ANIMAL MODEL OF HUMAN DISEASE
Nialignant Mfelanoma Animal: Hereditary Malignant Nelanomas in Platv,/Swordtail Hybrids
Contributed by: Harold J. Sobel, MD, Eugene Marquet, MS, Klaus D. Kallman, PhD, and Glenna J. Corley, MD, Department of Pathology, East Orange General Hospital, East Orange, New Jersey, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, Genetics Laboratory, Osborn Laboratories of Marine Sciences, New York Zoological Society at The Aquarium, Coney Island, and the Department of Pathology, Lenox Hill Hospital, New York, New York.
Bioogic Features
Haiissler.' Koss%vig,2 and Reed and Gordon 3 described invasive melanomas w-hich could be produced readilv in fish of the genus Xiphophorus (platy/swordtail hybrids) by following specific breeding regimes. These lesions have been subjected to detailed study which has been discussed bv Gordon,4 Anders,5 and Sobel et a.6 in reviews. All populations of platy fish (X. maculatus) are polymorphic for a variety of sex-linked codominant macromelanophore factors which, within their pool of modifier genes, give rise to specific pigment patterns. When any of these pigment genes are introduced through hybridization into a foreign genome (svordtail, X. helleri) the expression of the macromelanophore gene is greatly enhanced by a deficiency in modifier genes first leading to melanosis and finally to invasive melanomas. Not onlv is the site of the melanoma predictable in most instances, but so is its pigmentation. When an albino swordtail (one homozygous for the recessive albinism gene) is used as one of the parents, and the melanotic, heterozvgous F1 hybrids are backcrossed to an albino swordtail, half of their offspring develop amelanotic melanomas. Hereditary pigment cell abnormalities in Xiphophorus may also occur in other species combinations, in some interpopulation hybrids of X. nmaculatus, and with mutations including those induced by X-irradition. In hybrids, the macromelanophores proliferate. This may be present as Publication sponsored by the Registry of Comparatise
Pathology of the Armed Forces Institute of
Pathology and supported by Public Health Service Grant RR 00301 from the Division of Research
Resources. L-S Department of Health. Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. Address reprint requests to Dr. Harold J. Sobel. Department of Pathology. East Orange General Hospital. :300 Central Avenue, East Orange. NJ 07019. 441
SOBEL EL AL
442
American Journal of Pathology
\
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4m
a
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Figure 1-A melanomatous platy/swordtail hybrid with deeply pigmented tumorous involvement of the distal half of the body, including dorsal and caudal fins. Figure 2-Melanomatous involvement of corium and myoseptae with infiltration by deeply pigmented tumor cells between muscle bundles is shown (H&E, x 35). Figure 3-Melanoma cell with prominent melanosomes and compound Inset-A somewhat elongated developing pigment granule; note the melanosomes (X 12,200). deposition of electron-dense material over a crystalline lattice enclosed in a dilated sac of endoplasmic reticulum (X 58,600).
Vol. 82, No. 2 February 1976
MALIGNANT MELANOMA
443
Figures 4-7-Electron micrographs illustrating the development of the more common oval pigment 4-Note a single unit membrane-delimited body adjacent to the actively budding granules. Golgi apparatus that contains small vesicles resembling the Golgi vesicles. Some contain electron5-A structure similar to that in 4, but containing more electrondense material. (X 34,200) 6-This electron micrograph shows similar structures dense material, is shown (X 34,200). 7-The fusion of the electron-dense granules seen in 6 containing more pigment (X 39,600). forms the mature pigment granules (X 31,200).
early as the day of birth. At first they replace the normal corial and subcutaneous tissues. Then myoseptae are invaded from the subcutaneous tissue until a continuous replacement of the connective tissue from the corium to the central body mass occurs (Figures 1 and 2). Later masses of small, pigmented spindle cells with prominent mitotic activity (melanocytes) appear (Figures 3). Once they begin to grow-, there is tumorous development (Figure 1) with almost complete disappearance of the melanophores, and the fish succumb rapidly. WN"e feel that a reasonable explanation for this process is that, as the melanomatous process intensifies, melanocvtes multiply so rapidly that they are unable to differentiate into melanophores. With the electron microscope the tumors are found to be composed of a dense mesh-ork of cells infiltrating the adjacent tissues. Nlacromelanophores and melanocvtes are found to differ only in size and shape, although most macromelanophores contain more pigment and are thought to be older, more mature cells. Most melanin granules in these tumors are produced by the clumping of electron-dense particles in oval sacs of endoplasmic reticulum. These particles appear to be transported to the sacs at least in part via Golgi vesicles (Figures 4-7). Less common, more elongated granules appear to form by the deposition of electron-dense material on a crystalline matrix (Figure :3, inset). Later, these granules coalesce to form compound melanosomes (autophagic vacuoles) (Figure 3).
