PUBLICATION
A novel zebrafish model of metastasis identifies the HSD11β1 inhibitor Adrenosterone as a suppressor of epithelial-mesenchymal transition and metastatic dissemination
- Authors
- Nakayama, J., Lu, J.W., Makinoshima, H., Gong, Z.
- ID
- ZDB-PUB-191122-2
- Date
- 2019
- Source
- Molecular cancer research : MCR 18(3): 477-487 (Journal)
- Registered Authors
- Gong, Zhiyuan, Lu, Jeng-Wei
- Keywords
- none
- MeSH Terms
-
- 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors*
- Androstenes/pharmacology*
- Animals
- Animals, Genetically Modified
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Breast Neoplasms/drug therapy
- Breast Neoplasms/enzymology
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Epithelial-Mesenchymal Transition/drug effects
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- MCF-7 Cells
- Neoplasm Metastasis
- Receptors, Estrogen/genetics
- Xenograft Model Antitumor Assays
- Zebrafish
- Zebrafish Proteins/genetics
- PubMed
- 31748280 Full text @ Mol. Cancer Res.
Citation
Nakayama, J., Lu, J.W., Makinoshima, H., Gong, Z. (2019) A novel zebrafish model of metastasis identifies the HSD11β1 inhibitor Adrenosterone as a suppressor of epithelial-mesenchymal transition and metastatic dissemination. Molecular cancer research : MCR. 18(3):477-487.
Abstract
Metastasis of cancer cells is multi-step process and dissemination is an initial step. Here we report a Tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of anti-metastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of epidermal growth factor receptor) transgenic zebrafish, which develops hepatocellular carcinoma, ~80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labelled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in five days through induction of an epithelial to mesenchymal transition (EMT). Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, Adrenosterone, an inhibitor for Hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in this model. Pharmacological and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through down-regulation of Snail and Slug, Adrenosterone-treated cells recovered expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of anti-metastasis drugs targeting metastatic dissemination of cancer cells. Implications: This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification some drugs to inhibit metastatic dissemination of human cancer cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping