Zebrafish provides cancer researchers powerful new insights into the development of malignant melanoma

The embryo of a tiny, silvery tropical fish found in many home aquariums is providing cancer researchers at Northwestern University Feinberg School of Medicine with powerful new insights into the development of malignant melanoma, the deadliest form of skin cancer.

In a study described in an article in the August issue of Developmental Dynamics, the laboratory groups of Mary J. C. Hendrix, at Feinberg, and of Robert A. Cornell, at The University of Iowa Carver College of Medicine, showed that zebrafish embryos implanted with human metastatic melanoma cells provide molecular cues that suppress tumor development.

Hendrix is president and scientific director of the Children's Memorial Research Center, professor of pediatrics at Feinberg and a member of the executive committee of The Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Lisa M. J. Lee is the lead author on the study, and is a graduate student in the Hendrix laboratory.

The researchers found that fluorescently tagged human metastatic melanoma cells placed in the zebrafish embryo survive, are motile and divide. The melanoma cells do not form tumors in the embryonic microenvironment. Instead, they maintain their plastic phenotype, expressing genes that are characteristic of various cell types, including endothelial, neural and stem cells, and scatter throughout various spaces in the embryo.

One of the hallmarks of aggressive cancer cells, including malignant melanoma, is their unspecified, plastic nature, which is similar to that of embryonic stem cells, Hendrix explained.

The Hendrix lab has hypothesized that the unspecified or poorly differentiated phenotype serves as an advantage to cancer cells by enhancing their ability to migrate, invade and metastasize virtually undetected by the immune system.

Results of the group's earlier studies in mice led them to wonder whether malignant melanoma cells might respond to environmental cues present in an embryo model. They chose the zebrafish embryo, which is easily accessible and transparent and has been applied to the study of human cancer.

The group questioned whether, despite an evolutionary distance of more than 300 million years separating zebrafish from humans, the zebrafish embryo might contain cues that could influence the behavior of human metastatic melanoma cells.

As in Hendrix's previous studies using other laboratory models, the current study showed that within the zebrafish embryo, metastatic melanoma cells retain their plastic phenotype; that is, the zebrafish microenvironment appears to suppress the tumor-forming abilities of malignant melanoma cells.

"The significance of this study is the potential offered by the zebrafish embryonic model to identify the tumor suppressive signals in the microenvironment that result in the reversal of the metastatic behavior of the tumor cells," Hendrix stated.

The researchers also found that human melanocytes (normal skin cells that contain melanin and may transform into cancerous melanoma tumors) transplanted into zebrafish embryos most frequently became distributed to the normal microenvironment of the skin.

This finding suggested that the zebrafish embryo contains possible homing cues that can be interpreted by normal human cells. Results of this study demonstrate the utility of the zebrafish embryonic model for the study of tumor cell plasticity and suggest that this experimental paradigm can be a powerful one in which to investigate tumor-microenvironment interactions leading to the reversal of the aggressive phenotype of tumor cells.