Zebrafish Hagoromo Mutants Up-Regulate fgf8 Postembryonically and Develop Neuroblastoma

Abstract

We screened an existing collection of zebrafish insertional mutants for cancer susceptibility by histologic examination of heterozygotes at 2 years of age. As most mutants had no altered cancer predisposition, this provided the first comprehensive description of spontaneous tumor spectrum and frequency in adult zebrafish. Moreover, the screen identified four lines, each carrying a different dominant mutant allele of Hagoromo previously linked to adult pigmentation defects, which develop tumors with high penetrance and that histologically resemble neuroblastoma. These tumors are clearly neural in origin, although they do not express catecholaminergic neuronal markers characteristic of human neuroblastoma. The zebrafish tumors result from inappropriate maintenance of a cell population within the cranial ganglia that are likely neural precursors. These neoplasias typically remain small but they can become highly aggressive, initially traveling along cranial nerves, and ultimately filling the head. The developmental origin of these tumors is highly reminiscent of human neuroblastoma. The four mutant Hagoromo alleles all contain viral insertions in the fbxw4 gene, which encodes an F-box WD40 domain-containing protein. However, although one allele clearly reduced the levels of fbxw4 mRNA, the other three insertions had no detectable effect on fbw4 expression. Instead, we showed that all four mutations result in the postembryonic up-regulation of the neighboring gene, fibroblast growth factor 8 (fgf8). Moreover, fgf8 is highly expressed in the tumorigenic lesions. Although fgf8 overexpression is known to be associated with breast and prostate cancer in mammals, this study provides the first evidence that fgf8 misregulation can lead to neural tumors. (Mol Cancer Res 2009;7(6):841-50)

Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers

“…The fgf gene family contains many members, but in mammals they can all bind to four FGF receptors, members of the receptor tyrosine kinase superfamily, suggesting that they might have similar ability to signal through common MAP-kinase signaling pathways. Although we do not have a mutant line of fish that overexpresses fgf6a, a mutant line designated Hag D1 overexpresses fgf8a as a result of a retroviral insertion (25). This line develops large neuroblastomas at a low frequency and rarely before 1 y of age (25).…”

Zebrafish Models for Human Cancer

“…39 Although the use of forward genetic screens to develop cancer models is not typical in traditional animal models, multiple zebrafish cancer models have been successfully derived by this method. 4,5,32,73,97,98 In some cases, this approach has identified novel genes with a previously unknown or poorly defined link to cancer susceptibility. 4,97,98 Multiple chemical carcinogens have been studied in fish species to determine their efficacy in fish, to model human carcinogen exposure, and to assess environmental toxins.…”

“…4,5,32,73,97,98 In some cases, this approach has identified novel genes with a previously unknown or poorly defined link to cancer susceptibility. 4,97,98 Multiple chemical carcinogens have been studied in fish species to determine their efficacy in fish, to model human carcinogen exposure, and to assess environmental toxins. 7,11,56,104,105 The most common routes of carcinogen exposure in zebrafish are aqueous and dietary.…”

“…4 In all 4 lines, retroviral integration resulted in activation of an upstream gene, fibroblast growth factor 8 (fgf8). 4 The role for fgf8 in neoplastic transformation or progression is unclear but may promote progenitor cell proliferation or survival. 4 There are very few models for tumors of neuroendocrine origin in zebrafish (Table 6).…”

“…4 The role for fgf8 in neoplastic transformation or progression is unclear but may promote progenitor cell proliferation or survival. 4 There are very few models for tumors of neuroendocrine origin in zebrafish (Table 6). A single zebrafish model for pituitary corticotroph adenoma has been described.…”