A Mouse Model of Melanoma Driven by Oncogenic KRAS
FC Geyer, C Milagre, N Dhomen, R Hayward, L Larue, JS Reis-Filho, R Marais. Institute of Cancer Research, London, United Kingdom; Institut Curie, Orsay, France
Background: Hyper-activation of RAS/RAF/MEK/ERK pathway is present in 30% of malignant tumours and may occur due to activation of several of its members. In melanomas, NRAS is mutated in 19% of cases, whereas HRAS and KRAS are mutated in 5 and 2% respectively. Previous animal models have shown that activation of G12VHRAS and Q61KNRAS are able to induce melanoma formation. Here we describe a mouse model of melanoma driven by G12VKRAS.
Design: We used a Cre recombinase/loxP system in which G12VKRAS expression is induced in the melanocytic lineage following topical application of tamoxifen. Selected lesions were subjected to immunohistochemical analysis with antibodies against S100, Ki67 and p16 proteins, and reverse transcriptase PCR (RT-PCR) for Tyrosinase, Trp2, Pax3, Silver.
Results: The mice developed skin hyper-pigmentation and skin lesions of varying pathological features and degree of malignancy as early as one month after tamoxifen application. Dermal lesions were present in 30% of the mice, resembled human blue naevi, were composed of pigmented epithelioid and dendritic cells, and expressed very low levels of Ki67 (<1%). In peri-orbital areas, slightly larger lesions, consistent with the diagnosis of pigmented epithelioid melanocytoma were observed,. Furthermore, rapidly-growing lesions, predominantly composed of hypo/amelanotic, mitotically active, spindle cells, developed in the back and peri-anal areas of 80% of the treated mice. These lesions displayed aggressive behaviour, invading and destroying the subcutaneous tissue and skeletal muscle. Diffuse positivity for S100 and expression of melanoma markers by RT-PCR confirmed the diagnosis of malignant melanoma. Additionally, cultured cells from these lesions were able to seed to the lungs of nude mice when injected via the tail vein.
Conclusions: Expression of oncogenic KRAS in melanocytes can induce naevus formation and melanomagenesis in vivo. Establishing an in vivo model of KRAS-driven melanoma provides novel opportunities to examine the apparent differences between the three RAS family members and to develop therapeutic approaches tailored to melanomas driven by mutation of specific RAS genes.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 66, Monday Morning