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Breast Cancer Research

, 15:R106

First Online: 07 November 2013Received: 12 July 2013Accepted: 21 October 2013DOI: 10.1186-bcr3573

Cite this article as: Drabsch, Y., He, S., Zhang, L. et al. Breast Cancer Res 2013 15: R106. doi:10.1186-bcr3573

Abstract

IntroductionThe transforming growth factor beta TGF-β signalling pathway is known to control human breast cancer invasion and metastasis. We demonstrate that the zebrafish xenograft assay is a robust and dependable animal model for examining the role of pharmacological modulators and genetic perturbation of TGF-β signalling in human breast tumour cells.

MethodsWe injected cancer cells into the embryonic circulation duct of cuvier and examined their invasion and metastasis into the avascular collagenous tail. Various aspects of the TGF-β signalling pathway were blocked by chemical inhibition, small interfering RNA siRNA, or small hairpin RNA shRNA. Analysis was conducted using fluorescent microscopy.

ResultsBreast cancer cells with different levels of malignancy, according to in vitro and in vivo mouse studies, demonstrated invasive and metastatic properties within the embryonic zebrafish model that nicely correlated with their differential tumourigenicity in mouse models. Interestingly, MCF10A M2 and M4 cells invaded into the caudal hematopoietic tissue and were visible as a cluster of cells, whereas MDA MB 231 cells invaded into the tail fin and were visible as individual cells. Pharmacological inhibition with TGF-β receptor kinase inhibitors or tumour specific Smad4 knockdown disturbed invasion and metastasis in the zebrafish xenograft model and closely mimicked the results we obtained with these cells in a mouse metastasis model. Inhibition of matrix metallo proteinases, which are induced by TGF-β in breast cancer cells, blocked invasion and metastasis of breast cancer cells.

ConclusionsThe zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understanding, screening and development of anti-TGF-β drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner.

AbbreviationsCHTCaudal haematopoietic tissue

DMEMDulbecco’s modified Eagle-s medium

DoCDuct of cuvier

dpfDays post fertilisation

EMTEpithelial mesenchymal transition

FAF1FAS-associated factor 1

FASFas TNF receptor superfamily, member 6

FCSFetal calf serum

GFPGreen fluorescent protein

hpfHours post fertilisation

hpiHours post implantation

M1MCF10A

M2MCF10AT1k.cl2

M4MCF10CA1a.cl1

MMPMatrix metalloprotease

PBSPhosphate-buffered saline

PFAParaformaldehyde

pSmad2Phosphorylated Smad2

TgTransgenic

TGF-βTransforming growth factor β

TRAF4TNF receptor-associated factor 4 TRAF4

TRKITGF-β receptor kinase inhibitor

USP4Ubiquitin-specific protease 4

zTGF-βZebrafish transforming growth factor β.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3573 contains supplementary material, which is available to authorized users.

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Autor: Yvette Drabsch - Shuning He - Long Zhang - B Ewa Snaar-Jagalska - Peter ten Dijke

Fuente: https://link.springer.com/



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