Species-Specific In vivo Engraftment of the Human BL Melanoma Cell Line Results in an Invasive Dedifferentiated Phenotype Not Present in Xenografts

Departments of ¹Woman and Child Health, ²Clinical Neuroscience, and ³Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden; ⁴Department of Tumor Biology and the Cancer Stem Cell Innovation Center, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital; ⁵Department of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Faculty Division, University of Oslo, Oslo, Norway; and ⁶Department of Pathology and Cytology, Central Hospital, Gävle, Sweden

^* To whom correspondence should be addressed. E-mail: lars.ahrlund{at}ki.se.

	Abstract

For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell–derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo. [Cancer Res 2009;69(9):3746–54]

Key Words: in vivo, melanoma