Abstract
A quantitative bio-imaging platform is developed for analysis of human cancer dissemination in a short-term vertebrate xenotransplantation assay. Six days after implantation of cancer cells in zebrafish embryos, automated imaging in 96 well plates coupled to image analysis algorithms quantifies spreading throughout the host. Findings in this model correlate with behavior in long-term rodent xenograft models for panels of poorly- versus highly malignant cell lines derived from breast, colorectal, and prostate cancer. In addition, cancer cells with scattered mesenchymal characteristics show higher dissemination capacity than cell types with epithelial appearance. Moreover, RNA interference establishes the metastasis-suppressor role for E-cadherin in this model. This automated quantitative whole animal bio-imaging assay can serve as a first-line in vivo screening step in the anti-cancer drug target discovery pipeline.
Highlights
Traditional anti-cancer drug screens are performed using cell lines grown in 2D culture or using in vitro protein binding assays
ZF embryos that are used for this purpose lack an adaptive immune system, which increases the success of xenotransplantation while they provide a microenvironment where human tumor cells proliferate, migrate, form tumor masses, and stimulate angiogenesis [5,6,7,8]
Automated image capturing and pre-processing CMDiI-labeled tumor cells were injected in the yolk sac of 2
Summary
Traditional anti-cancer drug screens are performed using cell lines grown in 2D culture or using in vitro protein binding assays. Cancer progression is a complex process of dynamic interactions between cancer cells and the organism that involves genetic alterations leading to deregulated survival and proliferation, angiogenesis, invasion, and metastasis [1]. Genetic mouse models for cancer and human tumor cell xenotransplantation models in rodents remain essential, such systems are costly, slow, and less amenable to highthroughput assays for cancer drug target discovery. There is a clear need to develop fast, semi-automated in vivo systems for medium to high-throughput screening applications in preclinical target discovery and lead compound identification. In this respect, zebrafish (ZF) offer a number of unique advantages for investigating the mechanisms that drive cancer formation and progression. ZF embryos that are used for this purpose lack an adaptive immune system, which increases the success of xenotransplantation while they provide a microenvironment where human tumor cells proliferate, migrate, form tumor masses, and stimulate angiogenesis [5,6,7,8]
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