Induction of melanoma in TPras transgenic mice

Abstract

In order to study the oncogenesis of melanocytes, transgenic mouse lines were established that express a mutated human Ha-ras (TPras) gene in pigment producing cells. The ras transgenic mice exhibit an altered phenotype, including melanocytic hyperplasia and a muted agouti coat, indicative of hyperproliferative melanocytes. These mice and their wild-type littermates have been subjected to a variety of carcinogenesis protocols, including 7, 12-dimethylbenz-[a]anthracene (DMBA), 12-O-tetradecanoylphorbol-13-acetate (TPA) and UV radiation exposure. Topical DMBA treatment of TPras mice resulted in a high incidence of melanomas. Metastatic lesions were observed in skin, lungs and lymph nodes. TPA treatment of TPras mice induced a small number of papillomas but no nevi or melanomas. UV light exposures induced papillomas in negative littermate and melanomas in some albino TPras mice. These results show that melanocytes expressing an activated Ha-ras in the TPras transgenic mice are susceptible to induction of melanoma by DMBA.

Nuclear Factor-κB Activation by the CXC Chemokine Melanoma Growth-stimulatory Activity/Growth-regulated Protein Involves the MEKK1/p38 Mitogen-activated Protein Kinase Pathway

“…Ras activation has been shown to contribute to melanoma tumor development (55)(56)(57). Our earlier results showed that Ras is required for MGSA/GRO␣-induced melanocyte transformation (36).…”

Metastasizing Melanoma Formation Caused by Expression of Activated N-RasQ61K on an INK4a-Deficient Background

“…Transgenic mice that express a mutant form of H-ras specifically in melanocytes showed melanocytic hyperplasia with intense skin pigmentation (9), which after treatment with carcinogens progressed into skin melanoma with metastasis formation in lymph nodes and lung (10). Breeding of Tyr::H-Ras V12G transgenic mice on an INK4a/ARF-or p53-deficient background resulted in the development of highly vascularized but amelanotic melanomas resembling nodular melanoma (11,12).…”

Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line

“…While marginally active, Apomine was found to be well tolerated and was not myelosuppressive, which would make it a possible candidate for combination therapy with myelosuppressive agents. The stabilization of disease seen in the Phase I clinical trial and the low toxicity associated with Apomine, led to the investigation of this agent in a TPras transgenic mouse melanoma prevention model [10,11]. The TPras mice express a mutated Ha-ras gene in pigment producing cells, which leads to development of cutaneous melanoma following topical treatment with dimethylbenzanthracene (DMBA).…”