Hallmarks of Cancer: New Dimensions

Introduction

• Concept of Hallmarks of Cancer introduced by Bob Weinberg and Douglas Hanahan.
• Initial proposal included six hallmark capabilities, expanded to eight.
• Hallmarks are acquired capabilities crucial for malignant tumor formation:
  • Sustaining proliferative signaling
  • Evading growth suppressors
  • Resisting cell death
  • Enabling replicative immortality
  • Inducing/accessing vasculature
  • Activating invasion and metastasis
  • Reprogramming cellular metabolism
  • Avoiding immune destruction
• Two enabling characteristics:
  • Genome instability
  • Tumor-promoting inflammation

Hallmarks of Cancer: New Perspectives

• New dimensions added to the hallmarks:
  • Phenotypic plasticity and disrupted differentiation as a discrete hallmark capability.
  • Nonmutational epigenetic reprogramming.
  • Polymorphic microbiomes as enabling characteristics.
  • Senescent cells in the tumor microenvironment.

Phenotypic Plasticity

• Dedifferentiation: Mature cells revert to progenitor states.
• Blocked Differentiation: Progenitor cells are blocked from fully differentiating.
• Transdifferentiation: Cells switch differentiation pathways, acquiring new tissue-specific traits.
• Examples:
  • Colon carcinogenesis and melanoma display dedifferentiation.
  • Acute promyelocytic leukemia as a case of blocked differentiation.
  • Barrett's esophagus as an example of transdifferentiation.

Nonmutational Epigenetic Reprogramming

• Genome reprogramming through epigenetic changes, independent of mutations.
• Tumor microenvironment can epigenetically regulate cancer cells.
• Influence of hypoxia and nutrient deprivation on epigenetic states.
• Examples of epigenetic regulation:
  • Hypoxia in tumors.
  • Epithelial-to-mesenchymal transition (EMT) in invasiveness.

Polymorphic Microbiomes

• Microbiomes influence cancer development, progression, and therapy response.
• Gut microbiome has cancer-protective and tumor-promoting effects.
• Mechanisms: Mutagenesis, epithelial proliferation, and immune modulation.
• Impact beyond the gut: Skin, lungs, urogenital systems, and tumors themselves.

Senescent Cells

• Senescence is a form of proliferative arrest.
• Senescence-associated secretory phenotype (SASP) influences tumor microenvironment.
• Senescent cells can promote tumor phenotypes.
• Potential for reversible senescence, contributing to therapy resistance.
• Importance in aging tissues and tumors.

Concluding Remarks

• Eight core hallmarks and enabling characteristics have heuristic value.
• New facets (phenotypic plasticity, epigenetic reprogramming, microbiomes, and senescence) suggested for broader understanding.
• Encourages debate and further research in cancer biology and pathogenesis.