Intravasation & circulating tumour cells
Getting into the bloodstream and surviving there is brutal: cells are ripped from their neighbours, battered by flow, and hunted by NK cells. Fewer than one in a thousand survive. The ones that do travel in clusters, wear a cloak of platelets, or ride with neutrophils. Liquid biopsies catch what is left.
Intravasation happens at 'TMEM doorways' (a tumour cell, a perivascular TIE2+ macrophage and an endothelial cell in direct contact) where macrophage-derived VEGF-A transiently opens the vessel; leaky angiogenic vessels and lymphatics (VEGF-C) also admit cells. In the blood, detachment triggers anoikis (integrin loss → BIM/BMF → apoptosis), which metastatic cells resist via TrkB, PI3K, and mesenchymal states; shear stress and oxidative stress (antioxidants paradoxically aid metastasis) kill most; NK cells clear the rest. Survivors use platelet cloaking (P-selectin, tissue-factor-thrombin, platelet TGF-β shielding from NK and inducing EMT), neutrophil escorts and NETs, and travel as clusters held by plakoglobin and CD44, which are up to 50-fold more metastatic than singles and carry hypomethylated stemness genes. CTCs (EpCAM-based CellSearch; ≥5 per 7.5 mL prognostic in breast, prostate, colorectal) and ctDNA are the clinical windows; fragmentomics and methylation extend detection. Aspirin and anticoagulants reduce metastasis in models via the platelet arm; Na+/K+-ATPase inhibitors dissolve clusters preclinically.
In one picture
Leaving a fortress through the drains and swimming a river in flood while archers (NK cells) fire from the bank. Survivors go in rafts (clusters), under wet blankets (platelets), and with a friendly escort (neutrophils).
Diagram
top- Liquid biopsy: CTC enumeration (CellSearch), ctDNA (Signatera, Guardant Reveal), fragmentomics for detection and MRD
- Aspirin and low-molecular-weight heparin target platelet cloaking; aspirin reduces recurrence in PIK3CA-mutant colorectal cancer (ALASCCA)
- Anti-VEGF and CSF1R inhibition close TMEM doorways in models
- Cluster-dissociating agents (digoxin analogues) and NK-boosting therapies are experimental
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