Lecture Notes: Evading Growth Suppression in Cancer

Overview

• Sustained Proliferative Signaling: Opposite concept to evading growth suppression.
• Evading Growth Suppression: Critical for cancer development; involves overcoming the function of tumor suppressor genes.

Tumor Suppressor Genes

• Function: Suppress cell growth and prevent uncontrolled cell proliferation.
• Cancer Mechanism: Cancer cells must evade this suppression to proliferate uncontrollably.
• Mutations:
  • Point Mutations: Can introduce premature stop codons, creating non-functional proteins.
  • Epigenetic Silencing: Turning off expression of essential tumor suppressor genes without actual gene mutations.
  • Deletions: Entire chromosomal regions may be deleted, leading to loss of tumor suppressor function.

Key Concepts

• Loss of Heterozygosity (LOH): Refers to the loss of the normal allele in a heterozygote, leading to cancer risk.
  • Example: Retinoblastoma requires the loss of the second normal copy for cancer to develop.
• Deletion Consequences: Despite often leading to cell death, surviving cells may gain a growth advantage.

Key Tumor Suppressors

• p53: Known as the "guardian of the genome."
  • Role: Monitors DNA integrity and cell cycle progression.
  • Regulation: Held inactive by MDM2 until DNA damage occurs.
  • Cell Cycle Checkpoints: Can arrest cell cycle at multiple checkpoints (G1, G2, metaphase).
  • DNA Repair or Apoptosis:
    • Prompts repair, allowing cell cycle continuation upon successful repair.
    • Initiates apoptosis if repair fails.
• Retinoblastoma (RB): Another key tumor suppressor under study.
• BRCA1/BRCA2: Breast cancer susceptibility genes.

Importance of p53

• Mutation Prevalence: Found in 60-70% of tumors; essential for cancer progression due to its role in preventing mutation accumulation.
• Consequences of p53 Mutation:
  • Allows accumulation of mutations and chromosomal abnormalities.
  • Facilitates malignant transformation of cells.

Apoptosis

• Definition: Programmed cell death to remove damaged cells.
  • Pronunciation: "Apoptosis" (P may be silent as "a-poptosis").

Conclusion

• Cellular and Genetic Stability: p53 ensures integrity by fixing mutations or removing faulty cells.
• Role in Cancer: Mutations in these pathways are critical for cancer cell survival and proliferation.

• Note: Understanding these pathways is crucial for exploring cancer biology and potential therapeutic targets.