Development of cutaneous amelanotic melanoma in the absence of a functional tyrosinase.

Abstract

Lack of characteristic pigmentation and a wide range of clinical presentations account for the diagnostic challenge associated with amelanotic malignant melanoma. Experimental studies of this important human cancer have been hampered by the lack of an appropriate animal model. We previously described a transgenic mouse line (TG-3) that spontaneously develops pigmented cutaneous melanoma. F1 crosses were generated with TG-3 and several albino strains, and backcrosses were then made with the albinos. In the present report, we describe the restricted development and characterization of cutaneous amelanotic melanoma in these albino transgenic backcrosses. The incidence and behavior of melanoma in these mice were monitored. A high incidence (80-100%) of spontaneous amelanotic melanoma was observed in albino transgenic mice derived from backcrosses with A, AKR, FVB, and SJL strains. The lowest incidence (30%) was obtained in BALB/c-derived crosses. No tumors were observed in non-transgenic mice. Immunohistochemical and western blot analyses using antibodies against three melanocyte-specific markers of the tyrosinase family of proteins confirmed that the tumors were composed of amelanotic melanocytes. Furthermore, the presence of numerous premelanosomes observed by electron microscopy further supported the melanocytic origin of these tumors. Previous in vitro studies on human melanoma have suggested that cutaneous amelanotic melanoma was evolving from preexisting pigmented cutaneous melanoma. However, our results indicate that it can occur directly, as evidenced by the appearance of cutaneous amelanotic melanoma in the tyrosinase-deficient albino mice. These mice represent a potentially valuable model for studying the mechanistic, diagnostic, and therapeutic features of this highly malignant neoplasm.

• Authors: K A Cohen-Solal, K R Reuhl, K B Ryan, K G Roberts, S Chen
• Journal: Pigment cell research (Pigment Cell Res) Vol. 14 Issue 6 Pg. 466-74 (Dec 2001) ISSN: 0893-5785 [Print] Denmark
• PMID: 11775059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Membrane Glycoproteins
• Proteins
• Oxidoreductases
• TYRP1 protein, human
• Tyrp1 protein, mouse
• tyrosinase-related protein-1
• Monophenol Monooxygenase
• Intramolecular Oxidoreductases
• dopachrome isomerase

Topics

• Animals
• Disease Models, Animal
• Female
• Intramolecular Oxidoreductases (genetics, metabolism)
• Male
• Melanocytes (enzymology, pathology, ultrastructure)
• Melanoma, Amelanotic (enzymology, genetics, pathology)
• Melanoma, Experimental (enzymology, genetics, pathology)
• Melanosomes (enzymology, pathology, ultrastructure)
• Membrane Glycoproteins
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Monophenol Monooxygenase (deficiency, genetics)
• Mutation (genetics)
• Oxidoreductases
• Phenotype
• Proteins (genetics, metabolism)
• Skin (enzymology, pathology, ultrastructure)
• Up-Regulation (genetics)