cell death
        During maturation of lymphocytes in the thymus (T-cell) or bone marrow (B-cell), immature lymphocytes that recognise ubiquitous self-antigen with high affinity are deleted by negative selection
  2. peripheral tolerance
    1. induced in peripheral organs as aresult of mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions
      1. Clonal anergy
        functional inactivation without cell death: lack of co-stimulatory signal
Viruses and Cancer
1. General Rules
  1. Viruses linked to cancer can also be found in the healthy population
    1. "cancer therefore represent a rare accident of long term infection"
    2. In carcingogenesis, one of the genetic mutations is viral infection.
  2. cancer develops only in a small proportion of infected people, usually many years after initial infection
  3. Virual infection is just one in a complex chain of events required for cancer development
2. Causal Association
  1. evidence linking a virus with cancer is difficult because of its presence in the healthy population
    1. most virus types linked to cancer is present within the cells of the malignancy as viral genetic information
      1. in these cases, cancer is made up of a clonal population of cells descended from a proginator cell infected with the virus before clonal growth began
        strong evidence that the virus acts directly to promote tumour growth
        in most cases infecting normal cells with the virus alters cell growth
  2. not all infectious agents act like viruses. Some agents promote cancer development indirectly
    1. establishing a chronic infection in certain sites in the body create environments were even the uninfected cells, are at a greater risk of becoming cancerous
Genes and Chromosomes
1. genes are sections of DNA
  1. a gene is an instruction for the body that has a functional purpose
    1. (A)denine; (C)ytosine; (G)uanine; (T)hymine are the bases that make up genes
2. Genes are found on chromosomes
  1. each 23 pairs of chromosomes are unique
    1. different versions of genes are called alleles
      1. different allels code for the same thing, but a different version of it; both determine eye colour, but one is for brown eyes and one is for blue
3. Genetic Disease
  1. genetic disease is caused by a combination of genetic abnormalities and environmental factors
    1. There are four types of genetic disorders
      1. single gene
        multifactoral
      2. chromosomal
        mitochondrial
  2. Chromosomal Abnormalities
    1. When the chromosome structure of a chromosome is altered the genetic material can be too
    2. abnormalities may include extra, missing or disordered segments of one or more chromosomes can lead to disease
    3. some of these structural changes are passed down from parent to child
    4. some changes have no effect; some are serious
    5. chromosomes can be seen in a karyotype
    6. 23rd pair are x and y
    7. Down's Syndrome
      1. Down's is trisomy 21
        1/700-1000
        incidence increases with maternal age
      2. characteristic facial features, short, mental retardation, susceptible to heart defects, leukaemia, alzheimer's
      3. almost half have heart defects, some untreatable; many have gut problems and thyroid disorders...cataracts, hearing and sight problems, and autistic spectrum disorders
    8. Other chromosomal disorders
      1. Klinefelter syndrome (XXY)
        turner syndrome (XO)
        Cri du Chat syndrome (part of chromosome 5 missing)
Cancer Immunology
1. Immune system continually surveys for the presence of abnormal cells
  1. cancer cells frequently arise
    1. however, eliminated by the immune system
      1. tumours arise when they can evade the immune system
        post mortems suggest there are more tumours in the body than clinically present
        Many tumours contain lymphoid cell infiltrates and in some tumours this may be favourable
        tumours occur more frequently in the neonatal period and in old age; when the immune system is less effective
        tumours frequently arise in the immunosupressed
        data now shows that the tumours in these individuals are caused by such viruses as EBV
        so as an individual becomes immune supressed they are no longer able to control the replication of these viruses
2. Tumour Antigens
  1. TSA - unique to tumours
  2. TAA - on non/tumour cells
    1. May be increased in tumours
  3. taa and tsa must both be able to induce antibody or cell- mediated response
  4. most tumour antigens elicit a CM response

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	Created by Sami-Jaine almost 11 years ago