# Intravasation & circulating tumour cells

Source: https://onco.cc/pathways/intravasation-ctc-survival/  
OnCo record `intravasation-ctc-survival` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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).
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Circulating_tumor_cell
- Aceto et al., Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis (Cell 2014): https://doi.org/10.1016/j.cell.2014.07.013
- Massagué & Obenauf, Metastatic colonization by circulating tumour cells (Nature 2016): https://doi.org/10.1038/nature17038

## Connected records

- technologies: [Aspirin for cancer prevention and adjuvant therapy](https://onco.cc/technologies/aspirin-cancer-prevention/), [Cancer-associated thrombosis prevention and treatment](https://onco.cc/technologies/cancer-associated-thrombosis/), [cfDNA fragmentomics](https://onco.cc/technologies/fragmentomics/), [Continuous and near-continuous ctDNA monitoring](https://onco.cc/technologies/continuous-ctdna-monitoring/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/)
- targets: [CD44](https://onco.cc/targets/cd44/), [CSF1R](https://onco.cc/targets/csf1r/), [EpCAM](https://onco.cc/targets/epcam/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Shield](https://onco.cc/drugs/shield/), [Signatera](https://onco.cc/drugs/signatera/)
- pathways: [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [NK-cell recognition: missing self & stress ligands](https://onco.cc/pathways/nk-cell-recognition/), [The angiogenic switch & tumour vessels](https://onco.cc/pathways/angiogenic-switch/), [The metastatic cascade](https://onco.cc/pathways/metastatic-cascade/), [The pre-metastatic niche](https://onco.cc/pathways/pre-metastatic-niche/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Disseminated tumour cells (DTCs)](https://onco.cc/terms/disseminated-tumor-cells/), [Hallmark: activating invasion and metastasis](https://onco.cc/terms/activating-invasion-metastasis/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/), [Seed and soil hypothesis of metastasis (Paget)](https://onco.cc/terms/seed-and-soil-hypothesis/), [Variant allele frequency (VAF)](https://onco.cc/terms/vaf/)
- bottlenecks: [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/), [Metastasis is understood least and studied last](https://onco.cc/bottlenecks/b-metastasis-biology/)
- key papers: [AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer](https://onco.cc/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/), [Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis](https://onco.cc/key-papers/paper-aceto-cell/), [Metastatic colonization by circulating tumour cells](https://onco.cc/key-papers/paper-massague-nature/), [Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer](https://onco.cc/key-papers/paper-scher-nuclear-arv7-taxane-vs-arsi-jama-oncol-2018/), [PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer](https://onco.cc/key-papers/paper-prophecy-arv7-validation-jco-2019/)
- cancers: [Prostate cancer](https://onco.cc/cancers/prostate/)

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