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Mechanism of metastasis in form of flow chart

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I have excellent textbook content including a metastatic cascade diagram. Let me fetch that image and also get more detail from the Robbins pathology context.
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I now have excellent source material. Let me generate a clear, detailed flowchart image of the metastasis mechanism.
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A detailed medical flowchart showing the mechanism of metastasis (the metastatic cascade). The flowchart flows top to bottom with labeled boxes and arrows. Steps in order: 1. PRIMARY TUMOR - Clonal expansion, growth, genetic instability, diversification. 2. EMT (Epithelial-to-Mesenchymal Transition) - Loss of E-cadherin, gain of N-cadherin/Vimentin/Fibronectin, increased motility. 3. LOCAL INVASION - Degradation of ECM by MMPs, tumor cells invade surrounding stroma and basement membrane. 4. INTRAVASATION - Tumor cells enter blood vessels or lymphatics assisted by TAMs and VEGF-mediated angiogenesis. 5. SURVIVAL IN CIRCULATION - CTCs travel as single cells or clusters, associated with platelets and neutrophils for immune evasion, anoikis resistance. 6. ARREST AND EXTRAVASATION - Tumor cells arrest at distant capillaries via chemokine receptors (CXCR4/CCR7), adhere to endothelium, then extravasate into organ parenchyma. 7. PREMETASTATIC NICHE FORMATION - Bone marrow-derived cells and exosomes from primary tumor prime the distant organ microenvironment. 8. COLONIZATION AND DORMANCY - DTCs may remain dormant OR reactivate; MET (Mesenchymal-to-Epithelial Transition) occurs. 9. OVERT METASTASIS - Angiogenesis, immune evasion, proliferation leading to macrometastasis. Seed and Soil Hypothesis noted at the side. Clean white background, professional medical illustration style, color-coded steps with blue arrows connecting each box.

Here is the complete mechanism of metastasis as a flowchart, followed by the textbook diagram of the metastatic cascade:

Mechanism of Metastasis - The Metastatic Cascade

Mechanism of Metastasis Flowchart

Textbook Diagram: Metastatic Cascade (Tietz Textbook of Laboratory Medicine)

Metastatic cascade diagram showing primary tumor, EMT/MET plasticity, CTC circulation, and distant metastasis

Step-by-Step Explanation

Step 1 - Primary Tumor

  • Clonal expansion of transformed cells with genetic instability
  • Tumor heterogeneity develops through mutation and selection pressure
  • Must reach >1-2 mm to require new blood supply (angiogenic switch)

Step 2 - EMT (Epithelial-to-Mesenchymal Transition)

  • Loss of E-cadherin, Cytokeratin, EpCAM (epithelial markers)
  • Gain of N-cadherin, Vimentin, Fibronectin (mesenchymal markers)
  • Driven by TGF-β, Wnt, Notch, and cancer stem cell (CSC) signals
  • Cells become motile, invasive, and resistant to anoikis

Step 3 - Local Invasion

  • Matrix metalloproteinases (MMPs) degrade the basement membrane and ECM
  • Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) remodel stroma
  • Invadopodia form at the leading edge of invading cells

Step 4 - Intravasation

  • Tumor cells penetrate blood vessel or lymphatic vessel walls
  • VEGF promotes angiogenesis and increases vascular permeability
  • TAMs (M2 macrophages) facilitate entry into the vasculature
  • Angptl4 (induced by TGF-β) disrupts pulmonary microvascular junctions to promote lung-specific seeding

Step 5 - Survival in Circulation

  • Circulating tumor cells (CTCs) travel alone or in clusters/microemboli
  • Platelets and neutrophils coat CTCs → immune evasion, protection from NK cells
  • CTC clusters have 50x higher metastatic potential than single CTCs
  • Anoikis resistance is required for survival without ECM contact

Step 6 - Arrest and Extravasation

  • CTCs arrest in distant capillaries (size-dependent or receptor-mediated)
  • Chemokine receptors on tumor cells (e.g., CXCR4, CCR7) bind organ-specific ligands (CXCL12, CCL21) - this explains organ tropism ("seed and soil")
  • Surface protein metadherin facilitates adherence to pulmonary vascular endothelium
  • Cells then extravasate into the organ parenchyma

Step 7 - Premetastatic Niche Formation

  • Exosomes from the primary tumor travel ahead to distant organs
  • Bone marrow-derived VEGFR1+ cells establish a permissive microenvironment before tumor cells arrive
  • The niche is tumor-type specific (explains why different cancers favor different organs)

Step 8 - Dormancy vs. Reactivation

  • Disseminated tumor cells (DTCs) may enter dormancy (months to years) - controlled by dormancy gene signatures
  • MET (Mesenchymal-to-Epithelial Transition) reverses EMT to allow proliferation at the new site
  • Immune surveillance, nutrient availability, and microenvironmental signals determine fate

Step 9 - Overt Metastasis (Colonization)

  • Micrometastasis → macrometastasis via angiogenesis and immune evasion
  • Metastasis-initiator cells (MICs) with stemness features drive outgrowth
  • Final clinically detectable metastatic lesion

Key Molecular Players Summary

StepKey Molecules
EMTTGF-β, Wnt, Notch, Snail, Twist, E-cadherin ↓
InvasionMMPs, uPA, integrins
IntravasationVEGF, Angptl4, TAMs
CirculationPlatelets, neutrophils, CXCR4/CCR7
Niche formationExosomes, VEGFR1+ BMDCs
ColonizationMET, stemness genes, angiogenesis
"Seed and Soil" Hypothesis (Paget, 1889): Metastasis is not random - specific tumor cells (the seed) thrive only in compatible organ microenvironments (the soil). Chemokine receptor-ligand pairs are the molecular basis for this organ tropism.
  • Tietz Textbook of Laboratory Medicine, 7th Edition (Fig. 71.13)
  • Murray & Nadel's Textbook of Respiratory Medicine
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