Module 2: Understanding Cancer Metastasis
A deep dive into the complex process of cancer metastasis, from molecular mechanisms to clinical applications and therapeutic strategies.
Dormancy and Secondary Tumor Growth
Why cancer returns years after treatment
Cancer dormancy explains why patients can experience cancer recurrence years or even decades after successful treatment of their primary tumor. Understanding this phenomenon is crucial for developing strategies to prevent metastatic recurrence, the leading cause of cancer death.
Key Questions This Section Addresses:
- •Why do different cancers metastasize to different organs?
- •Why do cancer patients relapse years after surgery?
- •What controls dormant cell reactivation?
- •How can we therapeutically target dormant cells?
🌱 The Seed and Soil Hypothesis
Stephen Paget (1889): "When a plant goes to seed, its seeds are carried in all directions. But they can only live and grow if they fall on congenial soil."
🌰 Seed (Cancer Cell)
Disseminated tumor cells that travel through circulation to distant organs
🌱 Soil (Organ Environment)
Microenvironment of the target organ, including cell types, ECM, and signaling factors
Organ-Specific Metastasis Patterns
Breast Cancer
Common Sites: Bone, Liver, Lung, Brain
Key Mechanisms: CXCR4/CXCL12 chemokine signaling and osteomimicry, Osteomimicry, VEGF expression
Clinical Impact: Bone metastases: 2-3 years median survival
Prostate Cancer
Common Sites: Bone, Lymph nodes
Key Mechanisms: PSA-mediated bone matrix degradation and osteoblast mimicry, Osteoblastic factors, PSA signaling
Clinical Impact: Bone metastases: 1-3 years median survival
Melanoma
Common Sites: Brain, Liver, Lung, Skin
Key Mechanisms: Blood-brain barrier penetration and neurotropic factors, Neurotrophin signaling
Clinical Impact: Brain metastases: 4-5 months median survival
Understanding Cell States: Quiescence vs Senescence vs Dormancy
Active Proliferation
Definition: Rapidly dividing cancer cells forming growing metastases
Duration: Continuous until growth constraints
Characteristics: High Ki-67 expression, Active cell cycle
Active Proliferation
Key Features:
• High Ki-67 expression
• Active cell cycle
• High metabolic activity
• Angiogenesis stimulation
Reactivation:
Not applicable - already active
Dormant (Quiescent)
Definition: Reversibly arrested cells that can reactivate
Duration: Months to decades
Characteristics: G0/G1 arrest, Low Ki-67
Dormant (Quiescent)
Key Features:
• G0/G1 arrest
• Low Ki-67
• Stress resistance
• Maintained viability
Reactivation:
Growth factor stimulation
Microenvironment changes
Senescent
Definition: Permanently growth-arrested cells with secretory phenotype
Duration: Permanent (until clearance)
Characteristics: Irreversible growth arrest, SASP activation
Senescent
Key Features:
• Irreversible growth arrest
• SASP activation
• DNA damage response
• Enlarged morphology
Reactivation:
Generally irreversible
🎯 Key Takeaways
Clinical Significance
- • Dormancy explains late cancer recurrence
- • 62% of breast cancer deaths occur >5 years post-surgery
- • Current imaging cannot detect dormant cells
- • Dormant cells are the seeds of metastasis
Research Challenges
- • Difficult to study dormant cells in lab
- • Unknown mechanisms of dormancy maintenance
- • Limited therapeutic targets
- • Need for dormancy-specific biomarkers