TR

Cancer

What Is Cancer?

  • Cancer: the continuous uncontrolled growth of cells.  
  • Tumor: any abnormal proliferation of cells.
  • Benign tumors: stay confined to its original location
  • Malignant tumors: capable of invading surrounding tissue or invading the entire body
  • Tumors are classified as to their cell type
  • Tumors can arise from any cell type in the body

Cancer Terminology

  • Neoplasm: tumor
  • Benign: cells of neoplasm are clustered together
  • Malignant: cells have acquired ability to invade surrounding tissue
  • Types of malignant tumors
    • Carcinomas: cancers arising from epithelial cells
    • Sarcomas: arise from connective tissue or muscle cell
    • Leukemias: hematopoietic cells and nervous system

Normal Cells vs Cancer Cells

  • Normal cells
    • Replicative senescence: finite number of cell divisions most likely due to loss of telomerase activity
    • Anchorage
    • Contact Inhibition
    • Normal karyotype and no chromosomal aberrations
    • Normal cells are fussy about nutrients
  • Cancer cells
    • Cancer cells may be immortal
    • Ignore normal growth regulatory mechanisms
    • Loss of contact inhibition
    • Genetic Instability
    • Abnormal karyotype
      • Translocations
      • Deletions
      • Duplications
      • Inversions

6 Properties That Makes Cells Capable Of Becoming Cancerous

  • Disregard signals that regulate cell proliferation
  • Avoid apoptosis
  • Escape replicative senescence
  • Genetically unstable
  • Invasive
  • Metastasize 

Carcinogens

  • About 80% of all human cancers are related to exposure to carcinogens
    • Carcinogens: agents that increase the likelihood of developing cancer
  • Most carcinogens, such as UV light and certain chemicals in cigarette smoke, are mutagens that promote genetic changes in somatic cells
  • DNA alterations can lead to effects on gene expression that ultimately affect cell division, and thereby lead to cancer

Oncogenes

  • Cell division regulated by hormones called growth factors
  • Growth factors bind to cell surface and initiate cascade, activating specific genes, leading to cell division
  • Mutations in genes for cell growth signaling proteins can change them into oncogenes – producing abnormally high level of activity
  • An oncogene may promote cancer by keeping the cell division signaling pathway in a permanent “on” position
    • In some cancers the amount of gene produced is too high
    • In others, the gene produces a functionally hyperactive protein

Proto-oncogene

  • Normal gene that, if mutated, can become an oncogene

  • Four common genetic changes

    1. Missense mutations: chemical mutagens have been shown to cause missense mutations leading to cancer

    2. Gene amplifications: increase in copy number results in too much protein

      1. Many human cancers are associated with amplification of particular proto-oncogenes

    3. Chromosomal translocations: two chromosomes break and switch ends

      1. Very specific translocations associated with certain types of tumors
      2. Can create chimeric genes

    4. Retroviral insertions: viral DNA inserts into a chromosome, putting a viral promoter next to a proto-oncogene

      1. If a proto-oncogene becomes overexpressed, it will promote cancer
      2. Some viruses cause cancer because they carry an oncogene in the viral genome

Cancers Develop By Accumulation of Mutations

  • Mainly somatic mutations
    • Non-germ line mutations
    • Mutations in genes that control cell cycle 
      • Oncogene – mutant form of a normal gene
      • Tumor suppressor genes
    • Mutations in genes that control apoptosis
    • Mutations in genes which lead to metastasis
      • E-cadherin – keeps cells of tissue adhering to each other
      • Integrins – keeps cells adhering to their substrate
    • Mutations in genes that enable telomeres to maintaining their status quo

Tumor-suppressor Genes

  • Normal role to prevent cancerous growth

  • Typical functions:

    1. Maintain genome integrity by monitoring and/or repairing DNA damage
    • Checkpoint proteins check the integrity of the genome and prevent a cell from progressing past a certain point in the cell cycle
    1. Inhibitors of cell division
    • Necessary to properly halt cell division otherwise division becomes abnormally accelerated

Checkpoint Proteins

  • Proteins called cyclins and cyclin-dependent protein kinases (cdks) are responsible for advancing a cell through the four phases of the cell cycle
  • Formation of activated cyclin/cdk complexes can be stopped by checkpoint proteins
  • p53 – about 50% of all human cancers are associated with defects in this gene
  • When checkpoint genes are broken by mutation, the division of normal healthy cells may not be affected
    • For example, mice that are missing the p53 gene are born healthy
    • Cell division leading to normal growth is regulated properly 
    • Checkpoint proteins such as p53 are not necessary for normal cell growth and division
    • However, these mice are very sensitive to mutagens and easily develop cancer
    • Loss of checkpoint protein function makes it more likely that genetic changes will occur that could cause cancerous growth

p53 Is A Critical Tumor Suppressor

  • The p53 protein stops the cell cycle if
    • DNA is damaged 
    • the cell has other types of damage
  •  If the damage is minor, p53 halts the cell cycle until the damage is repaired.
  • If the damage is major and cannot be repaired, p53 triggers entry into apoptosis.
  • More than half of all human cancers do, in fact, harbor p53 mutations and have no functioning p53 protein 

Negative Regulators of Cell Division

  • Second category of a tumor-suppressor gene
  • ex: Rb (retinoblastoma)
    • First tumor-suppressor gene to be identified in humans by studying patients with the disease retinoblastoma
    • Some people have an inherited form that occurs early
    • Other forms caused by environmental agents occur later in life