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Cancer Heterogeneity Lecture Notes

Heterogeneity in Cancer

  • Definition of Heterogeneity

    • Heterogeneity = diversity; distinguishing characteristics among constituent parts of a whole
    • Example: A classroom populated with diverse traits (age, sex, hair color, height) demonstrates heterogeneity.

  • Homogeneity

    • Homogeneity = similarity; characteristics shared among parts of a whole.
    • Example: A classroom composed entirely of university students is homogeneous in educational status.

Cancer as a Complex Disease

  • Cancer is not a single disease

    • Sources of cancer heterogeneity vary greatly and influence treatment and development of the disease.

  • Global Incidence Variation

    • Example: Significant differences in stomach cancer rates across different countries indicate variable cancer incidence at the population level.

Types of Cancer and Their Origins

  • Organ/Tissue of Origin

    • Breast Adenocarcinoma:
    • Driven by estrogen; 5-year survival rate: ~90% overall, ~20% for stage IV.
    • Pancreatic Adenocarcinoma:
    • Driven by KRAS mutation; 5-year survival rate: 10% overall, 2% for stage IV.
    • Origin of cancer cells influences their heterogeneity.

  • Cell of Origin

    • Variability in cancer appears based on the original cell type observed under a microscope; individual cancers are unique due to their cellular origins.

Tumor Microenvironment

  • Heterogeneity in Tumor Microenvironment
    • Tumors consist of various components:
    • Tumor-infiltrating leukocytes
    • Cancer-associated fibroblasts
    • Endothelial cells
    • This diversity contributes to the overall heterogeneity of cancer.

Individual Patient Cancer Heterogeneity

  • Heterogeneity in Cancer Cell Populations
    • Cancer cells are clonal; however, they exhibit phenotypic and genotypic variations, raising questions about their differences despite shared origins.

Evolutionary Principles in Cancer

  • Darwinian Evolution

    • “Survival of the fittest”; natural selection leads to genetic mutations that improve survival chances.
    • These mutations can lead to variations that confer selective advantages in cancer development.

  • Cancer and Clonal Evolution

    • Acquired DNA mutations contribute to cancer development and progression.
    • Mutations can increase over time due to errors in DNA replication, leading to the emergence of genetically varied subclones.

  • Selective Advantage

    • Some mutations may confer advantages, enabling certain clones to dominate within the tumor, shaped by selective pressures in the environment.

Phenotypic Variability

  • Combined Influences on Heterogeneity
    • Phenotypic heterogeneity: Arises not only from genomic differences but also from factors such as epigenetic changes and altered gene expression.
    • Cancer Stem Cell Hypothesis: A subset of cancer cells can both replicate and differentiate, contributing to tumor expansion.

Clinical Implications of Heterogeneity

  • Cancer Treatment and Resistance

    • Treatment can create selective pressures leading to resistance; e.g., mutations might allow cancer cells to survive therapies.

  • Examples

    • Advanced Lung Cancer with EGFR Mutation: Progression through various treatments can lead to treatment resistance due to new mutations (e.g., T790M).
    • Multiple Myeloma Immunotherapy: Initially responsive cancer may become resistant due to loss of targeted antigen and additional genomic changes.

Conclusion and Reflections

  • Sources of Cancer Heterogeneity
    • Varying levels include population characteristics, the specific organ/tissue type, and intra-patient (even intra-tumor) variability.
  • Why a Cure Remains Elusive
    • The complexity and heterogeneity of cancer mean that individual cases can differ significantly, complicating treatment approaches.
  • While some cancers can be cured, the diversity of cancer types challenges the development of universally effective treatments.