Xiphophorus maculatus

The platyfish Xiphophorus maculatus (photo courtesy of Manfred Schartl, Würzburg)

Xiphophorus is a freshwater fish genus belonging to the family Poeciliidae like the guppies (Poecilia reticulata) and mollies (Poecilia latipinna). The name Xiphophorus itself derives from the Greek words xiphos (sword) and phoros (bearer). Xiphophorus includes 23 species that live in eastern drainages in Mexico, Guatemala, Belize and Honduras and are classified into Northern swordtails, Southern swordtails and platyfishes. Xiphophorus are live-bearers, meaning that females retain the eggs inside the body and give birth to live, free-swimming young fishes. More precisely, Xiphophorus is ovoviviparous: while eggs are retained inside the body of the female for protection, they are essentially independent of the mother and she does not provide them with any nutrients. Xiphophorus is very popular (the definition of Xiphophorus by P. Desproges) and commonly reared by aquarium hobbyists.

Hereditary melanoma and sex-chromosomal cancer genes in Xiphophorus

Fig2.: Crossing scheme showing the segregation of Tu (tumour locus) and R (regulatory locus) in Xiphophorus interspecific hybrids. The crossing depicted here is the so-called “Gordon-Kosswig” model, where the platyfish X. maculatus and the swordtail X. hellerii are used as parental fishes.

Melanoma are among the most aggressive forms of human cancer. In the 1920’s, it was realized by scientists in Germany and the USA that melanoma can occur without any exogenous treatment in Xiphophorus simply by crossing different species, for example the platyfish Xiphophorus maculatus and the swordtail Xiphophorus hellerii (Fig. 2). These melanomas are derived from dysregulated melanin-producing pigment cells called the macromelanophores. Subsequently, Xiphophorus became a well-established model for the study of hereditary cancer.

In Xiphophorus, melanoma development is induced by generating a regulatory imbalance between a dominant sex chromosomal tumour-inducing locus (Tu) and an autosomal Tu-repressing regulatory locus (R), which are present in the platyfish but absent from the swordtail. The presence of R and Tu on different chromosomes allow for their separation through selective breeding. When X. maculatus is crossed with X. hellerii, the F1 progeny is heterozygous for both R and Tu. Further crossing of F1 animals with X. hellerii produces 25% offspring heterozygous for the Tu locus, but devoid of R. In this situation, Tu is out of control in pigment cells, where it is overexpressed and performs its oncogenic function. This results in the formation of highly malignant, invasive and exophytic melanomas, which are generally fatal to the fish.

Xmrk, the gene responsible for tumour development at the Tu locus, encodes a subclass I receptor tyrosine kinase belonging to the epidermal growth factor receptor (Egfr) family (Wittbrodt et al. 1989, Nature 341:415). The Xmrk oncogene was generated through duplication of the egfrb proto-oncogene early during the evolution of the genus Xiphophorus (Adam et al. 1993, Science 259:816). Compared to its proto-oncogenic counterpart, Xmrk displays a completely new transcriptional regulation as well as activating mutations conferring a ligand-independent constitutive activity to the receptor. Xmrk and egfrb are located in the subtelomeric region of the sex chromosomes of X. maculatus. Both genes are closely linked to the master sex-determining gene SD of the platyfish on the X and Y chromosomes. Xmrk is potentially hazardous, non-essential and located in a very unstable genomic region. Nevertheless, Xmrk has been maintained functional in divergent Xiphophorus species. Hence, Xmrk has probably a beneficial function under certain conditions. The analysis of this function is a major challenge for future research in the Xiphophorus model.

Another sex-chromosomal locus of high relevance for the formation of melanoma in Xiphophorus is Mdl, the macromelanophore-determining locus. Macromelanophores are large melanin-containing cells that produce highly polymorphic pigment patterns. They are the cellular progenitors of Xmrk-induced melanomas. Mdl determines not only the phenotype of macromelanophore patterns, but also, probably in combination with Xmrk, the location, onset and malignancy of melanoma. Therefore, Mdl can be defined as a tumour modifier. Mdl is intimately linked to Xmrk but has not been identified so far at the molecular level.