WEEK 4.1

• In developed countries, cancer is the second leading cause of death
• In the UK, cancer will kill over 100,000 people in the next 12 months, or about 30 people by the time this lecture is over today
• Incidence of cancer types
• Cancer incidence and mortality by site and sex. (Adapted from Jemal A, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23, 2002.)
• Colorectal cancer is much commoner in countries whose inhabitants eat a more refined diet
• Low-incidence countries may conceal high-incidence regions or communities; for example, oesophageal carcinoma is relatively common among black people in the USA (lighter shaded area). Dietary associations with oesophageal cancer are less well defined.
• Approximate dose-response relationship between cigarette consumption and the relative risk of developing lung cancer. Smoking at the rate of 10 cigarettes per day increases the risk of developing lung cancer tenfold. (1 = non-smoker.)
• Neoplasia


  A set of disorders showing a disturbance in: Cell proliferation, Cell differentiation, Relationship between cells and the surrounding stroma
• Differentiation


  The sum of processes by which cells in a developing multicellular organism achieve their specific set of functional and morphological characteristics. It usually involves a progressive restriction of genomic expression. Impairment of differentiation is common in neoplasia.
• The poorer the degree of differentiation, the worse is the behaviours of the cancer and the poorer the prognosis.
• Metaplasia


  Changes from one fully differentiated form to another, which occurs frequently in chronically irritated cells or cells in a new hormonal milieu.
• Changes in differentiation are affected by the interaction of the cells within their microenvironment (e.g., between mesenchymal and epithelial elements) and between adjacent cells.
• Non-Neoplastic Proliferation


  • Hypertrophy - increase in cell SIZE, not number
  • Hyperplasia - increase in cell NUMBER which likely results in an increase in tissue SIZE
  • Metaplasia - a CHANGE in cell populations from one fully differentiated form to another fully differentiated form
  • Dysplasia - Abnormalities characteristic of neoplasia, but WITHOUT invasion of surrounding tissues (common in epithelium; squamous and transitional)
• Carcinoma 'in situ'


  Epithelial dysplasia in which the entire thickness of the epithelial covering shows dysplastic change. Has all the cellular features associated with malignancy but has not yet invaded through the epithelial basement membrane. Detection of carcinomas at this stage, or their precursors is the aim of population screening programmes for cervical, breast and some other carcinomas. The phase of in-situ-growth may last for several years before invasion commences.
• Differences between neoplasms and their corresponding normal tissues

  • Loss of differentiation
  • Loss of cellular cohesion
  • Nuclear enlargement
  • Increased mitotic activity
• Classification of Tumours


  Tumours are classified according to their: Behaviour (benign or malignant), Histogenesis (cell of origin). Precise classification is important for determining treatment.
• Nomenclature


  • Cell of origin + Suffix
  • Suffix: -oma (Fibroma, Osteoma, Adenoma, Papilloma, Chondroma)
  • Suffix: -carcinoma (Adenocarcinoma, Squamous cell carcinoma)
  • Exceptions: Leukemia, Lymphoma, Glioma
• Tumour Types


  • Benign tumours: Epithelial origin, Connective tissue origin
  • Malignant tumours: -sarcoma (Fibrosarcoma, Osteosarcoma, Chondrosarcoma)
• Benign Neoplasms


  Do not invade or metastasize
• Malignant Neoplasms


  Invade and metastasize
• Benign neoplasms cause significant disease by: Occupying space, Causing obstruction, Ulceration, bleeding, Secretion of synthesized products, Being a precursor to malignancy
• Malignant neoplasms cause significant disease by: Occupying space AND destroying tissue, Ulceration, bleeding, Obstruction, Destroying tissues distant from primary tissue, Secretion of synthesized products, Causing pain, Cachexia (wasting of muscles and general poor state of health; multifactorial in nature)
• Grading


  Cellular Differentiation (Microscopic)
• Staging


  Progression or Spread (clinical)
• Example of TNM system for staging of tumours
• Tumour Grading and Staging Example
• Cancer is a disease where normal control of cell proliferation is lost
• Normal cells


  Have a finite lifespan- e.g., 60 to 80 cellular divisions (Hayflick phenomenon)

  
  

  Require growth factors for mitogenic, or stimulatory, signalling

  
  

  Have tightly controlled regulation of proliferation
• Non-lethal genetic damage lies at the heart of carcinogenesis
• Six fundamental changes in cell physiology that dictate a malignant phenotype

  • Self-sufficiency with growth signals (e.g. oncogenes)
  • Insensitivity to growth-inhibitory signals (e.g. tumour suppressor proteins)
  • Evasion of apoptosis
  • Limitless replicative potential (i.e., overcoming cellular senescence)
  • Sustained angiogenesis
  • Ability to invade and metastasize (Invasion of extracellular matrix, Vascular dissemination and homing of tumour cells)
• The hallmarks of cancer (Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100: 57; Hanahan D, Weinberg RA. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144 (5), 646-674)
• (Proto)-Oncogenes


  Normal functions:

  • Promote cell division and proliferation

  Alleles that if mutated act in a dominant or positive fashion.

  
  

  Mutated functions:

  • Qualitative or quantitative alterations contribute to neoplastic transformation

  • Increase in growth factors or growth factor receptors

  • Increase in signal transduction

  • Increase in activation of transcription

  • Only one allele needs to be mutated

  • Examples include ras, myc, fos and jun.
• Tumour Suppressor Genes


  Alleles that must be inactivated.

  
  

  Both alleles must be mutated or lost.

  
  

  Tumour suppressor genes are recessive to wild type.

  
  

  Normal functions:

  • Suppress growth signal

  • Induce apoptosis

  • Respond to DNA damage and repair

  • Usually cell-cycle regulated

  
  

  Mutated case:

  • Inactivation by mutagenesis leads to oncogenesis

  • Loss of function

  • Deregulated growth signal

  • Recessive (usually both alleles need to be mutated)

  Examples includeRb(retinoblastoma) andp53.
• Cancer incidence in different age groups
• Multi-Hit Model Of Carcinogenesis
• Three key genetic events are the minimum needed to convert a normal human cell into a neoplastic cell:

  
  

  1. Telomerase expression prevents telomeric shortening with each cell division and thus thwarts cellular senescence
  2. Inactivation of tumour suppressor gene function in the immortalised cells removes inhibition of growth control
  3. Oncogene activation sets up autocrine growth stimulation; the cell is now fully transformed.
• Stages of tumour development:

  
  

  1. Initial genetic mutation resulting in increased cellular proliferation, 2. Hyperplasia - normal cells which divide too much

  3. Dysplasia - one in a million hyperplastic cells can undergo additional genetic mutations resulting in cells which no longer retain normal morphology

  4. Carcinoma 'in situ' - cells become increasingly abnormal but remain in their original location

  5. Cancer (malignant neoplasm) - cells acquire ability to leave original site and find their way into blood and lymph
• Vascular dissemination and homing of tumour cells (Metastasis Summary)
• TUMOUR STAGING EXAMPLE


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• Tumour Grading and Staging Example