Abstract
Animal models play important roles in investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic tools. Despite rapid progress in the understanding of disease mechanisms and technological advancement in drug discovery, negative trial outcomes are the most frequent incidences during a Phase III trial. Skin cancer is a potential life-threatening disease in humans and might be medically futile when tumors metastasize. This explains the low success rate of melanoma therapy amongst other malignancies. In the past decades, a number of skin cancer models in fish that showed a parallel development to the disease in humans have provided important insights into the fundamental biology of skin cancer and future treatment methods. With the diversity and breadth of advanced molecular genetic tools available in fish biology, fish skin cancer models will continue to be refined and expanded to keep pace with the rapid development of skin cancer research. This review begins with a brief introduction of molecular characteristics of skin cancers, followed by an overview of teleost models that have been used in the last decades in melanoma research. Next, we will detail the importance of the zebrafish (Danio rerio) animal model and other emerging fish models including platyfish (Xiphophorus sp.), and medaka (Oryzias latipes) in future cutaneous malignancy studies. The last part of this review provides the recent development and genome editing applications of skin cancer models in zebrafish and the progress in small molecule screening.
Highlights
Skin cancer, which includes squamous cell carcinoma (SCC) and melanoma, represents the most common type of cutaneous malignancy around the world and incidence rates are continuing to increase [1]
Exome sequencing in melanoma with high heterogeneity has identified a large catalogue of recurrent somatic variants, which were found to be mostly within the B-Raf proto-oncogene, serine/threonine kinase (BRAF) and Neuroblastoma RAS viral oncogene homolog (NRAS) genes [6]
BRAF (V600E) expression leads to melanoma on a tp53 mutant background Zebrafish melanoma model used for functional genetic screens to identify new oncogenes Genetic modulation of mitf leads to melanoma regression Zebrafish melanoma model used to screen for novel anti-melanoma drugs Transgenic expression of NRAS (Q61K) leads to melanomas Harvey Rat Sarcoma (HRAS) acts through PI3K signaling to induce melanoma HRAS expression in kit-expressing cells lead to highly penetrant and invasive phenotypes Co-activation of c-myc and cdc6 in zebrafish skin to induce skin cancer formation
Summary
Skin cancer, which includes squamous cell carcinoma (SCC) and melanoma, represents the most common type of cutaneous malignancy around the world and incidence rates are continuing to increase [1]. There has been an increasing number of application of fish used as human disease models, especially in melanoma research. It is well-known that humans and fish share very few differences at the molecular level [11]. Some aspects may diverge, such as the evolution of human chromosome 17 mapped to zebrafish Linkage group (LG) 3, 5, 12, and 15, which suggests an ancestral rearrangement [13] Another key feature of using the fish is to combine developmental biology with the power of genetics, whereby transgenic lines can produce insightful results. It is feasible to perform high-throughput approaches in fish models, such as whole genome mutagenesis and chemical library drug screening [14,15]
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