Analysis of cancer early processes initiation in Xiphophorus melanoma
(Ansatze zur Analyse der Initiation von Initialprozessen der
Krebsbildung am Melanom-Modellvon Xiphophorus)
A. Anders, F. Anders, Ch. Zechel, U. Schleenbecker, A. Smith
Genetisches Institut der Justus-Liebig-Universitšt Giessen,
6300 Giessen, FRG and Dept of Chemical Pathology, University
College and Middlesex School of Medicine, London W1P 6DB, UK
Certain backcross hybrids (BC8-22) of a spotted X.maculatus
(platyfish) and a non-spotted X.helleri (swordtail; recurrent parent) are highly
sensitive to mutagenic carcinogens and, after a latent period of 8 to 12 months, develop
melanoma of unicellular origin thar is genealogically, related to the spots of the
platyfish. Sensitivity to the carcinogen or susceptibility to melanoma, respectively, are
inherited in a Mendelian fashion and can be assigned to a " tumor gene-complex"
(Tu-complex) consisting probably of aImost 20 genes. The Tu-complex is
located at the end of an autosome or sex chromosome, and is largely deregulated by
crossing conditioned replacement of platyfish chromosome carrying regulatory genes (tumor
suppressor genes, oncostatic genes, antioncogenes for the Tu-complex by swordtail
chromosomes lacking them.
The melanoma-free condition of these BC-hybrids depends upon the skin-specific regulatory gene Bs (body side) that requires impairment in a pigment cell precursor for the out-growlh of melanoma.
Structural mutations involving different breakpoints indicate that the signal for melanona formation comes from a particular region of the Tu-complex where an accessory v-erbB related oncogene (v-erbB*a; 85% homology to the human EGF receptor gene) is located. Northern blot analyses of a melanoma cell line showed an about 20-fold overexpression of x-erbB*a. Both the inositol lipid turnover ((3H)inositol incorporated into phosphoinositides), and the xiphophorine pp60x-src kinase activity that are assumed to be causally involved in tumor formation showed a remarkable elevation in the melanoma as compared to the normal tissue (brain) of the tumorous and non-tumorous (with or without the Tu-complex) segregants.
Other BC hybrids carrying the Tu-complex but lacking the linked regulatory gene develop melanoma "spontaneously". This kind of melanoma occurres early in the course of life, is of multicellular origin, and is inherited as a Mendelian character. In contrast to the BC hybrids requiring somatic mutation for melanoma formation, both inositol lipid turnover and x-src activity are remarkably enhanced in both melanoma and normal tissues.
A mutant of the latter BC hybrids carrying in addition to the Tu-complex the homozygous oncostatic gene g (g/g, "golden") that arrests pigment cell differentiation in the stem cell stage is incapable to develop melanoma spontaneously. Nevertheless it shows the elevation of inositol lipid turnover and x-src activity in its always healthy tissues. Following treatment with tumor promoters such as TPA and steroid hormones pigment cell differentiation recovers and melanoma of multicellular origin develops within 4 to 8 weeks. This kind of melanoma adopts the elevated inositol lipid turnover and x-src activity of the normal tissue.
Another mutant of the BC hybrids carrying a Tu-complex that has lost a distal gene coding for pigment cell differentiation but has retained the x-erb*a showed, although incapable of melanoma development, the same elevation of inositol lipid turnover and x-src activity in the brain.
In contrast, a phenotypic similar mutant of the BC hybrids that, in addition to the loss of information for pigment cell differentiation (and for melanoma development) has lost the erbB*a gene, shows a resting phosphoinositide inositol turnover and a resting pp60x-src kinase activity in the normal tissues.
Our results indicate an enhancement of phosphatidyl inositol lipid turnover and an elevation of pp60x-src kinase activity in all melanomas tested.
This elevation is intimately linked with the inheritance and probably with the expression of x-erbB*a. If this gene is present in the genome of the hybrids carrying the deregulated Tu-complex the proposed molecular and biochemical machinery
of melanoma formation may be running by genetic reasons with or without forming melanoma; whether melanoma develops or fails to develop, respectively, depends upon the presence or lack of cells competent for transformation. If, however, the machinery is resting because of the lack or control of x-erbB*a containing region of the Tu-complex, no melanoma develops irrespective of whether the competent cells are present or lacking. It appears that x-erbB*a, x-src, and inositol lipid turnover might be involved in key processes preceding melanoma formation in Xiphophorus.