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.
Mintz B, Silvers WK. "Intrinsic" immunological tolerance in allophenic mice (Reprinted from Science, vol 158, pg 1484-1487, 1967). J Immunol. 2007 Apr;178(7):4007-10. PubMed
Blelloch RH, Hochedlinger K, Yamada Y, Brennan C, Kim MJ, Mintz B, Chin L, Jaenisch R. Nuclear cloning of embryonal carcinoma cells. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):13985-90. PubMed
Milling SW, Sai T, Silvers WK, Mintz B. Inhibition of melanoma growth after treatment with dendritic cells in a Tyr-SV40E murine model requires CD4+ T cells but not CD8+ T cells. Melanoma Res. 2004 Dec;14(6):555-62. PubMed
Milling SW, Silvers WK, Sai T, Mintz B. Decline in MHC class I expression with increasing thickness of cutaneous melanomas in standard-strain transgenic mouse models. Melanoma Res. 2002 Jun;12(3):221-30. PubMed
Sai T, Milling SW, Mintz B. Freezing and thawing of bone marrow-derived murine dendritic cells with subsequent retention of immunophenotype and of antigen processing and presentation characteristics. J Immunol Methods. 2002 Jun 1;264(1-2):153-62. PubMed
Kelsall SR, Mintz B. Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility. Cancer Res. 1998 Sep 15;58(18):4061-5. PubMed
Orlow SJ, Silvers WK, Zhou BK, Mintz B. Comparative decreases in tyrosinase, TRP-1, TRP-2, and Pmel 17/silver antigenic proteins from melanotic to amelanotic stages of syngeneic mouse cutaneous melanomas and metastases. Cancer Res. 1998 Apr 1;58(7):1521-3. PubMed
Silvers WK, Mintz B. Differences in latency and inducibility of mouse skin melanomas depending on the age and anatomic site of the skin. Cancer Res. 1998 Feb 15;58(4):630-2. PubMed
Kelsall SR, LeFur N, Mintz B. Qualitative and quantitative catalog of tyrosinase alternative transcripts in normal murine skin melanocytes as a basis for detecting melanoma-specific changes. Biochem Biophys Res Commun. 1997 Jul 9;236(1):173-7. PubMed
Le Fur N, Kelsall SR, Silvers WK, Mintz B. Selective increase in specific alternative splice variants of tyrosinase in murine melanomas: a projected basis for immunotherapy. Proc Natl Acad Sci U S A. 1997 May 13;94(10):5332-7. PubMed
Le Fur N, Silvers WK, Kelsall SR, Mintz B. Up-regulation of specific tyrosinase mRNAs in mouse melanomas with the c2j gene substituted for the wild-type tyrosinase allele: utilization in design of syngeneic immunotherapy models. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7561-5. PubMed
LeFur N, Kelsall SR, Mintz B. Base substitution at different alternative splice donor sites of the tyrosinase gene in murine albinism. Genomics. 1996 Oct 15;37(2):245-8. PubMed
Mintz B, Silvers WK. Accelerated growth of melanomas after specific immune destruction of tumor stroma in a mouse model. Cancer Res. 1996 Feb 1;56(3):463-6. PubMed
Devries TJ, Kitson JL, Silvers WK, Mintz B. Expression of Plasminogen Activators and Plasminogen-Activator Inhibitors in Cutaneous Melanomas of Transgenic Melanoma- Susceptible Mice. Cancer Res. 1995 Oct 15;55(20):4681-7. PubMed
Orlow SJ, Hearing VJ, Sakai C, Urabe K, Zhou BK, Silvers WK, Mintz B. Changes in Expression of Putative Antigens Encoded by Pigment Genes in Mouse Melanomas at Different Stages of Malignant Progression. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10152-6. PubMed
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