SOBEL EL AL
444
American Journal of Pathology
Comparisn With Human Disease
Fish melanomas are very similar to those of man. They differ most noticeably in that they contain melanophores and produce melanin granules in tw o -ays, wvith only few being produced by the deposition of electron-dense material on a crystalline matrix as in man. Fish melanomas are more uniformly invasive and destructive than their human counterpart. They are composed of more closely spaced cell groups and lack the irregular villous projections, junctional change, and desmosomes seen in human lesions. Wre have been unable to demonstrate microtubules in fish melanoma cells. Potential Usefukess of nTis Mod
Fish are commonly affected by melanomas as well as other neoplastic diseases that are often very similar to their human counterparts.7 Much can be gained from study of these lesions because of the ease with which the fish can be obtained and kept due to the large numbers of offspring, short gestational period, and ease of handling. These factors certainly facilitate genetic experiments as well as studies that require large numbers of relatively homogeneous animals. Availabit
At present, melanomatous fish are being bred and studied by one of us-Dr. Klaus D. Kallman, Genetics Laboratorv, Osborn Laboratories of Marine Sciences, New York Zoological Society at the Aquarium, Coney Island, NY 11224. References Uber melanombildungen bei bastarden von xiphophorus hellerii und Platypoecilus nmculatus var rubra. Klin \Wochenschrift 7:1561. 1928 Kosswig CZ: (ber geschw-ulstbildungen bei fischbastarden. Indukt Abstamm Vererbangst 39:61. 1931 Reed HD. Gordon 4: The morphology of melanotic overgrow-ths in hybrids of Mexican killifishes: A preliminary account. Am J Cancer 13:1324. 1931 Gordon M: The melanoma cell as an incompletely differentiated pigment cell. Pigment Cell Biology. Edited by \1 Gordon. New York, Academic Press. 1939. p 213 Anders F: Tumor formation in platyfish-swordtail hybrids as a problem of gene regulation. Experentia 2:3:1. 1967 Sobel HJ. Marquet E Kallman KD. Corley GJ: Melanomas in platy swordtail h-brids. The Pathology of Fishes. Edited by WN'E Ribelin. G Migaki. Madison. W'isconsin. Universitv of Wisconsin Press 1973, p 945 Scarpelli DG: Comparative aspects of neoplasia in fish and other laboratory animals. Fish In Research. Edited bv OW 'Newhaus. JE Halver. New York, Academic Press. 1969. p 43
1. Haussler G:
2.
:3. 4.
,. 6.
7.
Nialignant Mfelanoma Animal: Hereditary Malignant Nelanomas in Platv,/Swordtail Hybrids
Contributed by: Harold J. Sobel, MD, Eugene Marquet, MS, Klaus D. Kallman, PhD, and Glenna J. Corley, MD, Department of Pathology, East Orange General Hospital, East Orange, New Jersey, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, Genetics Laboratory, Osborn Laboratories of Marine Sciences, New York Zoological Society at The Aquarium, Coney Island, and the Department of Pathology, Lenox Hill Hospital, New York, New York.
Bioogic Features
Haiissler.' Koss%vig,2 and Reed and Gordon 3 described invasive melanomas w-hich could be produced readilv in fish of the genus Xiphophorus (platy/swordtail hybrids) by following specific breeding regimes. These lesions have been subjected to detailed study which has been discussed bv Gordon,4 Anders,5 and Sobel et a.6 in reviews. All populations of platy fish (X. maculatus) are polymorphic for a variety of sex-linked codominant macromelanophore factors which, within their pool of modifier genes, give rise to specific pigment patterns. When any of these pigment genes are introduced through hybridization into a foreign genome (svordtail, X. helleri) the expression of the macromelanophore gene is greatly enhanced by a deficiency in modifier genes first leading to melanosis and finally to invasive melanomas. Not onlv is the site of the melanoma predictable in most instances, but so is its pigmentation. When an albino swordtail (one homozygous for the recessive albinism gene) is used as one of the parents, and the melanotic, heterozvgous F1 hybrids are backcrossed to an albino swordtail, half of their offspring develop amelanotic melanomas. Hereditary pigment cell abnormalities in Xiphophorus may also occur in other species combinations, in some interpopulation hybrids of X. nmaculatus, and with mutations including those induced by X-irradition. In hybrids, the macromelanophores proliferate. This may be present as Publication sponsored by the Registry of Comparatise
Pathology of the Armed Forces Institute of
Pathology and supported by Public Health Service Grant RR 00301 from the Division of Research
Resources. L-S Department of Health. Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. Address reprint requests to Dr. Harold J. Sobel. Department of Pathology. East Orange General Hospital. :300 Central Avenue, East Orange. NJ 07019. 441
SOBEL EL AL
442
American Journal of Pathology
\
nil, 1,111 fillilli'l l'IIFRII linpi U11,11111-1101,110 .1,
4m
a
a
4
a
I
0
~~'UF~~~
~~~~~4
Figure 1-A melanomatous platy/swordtail hybrid with deeply pigmented tumorous involvement of the distal half of the body, including dorsal and caudal fins. Figure 2-Melanomatous involvement of corium and myoseptae with infiltration by deeply pigmented tumor cells between muscle bundles is shown (H&E, x 35). Figure 3-Melanoma cell with prominent melanosomes and compound Inset-A somewhat elongated developing pigment granule; note the melanosomes (X 12,200). deposition of electron-dense material over a crystalline lattice enclosed in a dilated sac of endoplasmic reticulum (X 58,600).
