Beatrice Mintz, PhD
Lab Phone: 15-728-2479
Cutaneous melanoma has continued to increase in incidence. It is an aggressive and often metastatic malignancy with limited responsiveness to available treatments. Surgical removal of a suspect early lesion, together with a margin of surrounding skin, may currently be the only cure. However, early lesions in human melanoma are often difficult to detect and may be phenotypically ambiguous. A useful mouse model would therefore have the following features: a standard-strain genetic background; early detectability of relevant skin lesions; occurrence of the major primary-tumor subtypes found in human cutaneous melanoma; propensity for widespread metastasis; and ease of accessibility for in vivo experimentation. Our Tyr-SV40E (C57BL/6 strain) transgenic mouse models fulfill these requirements. In the basic model, transgene DNA was injected into fertilized eggs and gave rise to a number of mouse lines, each with a distinctive level of transgene expression reflecting relative melanoma susceptibility. Mice of high-expressing lines were expected to have high susceptibility but died young; low-susceptibility lines were long-lived but remained free of skin melanomas. The problem was solved by grafting a small piece of skin from a high-susceptibility donor to a low-susceptibility host. Malignant primary melanomas, comprising the two main subtypes, developed solely in the skin grafts and metastasized into organs of the hosts under the influence of factors involved in wound repair. The tumors comprise the two major subtypes known in human melanoma, and they can metastasize widely. In an additional model, not involving skin grafting, skin melanomas were induced by limited exposure of very young low-susceptibility transgenic mice to ultraviolet radiation. In a still more recent model, with the same transgene conferring high-susceptibility, primary melanomas originated spontaneously at an early age in sites other than the skin. The tumors were found to arise from multipotent neural crest stem cells arrested or diverted in migration. Tumor cells were widely dispersed and were sometimes incorporated in developing organs. The various models of experimentally induced or spontaneous melanomas are providing a rich source of material with which to clarify events underlying malignant melanoma promotion, progression, and metastasis. We are also investigating the basis for tumor recurrence, in another mouse model in which apoptosis-resistant cells may generate melanomas.