Transgenic mouse model of malignant skin melanoma.

Abstract

Tyr-SV40E transgenlc mice are spedflcay susceptbl to meanma due to expresion of the oncogene in pigment ceDs. Mice of the more nes die young of early-onset eye meanmas, when skin menas are stfll infrequent and benig. To surmount this oa, in from donors oftwo high-cepiblitlines was grafted to hosts of a low-septibi line of the same inbred strain, thereby enabling the skin to outlive the donors and continue to grow in hmmunocompetent but tolerant hosts. Unexpectedly, donor pIgment cells in all the grafts soon seectivdy proliferated dose to areas of greatest wound healing, formig a dense black tracer, e at the outer rim of the grfts. These transcriptional control of the tyrosinase promoter expressed in pigment cells. Melanocytes in the hair follicles of the mice are hypomelanotic and the hairs, to which these cells contribute pigment granules, are lighter than normal as a result (5, 6). With increasing age, the skin itself becomes slightly darker due to melanocytic hyperplasia in the dermis. Localized foci appear as small flat black macules, some of which enlarge and thicken to become moles or nevi.Three classes of neoplasms have occurred: eye melanomas (4, 7), various other nonskin tumors associated with widespread distribution and hyperplasia of neurl crest-derived pigment cells (5), and skin melanomas (4). Different inbred lines of the mice, descended from separate founders, all express the T antigen to a degree specific for each line, as seen in the coat color reduction characteristic of each. They differ correspondingly in onset and progression of eye melanomas and were expected to differ in susceptibility to skin melanomas. At the extremes, early and rapidly growing eye tumors arise in mice oflines with lighter grey coats, while eye tumors are late and slow-growing in mice ofvery dark grey lines. Early eye tumors are fatal at a young age, due to invasion and metastasis; skin melanomas are then still infrequent and usually benign (4). The ultimate capacity ofthe transgenic skin melanocytes for malignancy was nevertheless demonstrated by establishing the cells in culture soon after birth and obtaining tumors after subcutaneous injection into immunodeficient nude (nu/nu) hosts (8,9). However, cell culture and injection do not reflect the genesis and biology of a melanoma in the skin. Some experimental intervention was therefore needed.The strategy we have devised is to circumvent the lethality of eye melanomas in the more susceptible transgenics by grafting skin from them to low-susceptibility young adult transgenic hosts. The skin can thus outlive the donor and grow for a long period in a histocompatible C57BL/6 host tolerant of the SV40 T antigen, which is known to be immunogenic (10). Such hosts have the further advantage that their skin (unlike that ofnude mice) is structurally similar to the donor skin; moreover, they would be capable (unlike any immunodeficient hosts) of responding to tumorassociated antigens.While the expectation of obtaining malignant skin melanomas was indeed fulfilled, the g...

Putting tumours in context

“…Acquired or inherited mutations that alter stromal-cell function can release the suppression placed on context-inhibited malignant cells. Literature that spans more than a century has shown that inflammation associated with tissue wounding can produce tumours (REFS [35][36][37][38] and references therein)…”

Modeling malignant melanoma in mice: pathogenesis and maintenance

“…Melanomas have been induced by carcinogenesis protocols but arise with low penetrance, long latencies and limited metastatic potential (Berkelhammer and Oxenhandler, 1987). Mintz and Silvers (1993) have produced a transgenic mouse melanoma model by the melanocyte-speci®c tyrosinase-directed expression of the SV40 early region (small and large T antigens). These mice develop ocular melanomas and, to a lesser extent, cutaneous melanomas.…”

Histopathogenesis of malignant skin melanoma induced in genetically susceptible transgenic mice.

“…The melanocytic lesions progressed to malignant melanoma in all skin grafts from the more susceptible of two transgenic donor lines tested, and in one-fourth of the grafts from another line; no melanomas of host onrgin developed. We have proposed that the induction of this maliancy in susceptible skin by wound healing is merely a caricature or exaggeration of the same basic biological and molecular events as ordinarily underlie the genesis of melanoma, without skin grafting, and that the exaggeration makes those events more accessible to analysis (3).…”

“…This problem was recently overcome, and malignant skin melanomas were obtained, by taking advantage experimentally of the fact that different inbred lines of the mice differ in level of expression of the transgene and hence in degree of susceptibility to melanoma; yet all are members of the same standard strain, C57BL/6. Thus, by grafting skin from high-susceptibility transgenic donors to low-susceptibility transgenic hosts, the skin outlived the donors in immunocompetent hosts tolerant of the transgene product (3).…”

“…Unexpectedly, melanocytes in the grafted skin proliferated excessively and selectively, close to areas of greatest wound healing, especially near the graft margins (3), thereby strongly suggesting a causal role of growth factors and cytokines associated with wound repair (4). The melanocytic lesions progressed to malignant melanoma in all skin grafts from the more susceptible of two transgenic donor lines tested, and in one-fourth of the grafts from another line; no melanomas of host onrgin developed.…”