Vol. 82, No. 2 February 1976
MALIGNANT MELANOMA
443
Figures 4-7-Electron micrographs illustrating the development of the more common oval pigment 4-Note a single unit membrane-delimited body adjacent to the actively budding granules. Golgi apparatus that contains small vesicles resembling the Golgi vesicles. Some contain electron5-A structure similar to that in 4, but containing more electrondense material. (X 34,200) 6-This electron micrograph shows similar structures dense material, is shown (X 34,200). 7-The fusion of the electron-dense granules seen in 6 containing more pigment (X 39,600). forms the mature pigment granules (X 31,200).
early as the day of birth. At first they replace the normal corial and subcutaneous tissues. Then myoseptae are invaded from the subcutaneous tissue until a continuous replacement of the connective tissue from the corium to the central body mass occurs (Figures 1 and 2). Later masses of small, pigmented spindle cells with prominent mitotic activity (melanocytes) appear (Figures 3). Once they begin to grow-, there is tumorous development (Figure 1) with almost complete disappearance of the melanophores, and the fish succumb rapidly. WN"e feel that a reasonable explanation for this process is that, as the melanomatous process intensifies, melanocvtes multiply so rapidly that they are unable to differentiate into melanophores. With the electron microscope the tumors are found to be composed of a dense mesh-ork of cells infiltrating the adjacent tissues. Nlacromelanophores and melanocvtes are found to differ only in size and shape, although most macromelanophores contain more pigment and are thought to be older, more mature cells. Most melanin granules in these tumors are produced by the clumping of electron-dense particles in oval sacs of endoplasmic reticulum. These particles appear to be transported to the sacs at least in part via Golgi vesicles (Figures 4-7). Less common, more elongated granules appear to form by the deposition of electron-dense material on a crystalline matrix (Figure :3, inset). Later, these granules coalesce to form compound melanosomes (autophagic vacuoles) (Figure 3).
SOBEL EL AL
444
American Journal of Pathology
Comparisn With Human Disease
Fish melanomas are very similar to those of man. They differ most noticeably in that they contain melanophores and produce melanin granules in tw o -ays, wvith only few being produced by the deposition of electron-dense material on a crystalline matrix as in man. Fish melanomas are more uniformly invasive and destructive than their human counterpart. They are composed of more closely spaced cell groups and lack the irregular villous projections, junctional change, and desmosomes seen in human lesions. Wre have been unable to demonstrate microtubules in fish melanoma cells. Potential Usefukess of nTis Mod
Fish are commonly affected by melanomas as well as other neoplastic diseases that are often very similar to their human counterparts.7 Much can be gained from study of these lesions because of the ease with which the fish can be obtained and kept due to the large numbers of offspring, short gestational period, and ease of handling. These factors certainly facilitate genetic experiments as well as studies that require large numbers of relatively homogeneous animals. Availabit
At present, melanomatous fish are being bred and studied by one of us-Dr. Klaus D. Kallman, Genetics Laboratorv, Osborn Laboratories of Marine Sciences, New York Zoological Society at the Aquarium, Coney Island, NY 11224. References Uber melanombildungen bei bastarden von xiphophorus hellerii und Platypoecilus nmculatus var rubra. Klin \Wochenschrift 7:1561. 1928 Kosswig CZ: (ber geschw-ulstbildungen bei fischbastarden. Indukt Abstamm Vererbangst 39:61. 1931 Reed HD. Gordon 4: The morphology of melanotic overgrow-ths in hybrids of Mexican killifishes: A preliminary account. Am J Cancer 13:1324. 1931 Gordon M: The melanoma cell as an incompletely differentiated pigment cell. Pigment Cell Biology. Edited by \1 Gordon. New York, Academic Press. 1939. p 213 Anders F: Tumor formation in platyfish-swordtail hybrids as a problem of gene regulation. Experentia 2:3:1. 1967 Sobel HJ. Marquet E Kallman KD. Corley GJ: Melanomas in platy swordtail h-brids. The Pathology of Fishes. Edited by WN'E Ribelin. G Migaki. Madison. W'isconsin. Universitv of Wisconsin Press 1973, p 945 Scarpelli DG: Comparative aspects of neoplasia in fish and other laboratory animals. Fish In Research. Edited bv OW 'Newhaus. JE Halver. New York, Academic Press. 1969. p 43
1. Haussler G:
2.
:3. 4.
,. 6.
7.
