Ozato K, Wakamatsu Y
Differentiation. 1983;24(3):181-90. doi: 10.1111/j.1432-0436.1983.tb01318.x.
Melanoma occurring spontaneously in Xiphophorus fish hybrids is a model system in which involvement of cellular oncogenes and multi-step regulation of their expression have been identified by classical genetics. The macromelanophore gene in platyfish (Xiphophorus maculatus) is a sex-linked codominant gene which determines the black spot patterns of macromelanophores in the skin. The macromelanophore locus includes a cellular oncogene which potentially induces neoplasms of the pigment cells. Expression of the oncogene is regulated by a multi-step genetic process and brings about a characteristic phenotype associated with pigment cell differentiation at each step. The multi-step genetic regulation of oncogene expression can be recognized by interspecific hybridization of the platyfish with swordtails (Xiphophorus helleri) which have not developed the macromelanophore gene. When platyfish are hybridized with swordtails, the F1 offspring carrying this gene develop a preneoplastic state. When the F1 offspring are back-crossed to swordtails, the backcross offspring develop a heritable form of melanoma with a characteristic inheritance pattern. This heritable form of melanoma occurs at an early age and has a well differentiated character. Thus, the first and second steps of oncogene expression bring about a preneoplastic state in the F1 offspring and a heritable form of melanoma in the backcross offspring, respectively. These steps may be due to progressive substitution of platyfish chromosomes with swordtail chromosomes in germ line cells, resulting in a progressive reduction of the dosage of regulatory genes in the platyfish genome. The third step of oncogene expression brings about a sporadic form of melanoma in the hybrid offspring bearing the preneoplastic state and heritable form of melanoma spontaneously or through induction by carcinogens. This form of melanoma has a poorly differentiated character. The incidence of this form is considerably enhanced by aging in adult life, thus exhibiting age-specific incidence. It is likely that this step is due to mutational events in regulatory genes, which occur in somatic cells following chromosome substitution in germ line cells by hybridization. The albino gene enhances the malignancy of the two forms of melanoma and the incidence of the sporadic form of melanoma, possibly by suppressing the differentiation of transformed pigment cells. These facts and speculations are summarized in Fig. 6. The molecular identification of oncogenes in this melanoma system and their transfer into the swordtail eggs may provide a useful means for studying oncogene expression during development, growth, and aging of animals.
剑尾鱼杂交后代中自发产生的黑色素瘤是一个模型系统，通过经典遗传学已确定细胞癌基因的参与及其表达的多步骤调控。月光鱼（Xiphophorus maculatus）中的大黑色素细胞基因是一个性连锁共显性基因，它决定了皮肤中大黑色素细胞的黑斑模式。大黑色素细胞基因座包含一个细胞癌基因，该基因可能诱导色素细胞肿瘤。癌基因的表达受多步骤遗传过程调控，并且在每个步骤都会产生与色素细胞分化相关的特征性表型。癌基因表达的多步骤遗传调控可以通过月光鱼与未发育出大黑色素细胞基因的剑尾鱼（Xiphophorus helleri）的种间杂交来识别。当月光鱼与剑尾鱼杂交时，携带该基因的F1代后代会发展为癌前状态。当F1代后代与剑尾鱼回交时，回交后代会发展出具有特征性遗传模式的可遗传性黑色素瘤。这种可遗传性黑色素瘤在幼年时出现，具有高度分化的特征。因此，癌基因表达的第一步和第二步分别在F1代后代中导致癌前状态，在回交后代中导致可遗传性黑色素瘤。这些步骤可能是由于种系细胞中月光鱼染色体被剑尾鱼染色体逐渐取代，导致月光鱼基因组中调控基因的剂量逐渐减少。癌基因表达的第三步在具有癌前状态和可遗传性黑色素瘤的杂交后代中自发地或通过致癌物诱导产生散发性黑色素瘤。这种形式的黑色素瘤具有分化不良的特征。这种形式的发病率在成年后会因衰老而显著增加，从而表现出年龄特异性发病率。很可能这一步骤是由于调控基因中的突变事件，这些事件发生在种系细胞通过杂交进行染色体取代后的体细胞中。白化基因可能通过抑制转化色素细胞的分化来增强两种形式黑色素瘤的恶性程度以及散发性黑色素瘤的发病率。这些事实和推测总结在图6中。在这个黑色素瘤系统中对癌基因进行分子鉴定并将其导入剑尾鱼卵中，可能为研究动物发育、生长和衰老过程中的癌基因表达提供一种有用的方法。
