Backcross hybrids

(four genotypes resulting in three phenotypes) melanoma melanosis no macromelanophores x-erb B*a/- x-erb B*a/- -/- -/-

Fig. 3.6. Inheritance of melanoma in hybrids of southern platyfish and swordtails. Fish with the x-erbB*a (Xmrk) oncogene have macromelanophores, but the promoter of this oncogene is repressed by the locus RDtff. Hybrids (F1 hybrids and some backcross hybrids) that are heterozygous for Rm and carry x-erbB*a have melanosis and sometimes develop melanoma when they are adults. Melanomas occur in very young backcross hybrids carrying the oncogene but lacking Rd^. (Based on Vielkind, 1976; A. Anders and Anders, 1978; Wakamatsu, 1980; Schartl and Adam, 1992; Zechel et al, 1992; Adam et al, 1993.)

The melanomas in Xiphophorus are caused by a dominant tumour locus known as Tu (Ahuja and Anders, 1976; Vielkind, 1976). Several genes that regulate the cell type affected and portion of the body in which neoplasms develop are located on the same chromosome (F. Anders et al., 1984). The Tu locus consists of macromelanophore-determining gene(s) and a v-erbB related sequence, designated x-erbB*a (Zechel et al., 1988, 1992) or Xmrk (Wittbrodt et al., 1989; Adam et al., 1991; Schartl and Adam, 1992), which is overexpressed in melanomas (Mäueler et al., 1988; Zechel et al., 1988; Adam et al., 1991; Wittbrodt et al., 1992). The x-erbB*a gene in the Tu locus is a translocated (or accessory) copy of the original x-erbB*i gene, which is indispensable or invariably present (Schartl and Adam, 1992; Zechel et al., 1992). The original x-erbB*i gene (also termed INV-Xmrk or Xmrk-1) has characteristics of a proto-oncogene (Schartl, 1990). The x-erbB*a gene (or Xmrk) is closely related but not equivalent to the epidermal growth factor receptor gene (Wittbrodt et al., 1989; Zechel et al., 1992). This gene is also overexpressed in spontaneous melanomas of nonhybrid Xiphophorus (Schartl et al., 1995).

A model to explain the occurrence of melanomas in Xiphophorus hybrids was proposed by F. Anders (1967). The distinctive feature of this model (Fig. 3.6) is a non-sex-linked locus RW (also designated Diff or R) that represses melanoma formation by inducing differentiation of macromelanophores (Vielkind, 1976; A. Anders and Anders, 1978). In wild fish, macromelanophores are completely differentiated and do not become neoplastic; the development of neoplasms requires that differentiation does not occur. The regulating locus RDiff can also be considered an anti-oncogene locus (Schartl, 1990). Although presentations of this model usually imply that the RDiff locus is absent from the swordtail, there may be species-specific Rdig loci in all species of Xiphophorus (Morizot etal., 1991). Adam etal. (1993) suggested that an unrelated locus (D) was the physiological target for the repressor locus, and that the translocated oncogene x-erbB*a accidentally acquired the promoter for the D locus.

Hybrids that are heterozygous for both the x-erbB*a oncogene and the regulatory locus Rag (F1 hybrid in Fig. 3.6) develop melanosis soon after birth (Gordon, 1958; Atz, 1962; Ozato and Wakamatsu, 1981). This condition has been termed premelanoma (Vielkind, 1976) or 'benign melanoma' (A. Anders and Anders, 1978; F. Anders et al., 1984) by some authors. Melanotic areas have melanocytes that are less differentiated than normal macromelanophores (Vielkind, 1976), and the location of melanosis is related to the location of the pigment pattern on the parent (Gordon, 1931). After these F1 hybrids are several months old, age-dependent melanomas often develop in the adult fish (F. Anders, 1967; Wakamatsu, 1980; Ozato and Wakamatsu, 1981). In melanomas that develop in adults, invasive neoplastic cells are sparsely pigmented, the neoplastic mass grows to a large size, and the fish usually dies within two months (Wakamatsu, 1980). The neoplastic cells are less differentiated than in melanomas that develop earlier in life in certain backcross hybrids of Xiphophorus (Esaka et al., 1981).

Backcross hybrids (Fig. 3.6) that carry the x-erbB*a oncogene and are homozygous for the absence of the repressor gene RDiff develop melanomas before birth or soon after birth (Gordon, 1937; Gordon and Smith, 1938; Wakamatsu, 1980). Initially located in the dermis, neoplastic cells infiltrate the adjacent muscle and spread through most outer portions of the body, causing destruction of fin rays and muscle (Gordon and Smith, 1938; Esaka et al., 1981). Invasion of myomeres extends inward to the vertebrae; however, mitotic figures are infrequent and metastasis has not been reported. In addition, melanomas similar to the type that occurs in F1 hybrids also develop in some adult backcross hybrids that already have early onset melanoma.

Amelanotic melanomas occur if an albino swordtail is mated with an appropriate F1 hybrid (Fig. 3.6). Compared with pigmented melanomas, amelanotic melanomas grow more rapidly, have more DNA, and contain less-differentiated melanocytes (Vielkind et al., 1971; Esaka et al., 1981).

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