Cancer and Control of the Cell Cycle Notes

Understanding Cancer

• What We Need to Know:
  • How cells normally function.
  • Cells and cell structures, DNA and Genes.
  • Gene expression: DNA à RNA à Proteins.
  • Cell cycle and its control mechanisms.
  • What goes wrong with mutations and loss of control.
  • Tumor progression.
  • Available treatments.

Cell Division Control

• Cell division is controlled by enzyme activation and inhibition.
• Three checkpoints monitor the cell cycle:
  • G1 checkpoint:
    • Occurs during the G1 phase of interphase.
    • Determines if the cell enters the S phase (DNA replication).
    • Some cells never pass the G1 checkpoint and enter G0 (e.g., CNS neurons).
  • G2 checkpoint:
    • Leads to mitosis.
  • M checkpoint:
    • Occurs during metaphase.
    • Triggers exit from mitosis and initiates cytokinesis.

Cancer Overview

• Cancer is a growth disorder of cells.
• Cells undifferentiate (become less unique).
• Cells grow and reproduce uncontrollably, resulting in a tumor (cluster of cells).
  • Benign tumors stay localized and are often encapsulated by healthy cells.
  • Malignant tumors are not encapsulated and are invasive.
    • Cells break off and colonize new areas (metastasis), forming new metastatic tumors.
    • Named for the tumor's origin.
• Cancer affects many types of cells and tissues.

Causes of Cancer

• Damaged genes fail to control the cell cycle.
• Genetic damage = mutation (changed DNA nucleotide sequence).
  • Result from chemical, environmental, or biological exposure (e.g., smoke, UV rays, viruses).
• Mutations cause the production of non-functional proteins.
• Two classes of genes often involved in cancer:
  • Proto-oncogenes:
    • Encode proteins that stimulate cell division.
    • When mutated, they become oncogenes, which induce tumor growth.
      Proto-oncogenes --> oncogenes
  • Tumor-suppressor genes:
    • Encode proteins that inhibit cell division.
    • When mutated, they fail to stop tumor growth.
      Tumor-suppressor genes -->(mutation) no inhibition

Example: Gene p53

• Protein p53 works at the G1 checkpoint.
  • If DNA is damaged, p53 prevents cell division until repaired.
  • If DNA cannot be fixed, p53 initiates cell death (apoptosis).
• If the p53 gene is damaged, the p53 protein doesn't work.
  • The cell divides uncontrolled.
  • The damaged gene (mutation) is passed to daughter cells, leading to a tumor.
• p53 gene is mutated in many cancers.

Cancer Characteristics

• Cancer cells look and act differently:
  • Larger or multiple nuclei.
  • Increased telomerase activity.
    • Telomerase enzyme usually decreases with age but is constantly replaced in cancer cells.
  • Lose the ability to differentiate.
    • Cells differentiate during development, but cancer cells are unspecialized.

Cancer Cell Behavior

• Cancer cells induce blood vessel growth (angiogenesis).
  • Rob surrounding tissues of oxygen and nutrients.
• Malignant (invasive) cells break off and spread, starting new tumors elsewhere (metastasis).
• Tumors disrupt homeostasis:
  • Block vessels.
  • Change chemical signals.
  • Inhibit immune and regulatory functions of affected organs.

Cancer Progression

• Defined based on characteristics and extremity:
  • Tumor size.
  • Spread to lymph nodes?
    • Lymphatic vessels recycle fluid from the body.
    • Nodes are junctions used by immune system cells.
    • Sentinel node – the closest lymph node to a tumor.
  • Movement to other organs?
• Stages:
  • Stage 0 & 1: small tumor, none to few local lymph nodes.
  • Stage 2: larger tumor, invasive, some lymph nodes.
  • Stage 3: spread outside of organ, with lymph nodes.
  • Stage 4: metastasized, "incurable."

Cancer Screening: Genetic Testing

• Look for mutations (alleles) at known genes.
  • PCR & gene sequencing.
    • Polymerase Chain Reaction: Target DNA sequences are amplified.
    • DNA sequencing: nucleotide code is "read."
  • Microarrays (gene chips).
    • Synthetic DNA placed on card.
    • mRNA transcripts of known cancer genes are isolated.
    • cDNA (complementary DNA) produced from transcripts using reverse transcriptase enzyme.
      cDNA <-- RNA (Reverse transcriptase)
    • cDNA washed over card and binds to synthetic DNA.

Cancer Screening: Blood Tests

• Look for:
  • Abnormal or “too many” white blood cells (leukemia).
  • Elevated blood calcium, enzymes, ions, indicating disrupted organ function.
  • Search for known cancer genes or proteins.

Cancer Screening: Imaging

• Mammogram:
  • X-ray of the breast shows lumps or cell clusters.
• CT scan (computerized tomography):
  • X-rays build a 3D image of organs.
• MRI (Magnetic Resonance Imaging):
  • Radio waves generate detailed 3D image.
• PET scan (Positron Emission Tomography):
  • Radioactive molecules are injected.
  • Cancer cells “eat” more and “glow” on image.

Cancer Treatment: Surgery & Chemotherapy

• Surgery removes tumors.
• Chemotherapy: using drugs to kill fast-dividing cells.
  • Alkylating agents – break DNA.
  • Taxanes – (taxol, pacific yew tree) impede spindle during mitosis.
  • Antimetabolites – interfere with DNA replication.
  • Topoisomerase inhibitors – prevent DNA replication.
• Has lots of side effects
  • Affects all cells, faster-dividing cells more.
  • Can cause other mutations.
  • Damage to the digestive tract, nausea, loss of appetite.

Cancer Treatment: Radiation

• Radiation damages DNA and prevents mitosis.
  • External: high-energy waves (gamma & x-rays) fired at tumors.
  • Internal: radioactive substances placed on or near tumors.
  • Systemic: radioactive substance injected or ingested.

Cancer Treatment: The Future

• Immunotherapy: use the immune system to attack cancer cells.
  • Vaccines that mimic cancer proteins.
  • Genetically engineered white blood cells.
  • “Nullomer” peptides that kill cells.
• Gene editing:
  • CRISPR - enzyme that modifies DNA.
    • Clustered Regularly Interspaced Short Palindromic Repeats.
    • Internal RNA template to edit genes.
    • Explored for gene therapy.