Dataset Information

Transforming growth factor-? signalling controls human breast cancer metastasis in a zebrafish xenograft model.

ABSTRACT: INTRODUCTION:The transforming growth factor beta (TGF-?) 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-? signalling in human breast tumour cells. METHODS:We 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-? signalling pathway were blocked by chemical inhibition, small interfering RNA (siRNA), or small hairpin RNA (shRNA). Analysis was conducted using fluorescent microscopy. RESULTS:Breast 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-? 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-? in breast cancer cells, blocked invasion and metastasis of breast cancer cells. CONCLUSIONS:The zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understanding, screening and development of anti-TGF-? drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner.

SUBMITTER: Drabsch Y

PROVIDER: S-EPMC3978640 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transforming growth factor-β signalling controls human breast cancer metastasis in a zebrafish xenograft model.

Drabsch Yvette Y He Shuning S Zhang Long L Snaar-Jagalska B Ewa BE ten Dijke Peter P

Breast cancer research : BCR 20131107 6

<h4>Introduction</h4>The 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.<h4>Methods</h4>We injected cancer cells into the embryonic circulation (duct of cuvier) and examined their invasion and metastasis in ...[more]

PMID: 24196484

Similar Datasets

Project description:Transforming growth factor beta (TGF?) plays a major role in the regulation of tumor initiation, progression, and metastasis. It is depended on the type II TGF? receptor (T?RII) for signaling. Previously, we have shown that deletion of T?RII in mammary epithelial of MMTV-PyMT mice results in shortened tumor latency and increased lung metastases. However, active TGF? signaling increased the number of circulating tumor cells and metastases in MMTV-Neu mice. In the current study, we describe a newly discovered connection between attenuated TGF? signaling and human epidermal growth factor receptor 2 (HER2) signaling in mammary tumor progression.All studies were performed on MMTV-Neu mice with and without dominant-negative T?RII (DNIIR) in mammary epithelium. Mammary tumors were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence staining. The levels of secreted proteins were measured by enzyme-linked immunosorbent assay. Whole-lung mount staining was used to quantitate lung metastasis. The Cancer Genome Atlas (TCGA) datasets were used to determine the relevance of our findings to human breast cancer.Attenuated TGF? signaling led to a delay tumor onset, but increased the number of metastases in MMTVNeu/DNIIR mice. The DNIIR tumors were characterized by increased vasculogenesis, vessel leakage, and increased expression of vascular endothelial growth factor (VEGF). During DNIIR tumor progression, both the levels of CXCL1/5 and the number of CD11b+Gr1+ cells and T cells decreased. Analysis of TCGA datasets demonstrated a significant negative correlation between TGFBR2 and VEGF genes expression. Higher VEGFA expression correlated with shorter distant metastasis-free survival only in HER2+ patients with no differences in HER2-, estrogen receptor +/- or progesterone receptor +/- breast cancer patients.Our studies provide insights into a novel mechanism by which epithelial TGF? signaling modulates the tumor microenvironment, and by which it is involved in lung metastasis in HER2+ breast cancer patients. The effects of pharmacological targeting of the TGF? pathway in vivo during tumor progression remain controversial. The targeting of TGF? signaling should be a viable option, but because VEGF has a protumorigenic effect on HER2+ tumors, the targeting of this protein could be considered when it is associated with attenuated TGF? signaling.

Dataset Information

Transforming growth factor-? signalling controls human breast cancer metastasis in a zebrafish xenograft model.

Publications

Transforming growth factor-β signalling controls human breast cancer metastasis in a zebrafish xenograft model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets