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Embryonic zebrafish xenograft assay of human cancer metastasis.

ABSTRACT: Cancer metastasis is the most important prognostic factor determining patient survival, but currently there are very few drugs or therapies that specifically inhibit the invasion and metastasis of cancer cells. Currently, human cancer metastasis is largely studied using transgenic and immunocompromised mouse xenograft models, which are useful for analysing end-point tumour growth but are unable to accurately and reliably monitor in vivo invasion, intravasation, extravasation or secondary tumour formation of human cancer cells. Furthermore, limits in our ability to accurately monitor early stages of tumour growth and detect micro-metastases likely results in pain and suffering to the mice used for cancer xenograft experiments. Zebrafish ( Danio rerio) embryos, however, offer many advantages as a model system for studying the complex, multi-step processes involved during cancer metastasis. This article describes a detailed method for the analysis of human cancer cell invasion and metastasis in zebrafish embryos before they reach protected status at 5 days post fertilisation. Results demonstrate that human cancer cells actively invade within a zebrafish microenvironment, and form metastatic tumours at secondary tissue sites, suggesting that the mechanisms involved during the different stages of metastasis are conserved between humans and zebrafish, supporting the use of zebrafish embryos as a viable model of human cancer metastasis. We suggest that the embryonic zebrafish xenograft model of human cancer is a tractable laboratory model that can be used to understand cancer biology, and as a direct replacement of mice for the analysis of drugs that target cancer invasion and metastasis.

SUBMITTER: Hill D

PROVIDER: S-EPMC6234738 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increased expression of ?v integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which ?v integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of ?v integrins in breast cancer also have yet to be investigated.We knocked down ?v integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the ?v antagonist GLPG0187. The effects of ?v integrin depletion on mesenchymal markers, transforming growth factor-? (TGF-?)/Smad signaling and TGF-?-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of ?v integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis.Genetic interference and pharmacological targeting of ?v integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of ?v integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-?/Smad response. TGF-? induced ?v integrin mRNA expression and ?v integrin was required for TGF-?-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-? signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments.These findings show that ?v integrin is required for efficient TGF-?/Smad signaling and TGF-?-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting ?v integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress ?v integrin.

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Embryonic zebrafish xenograft assay of human cancer metastasis.

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