8 February 2011 00:00 hrs.
Tumour vasculogenesis and micro-metastasis studied in a new zebrafish xenograft model: control by VEGF and leukocytes.

Ewa Snaar-Jagalska, IBL, University Leiden, The Netherlands


Sandra de Keijzer, Dept. of Tumor Immunology, NCMLS, Nijmegen

08-02-2011 00:00:00Europe/AmsterdamTumour vasculogenesis and micro-metastasis studied in a new zebrafish xenograft model: control by VEGF and leukocytes.

Remarks / more information:

We developed a novel xenograft model by injecting pro-angiogenic mammalian tumor cells into the zebrafish embryonic blood circulation. Injected cells immediately spread throughout the embryo via the circulating blood system, extravasated and invaded neighboring tissue at specific tail fin sites, where they gradually proliferated into micrometastatic clusters after a few days. Injected cancer cells also accumulated in the duct of Cuvier and induced formation of neo-vasculature. Time resolved, high-resolution, fluorescent imaging revealed the developmental steps of tumor induced vasculogenesis at the cellular level. Injected cancer cells immediately recruited and modulated the endothelial progenitor cells into the functional vessel network in the 4-6 days. This de novo, tumor-induced vasculogenesis was blocked by depletion of the endothelial progenitor cells by VE-cadherin knockdown and inhibition of VEGF signaling. In contrast, inhibition of VEGF signaling enhanced invasion of tumor cells and promoted formation of micrometastasis. We also tested the effect of genetic knock-down of the transcription factor (Pu1), responsible for myeloid cell differentiation. Engraftments of tumor cells into Pu1 knock-down fish with depleted embryonic neutrophils and macrophages resulted in an impaired tumor vascularization, invasion and micro-metastasis, proving the importance of myeloid cells in these processes. Using advanced imaging technology we show that the site of tumor cell invasion and micrometastasis is determined by non-pathological neutrophils transmigration, which remodeled collagen in the metastatic niche. As a result tumor cells "seeds" take advantage of prepared "soil" and invade the host tissue at the transmigration sites. We conclude that inhibition of VEGF signaling promotes tumor cells invasion and micrometastasis by enhancing the transmigration of neutrophils.

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