ArticleCell communication and signaling : CCS2025
Crosstalk between tumor endothelial cells and cancer cells is important for metastasis initiation.
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Pharmacological manipulation of Sema4D by salvianolic acid A mitigates diabetic retinopathy via inhibiting PlexinB1/RhoA/ROCK/pMLC2 signaling cascade involved in endothelial dysfunction.Chinese medicine · 2026Article
- Review
- Inflammasome-associated pyroptosis and tumor angiogenesis in prostate cancer.Iranian journal of basic medical sciences · 2026Review
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10 authors.
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Abstract
backgroundMetastasis is a major contributor of cancer-related mortality and involves complex crosstalk between cancer cells and stromal cells modulated by various cytokines and growth factors. While the endothelium is essential for supplying nutrients and oxygen, little is known about its role in metastasis initiation. Determining the effect of endothelial-derived angiocrine factors on cancer cells may explain the mechanisms regulating metastasis initiation.
resultsIn this study, we investigated the role of normal endothelial cells (NEC) and tumor endothelial cells (TEC) in regulating the rate-limiting steps of metastasis initiation. First, we demonstrated that TEC have a higher proliferation, migration, and angiogenic potential than NEC. TEC-conditioned media significantly promoted chemotaxis, invasion, and proliferation of cancer cells relative to NEC-conditioned media. Additionally, TEC facilitated faster cell-cell adhesion to tumor cells than NEC. Mass spectrometry analysis of endothelial cell secretome revealed higher levels of PDGF-AA, PDGF-C, and VEGFA in TEC-conditioned medium, which were associated with enriched PI3K-AKT, MAPK, and RAS signaling pathways, as well as regulation of actin cytoskeleton and focal adhesion. In vitro functional studies using recombinant proteins showed that PDGF-AA and PDGF-C significantly promoted cancer cell chemotaxis and invasion without affecting proliferation. However, unlike VEGFA, PDGF-AA and PDGF-C did not affect endothelial cell tube formation or vascular permeability. Interestingly, neutralization of TEC-derived PDGF-C signficantly inhibited tumor cell chemotaxis and invasion, and attenuated EphA2/AKT/P38/ERK signaling in vitro. In vivo, the co-injection of TEC and 4T1 cells resulted in significantly higher primary breast tumor growth and liver metastasis in an orthotopic mouse model.
conclusionOur results demonstrate that crosstalk between cancer cells and TEC, partly through angiocrine factors in the TME, induces the rate-limiting steps of metastasis initiation.
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