A Novel Zebrafish Model of Metastasis Identifies the HSD11β1 Inhibitor Adrenosterone as a Suppressor of Epithelial-Mesenchymal Transition and Metastatic Dissemination.

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 antimetastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. 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. Pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation 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 antimetastasis 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 of some drugs to inhibit metastatic dissemination of human cancer cells.

• Authors: Joji Nakayama, Jeng-Wei Lu, Hideki Makinoshima, Zhiyuan Gong
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 18 Issue 3 Pg. 477-487 (03 2020) ISSN: 1557-3125 [Electronic] United States
• PMID: 31748280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Androstenes
• Basic Helix-Loop-Helix Transcription Factors
• Receptors, Estrogen
• Zebrafish Proteins
• twist1a protein, zebrafish
• adrenosterone
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 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, enzymology, genetics, pathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Liver Neoplasms (drug therapy, enzymology, genetics, pathology)
• MCF-7 Cells
• Neoplasm Metastasis
• Receptors, Estrogen (genetics)
• Xenograft Model Antitumor Assays
• Zebrafish
• Zebrafish Proteins (genetics)