{"entity":{"id":"intravasation-ctc-survival","kind":"pathway","name":"Intravasation & circulating tumour cells","aka":[],"tldr":"Getting into the bloodstream kills almost every cell that tries: 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.","summary":"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.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Circulating_tumor_cell","links":[{"label":"Aceto et al., Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis (Cell 2014)","url":"https://doi.org/10.1016/j.cell.2014.07.013"},{"label":"Massagué & Obenauf, Metastatic colonization by circulating tumour cells (Nature 2016)","url":"https://doi.org/10.1038/nature17038"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["liquid-biopsy","mrd-testing","continuous-ctdna-monitoring","fragmentomics","aspirin-cancer-prevention","cancer-associated-thrombosis"],"targets":["vegf","csf1r","epcam","pik3ca"],"drugs":["signatera","shield","bevacizumab"],"companies":[],"institutions":[],"pathways":["metastatic-cascade","angiogenic-switch","nk-cell-recognition","emt","pre-metastatic-niche"],"terms":["ctdna","mrd","vaf","disseminated-tumor-cells","activating-invasion-metastasis"],"trials":[],"people":[],"bottlenecks":["b-metastasis-biology","b-dormancy-mrd"],"keyPapers":["paper-massague-nature","paper-aceto-cell"],"journals":[],"dependsOn":[],"notes":[],"analogy":"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).","nodes":[{"id":"tmem","label":"TMEM doorway (macrophage)","x":12,"y":15,"targetId":"csf1r"},{"id":"leak","label":"Leaky vessels (VEGF)","x":40,"y":15,"targetId":"vegf"},{"id":"intra","label":"Intravasation","x":68,"y":15},{"id":"anoik","label":"Anoikis (detachment death)","x":12,"y":48},{"id":"shear","label":"Shear, oxidative stress","x":40,"y":48},{"id":"nk","label":"NK-cell clearance","x":68,"y":48},{"id":"ctc","label":"Surviving CTCs / clusters","x":92,"y":48},{"id":"plat","label":"Platelet cloak, NETs","x":92,"y":82},{"id":"clust","label":"Clusters (plakoglobin, CD44)","x":62,"y":82},{"id":"lb","label":"Liquid biopsy detection","x":30,"y":82}],"edges":[{"from":"tmem","to":"intra","type":"activates"},{"from":"leak","to":"intra","type":"activates"},{"from":"intra","to":"ctc","type":"activates"},{"from":"anoik","to":"ctc","type":"inhibits"},{"from":"shear","to":"ctc","type":"inhibits"},{"from":"nk","to":"ctc","type":"inhibits"},{"from":"plat","to":"nk","type":"inhibits"},{"from":"clust","to":"anoik","type":"inhibits"},{"from":"plat","to":"ctc","type":"activates"},{"from":"clust","to":"ctc","type":"activates"},{"from":"ctc","to":"lb","type":"activates"}],"interventions":["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"]},"route":"/pathways/intravasation-ctc-survival/","neighbours":{"technology":[{"id":"aspirin-cancer-prevention","kind":"technology","name":"Aspirin for cancer prevention and adjuvant therapy","route":"/technologies/aspirin-cancer-prevention/"},{"id":"cancer-associated-thrombosis","kind":"technology","name":"Cancer-associated thrombosis prevention and treatment","route":"/technologies/cancer-associated-thrombosis/"},{"id":"fragmentomics","kind":"technology","name":"cfDNA fragmentomics","route":"/technologies/fragmentomics/"},{"id":"continuous-ctdna-monitoring","kind":"technology","name":"Continuous and near-continuous ctDNA monitoring","route":"/technologies/continuous-ctdna-monitoring/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"}],"target":[{"id":"cd44","kind":"target","name":"CD44","route":"/targets/cd44/"},{"id":"csf1r","kind":"target","name":"CSF1R","route":"/targets/csf1r/"},{"id":"epcam","kind":"target","name":"EpCAM","route":"/targets/epcam/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"bevacizumab","kind":"drug","name":"Bevacizumab","route":"/drugs/bevacizumab/"},{"id":"shield","kind":"drug","name":"Shield","route":"/drugs/shield/"},{"id":"signatera","kind":"drug","name":"Signatera","route":"/drugs/signatera/"}],"pathway":[{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"nk-cell-recognition","kind":"pathway","name":"NK-cell recognition: missing self & stress ligands","route":"/pathways/nk-cell-recognition/"},{"id":"angiogenic-switch","kind":"pathway","name":"The angiogenic switch & tumour vessels","route":"/pathways/angiogenic-switch/"},{"id":"metastatic-cascade","kind":"pathway","name":"The metastatic cascade","route":"/pathways/metastatic-cascade/"},{"id":"pre-metastatic-niche","kind":"pathway","name":"The pre-metastatic niche","route":"/pathways/pre-metastatic-niche/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"disseminated-tumor-cells","kind":"term","name":"Disseminated tumour cells (DTCs)","route":"/terms/disseminated-tumor-cells/"},{"id":"activating-invasion-metastasis","kind":"term","name":"Hallmark: activating invasion and metastasis","route":"/terms/activating-invasion-metastasis/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"seed-and-soil-hypothesis","kind":"term","name":"Seed and soil hypothesis of metastasis (Paget)","route":"/terms/seed-and-soil-hypothesis/"},{"id":"vaf","kind":"term","name":"Variant allele frequency (VAF)","route":"/terms/vaf/"}],"bottleneck":[{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/"},{"id":"b-metastasis-biology","kind":"bottleneck","name":"Metastasis is understood least and studied last","route":"/bottlenecks/b-metastasis-biology/"}],"paper":[{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","kind":"paper","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/"},{"id":"paper-aceto-cell","kind":"paper","name":"Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis","route":"/key-papers/paper-aceto-cell/"},{"id":"paper-massague-nature","kind":"paper","name":"Metastatic colonization by circulating tumour cells","route":"/key-papers/paper-massague-nature/"},{"id":"paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018","kind":"paper","name":"Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer","route":"/key-papers/paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018/"},{"id":"paper-prophecy-arv7-validation-jco-2019","kind":"paper","name":"PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer","route":"/key-papers/paper-prophecy-arv7-validation-jco-2019/"}],"cancer":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}]}}