Module 2: Understanding Cancer Metastasis
A deep dive into the complex process of cancer metastasis, from molecular mechanisms to clinical applications and therapeutic strategies.
Circulation Survival & Extravasation
Understanding how cancer cells survive the hostile circulation environment and successfully exit to establish metastases.
Learning Objectives
CTCs must survive anoikis, immune surveillance, and shear stress
Metastasis suppressor genes are lost in metastatic cancer cells
CTCs associate with other cell types for protection and assistance
Extravasation involves chemokine homing and dock-and-lock mechanisms
Key Terminology
Anoikis
A form of programmed cell death when cells detach from their native extracellular matrix (ECM)
Normal cells die without ECM attachment; cancer cells must evade this
Circulating Tumor Cell (CTC)
A tumor cell that has entered the bloodstream and lymphatics and is able to survive
CTCs are the vehicles of metastatic spread
Metastasis Suppressor Genes
Genes that act to slow or prevent metastases; these genes are lost in cancer cells
Loss of these genes dramatically increases metastatic ability
Extravasation
Movement of cancer cells out of a blood vessel into tissues during metastasis
Final step before establishing secondary tumors
Disseminated Tumor Cell (DTC)
A CTC that has left the circulation for a distant, secondary site
Represents successful completion of metastatic journey
The Lymphatic System in Metastasis
Cancer cells can enter circulation through lymphatic vessels, providing an alternative route to hematogenous spread
Lymphatic Structure & Function
Composition: Lymphatic vessels carry lymph fluid containing water, white blood cells (leukocytes), proteins, fats, and sugars
Function: Transports fluid from tissues to lymph nodes, then deposits into bloodstream; acts as immunological defense
Metastatic Advantage
Alternative Route: Cancer cells can reach bloodstream without directly intravasating blood vessels
Pathway:
• Cancer cells intravasate lymphatic vessels
• Travel through lymphatic system to lymph nodes
• Lymph drains into venous circulation
• Cancer cells enter systemic bloodstream
Metastasis Suppressor Genes
Specific genes lost in metastatic cancer cells that normally prevent metastatic spread
CD82 (KAI1)
Function: Allows normal cells to bind DARC on endothelial cells, preventing circulation
Loss Effect: Cancer cells can travel freely in circulation without getting stuck
Cancer Type: Particularly important in prostate cancer
MAP Kinase 4
Function: Regulates cellular stress responses and apoptosis
Loss Effect: Enhanced survival under stress conditions
RKIP
Function: Inhibits metastasis-promoting signaling pathways
Loss Effect: Increased invasive and metastatic potential
NM23-H1/H2
Function: Nucleoside diphosphate kinases involved in cell motility regulation
Loss Effect: Enhanced cell motility and metastatic spread
KISS1
Function: Encodes metastin, a metastasis suppressor peptide
Loss Effect: Loss of metastatic suppression signals
CD82/KAI1 Detailed Mechanism
Normal Function
Enables normal cells to bind Duffy Antigen Chemokine Receptor (DARC) on endothelial cells
Outcome: Cells get stuck and cannot traverse circulation
Cancer Loss
Cancer cells lose CD82 expression, particularly in prostate cancer
Outcome: Cells can travel to distant sites and activate oncogenes like Src
Anoikis Resistance in Cancer
Cancer cells use multiple pathways to survive detachment from ECM
Trigger
Upregulation of Epithelial Growth Factor Receptor (EGFR)
EGFR activation
PI3-kinase (phosphoinositide 3-kinase) upregulation
AKT phosphorylation
mTOR (Target of Rapamycin) activation
Anoikis resistance achieved
Outcome
Cancer cells survive without ECM attachment
CTC Survival Challenges
Anoikis
Cell death from ECM detachment
Evasion: Upregulated survival signaling (EGFR/PI3K/AKT pathway)
Immune Surveillance
Immune cells continuously monitor circulation for foreign cells
Evasion: Association with platelets and immune checkpoint expression
Shear Stress
Blood pressure and flow can cause cell lysis
Evasion: Structural adaptations and protective cell clusters
CTCs as Prognostic Markers
CTC count correlates with patient survival outcomes
Better Prognosis
< 5 CTCs in 7mL blood = ~22 months median survival
Worse Prognosis
≥ 5 CTCs in 7mL blood = ~11 months median survival
Detection Challenge: Finding ~5 CTCs among 50-60 million white blood cells in 7mL blood
Theories of Metastatic Homing
Random Distribution Theory
CTCs can travel anywhere in circulation like airport travel
"With enough resources, you can travel to any destination"
Limitation: Doesn't explain organ-specific metastatic patterns
Seed and Soil Hypothesis
Cancer cells (seeds) preferentially metastasize to environments (soil) where they can thrive
Author: Stephen Paget (1889)
Paper: The distribution of secondary growths in cancer of the breast
Prostate Cancer: Bone ✓, not Pancreas ✗
Breast Cancer: Bone ✓, not Peritoneum ✗
Stomach Cancer: Peritoneum ✓, not Bone ✗
Extravasation: Exit from Circulation
Multi-step process of CTC exit from blood vessels
Chemokine Attraction
CTCs attracted to secondary sites via chemokine gradients
Chemotaxis toward target organs
Docking
CTC attaches to endothelial cells using integrins
Integrin-mediated adhesion
Rolling
CTC rolls along vessel interior due to blood flow
Continuous blood flow causes rolling motion
Platelet Recruitment
Platelets are recruited to assist extravasation
CTC-platelet interactions
EMT Induction
Platelets secrete factors to induce EMT in CTCs
CTCs gain migratory and invasive properties
ECM Breakdown
CTCs break through blood vessel ECM
Enhanced invasive capabilities from EMT
Vascular Permeabilization
Platelets upregulate CCL2 to increase vessel permeability
Easier passage through vessel wall
Tissue Entry
CTC successfully exits circulation into target tissue
CTC becomes Disseminated Tumor Cell (DTC)
Clinical Implications
Understanding circulation survival and extravasation reveals the remarkable journey cancer cells must complete to establish distant metastases. Each step represents both a vulnerability and a potential therapeutic target.
Therapeutic Insight: The complexity of metastatic circulation offers multiple intervention points, from CTC detection for early diagnosis to targeting survival mechanisms, cellular partnerships, and homing pathways.