September 2014

Models of Transparency

Models of Transparency

Heath, J.K. Langenau, D. Sadler, K.C. and White, R. (2013) Models of Transparency. The Scientist.

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Researchers are taking advantage of small, transparent zebrafish embryos and larvae—and a special strain of see-through adults—to understand the development and spread of cancer.

The zebrafish model offers a major opportunity to discover impor­tant pathways underlying cancer and to identify novel therapies in high-throughput drug screens, in a way that mice never could.

From frogs to dogs and people, cancer wreaks havoc across the animal kingdom—and fish are no exception. Coral trout, for example, develop melanoma from overexposure to sun, just as humans do. Rainbow trout develop liver cancer in response to environmental toxins. And zebrafish—small, striped fish indigenous to the rivers of India and a widely used model organism—are susceptible to both malignant and benign tumors of the brain, nervous system, blood, liver, pancreas, skin, muscle, and intestine.

Importantly, tumors that arise in the same organs in humans and fish look and behave alike, and the cancers often share common genetic underpinnings. As a result, most researchers believe that the basic mechanisms underlying tumor formation are conserved across species, allowing them to study the formation, expansion, and spread of tumors in animal models with the hope of eventually finding new insights into cancer in people.

Zebrafish are an increasingly popular choice among cancer biologists. Between 1995 and 2012, there was a 10-fold increase in the number of yearly PubMed citations of cancer studies in the species, with more than 200 research papers published last year.  Although dwarfed by cancer studies using human tissue and mouse models, the optical transparency of zebrafish embryos and larvae—and now, adult fish of a recently created strain—allows researchers to track tumors in a way that is not possible in other vertebrate models. Furthermore, their small size—embryos are small enough to be reared in 96-well plates—make them a more practical laboratory system than other cancer models. Indeed, researchers are now using these fish to identify druggable oncogenic drivers of specific tumor types, to tease apart the complex network of cancer genes that cooperate in tumor formation and progression, to probe the interplay between the genes that govern embryonic development and those that cause cancer, and to uncover how tumors metastasize and kill their host. The zebrafish model offers a major opportunity to discover important pathways underlying cancer and to identify novel therapies in high-throughput drug screens in a way that mice never could.

Z ebrafish (Danio rerio) have fast made their way from pet stores and home aquaria into research laboratories worldwide. Their weekly matings produce 100 to 200 embryos that rapidly and synchronously march through embryonic development, so that within 5 days of fertilization, they are mature, feeding larvae. Zebrafish are small and inexpensive to maintain in high numbers, facilitating large-scale experimentation and cheap in vivo drug screens. Famously, the fish are transparent during early larval stages, allowing investigators to directly observe internal development and making the fish a favorite of developmental biologists since the 1960s. But in recent years, the utility of zebrafish has been proven beyond developmental fields, and they are now being found in more and more laboratories studying behavior, diabetes, heart disease, regeneration, stem cell biology—and cancer.

Critically, zebrafish can be used to identify the important pathways and processes that cause cancer in people. Common organ systems and cell types are shared between human and zebrafish, and whether induced by transgenesis or carcinogens, cancers arising from the blood (leukemia and lymphoma), pigmented cells of the skin (melanoma), and the cells that line the bile ducts (cholangiocarcinoma) have microscopic features that are essentially indistinguishable between humans and zebrafish.

The zebrafish model offers a major opportunity to discover impor­tant pathways underlying cancer and to identify novel therapies in high-throughput drug screens, in a way that mice never could.

Comparing gene-expression profiles of tumors across various species provides a powerful mechanism for identifying genes that likely represent core functions of cancer. For example, microarray gene-expression analyses have compared the gene signatures of fish hepatocellular carcinoma to that of human liver, gastric, prostate, and lung tumors. Remarkably, this analysis revealed that fish and human liver tumors are more similar to each other than either tumor type is to human tumors derived from different tissues. Moreover, comparative studies can often be used to pinpoint pathways that are active in human disease. This is illustrated by work on a zebrafish model of rhabdomyosarcoma (RMS), a cancer of skeletal muscle, which revealed a gene signature that is also commonly found in human RMS, highlighting the importance of the RAS signaling pathway in the genesis of human RMS

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