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