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.