Unit of the Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan.
Cancer Res. 2010 Jan 1;70(1):24-9. doi: 10.1158/0008-5472.CAN-09-2838.
Nevus-associated melanomas arise from pre-existing benign lesions, but de novo melanomas can also develop in the absence of such lesions. Few studies have addressed the latter phenomenon because no animal models have been described in which melanomas clearly develop in a de novo manner. In this study, we have address this need in defining RFP-RET-transgenic mice (RET mice) as a mouse model for multi-step melanomagenesis that proceeds via tumor-free, benign, premalignant, and malignant stages. Melanomas from RET mice exhibited decreased expression levels of endothelin receptor B (Ednrb) compared with benign tumors. In RET mice that were heterozygous for Ednrb (Ednrb+/-;RET mice), >80% of the arising primary tumors were malignant. Life span after tumor development in the mice was significantly shorter than in RET mice. Lung metastasis after tumor development was significantly higher than in RET mice. The observed process of melanomagenesis in Ednrb+/-;RET mice, which proceeded without a pre-existing benign lesion, along with the emergent characteristics in the model after tumor development corresponded well with the formation of de novo melanoma in humans. Our findings define a novel transgenic mouse model for de novo melanoma and suggest that reduced expression of Ednrb might facilitate the development of de novo melanoma in humans.
痣相关黑色素瘤起源于先前存在的良性病变，但也可以在没有这些病变的情况下发生新发性黑色素瘤。由于尚未描述明确以新发性方式发展黑色素瘤的动物模型，因此很少有研究涉及后一种现象。在本研究中，我们通过定义 RFP-RET 转基因小鼠（RET 小鼠）作为多步骤黑色素瘤发生的小鼠模型来满足这一需求，该模型通过无肿瘤、良性、癌前和恶性阶段进行。与良性肿瘤相比，RET 小鼠的黑色素瘤表现出内皮素受体 B（Ednrb）表达水平降低。在 Ednrb 杂合子（Ednrb+/-;RET 小鼠）的 RET 小鼠中，超过 80%的原发性肿瘤为恶性。与 RET 小鼠相比，这些小鼠在肿瘤发展后的寿命明显缩短。与 RET 小鼠相比，肿瘤发展后的肺转移明显更高。在 Ednrb+/-;RET 小鼠中观察到的黑色素瘤发生过程没有先前存在的良性病变，并且在肿瘤发展后的模型中出现的特征与人类新发性黑色素瘤的形成非常吻合。我们的研究结果定义了一种新的用于新发性黑色素瘤的转基因小鼠模型，并表明 Ednrb 表达降低可能有助于人类新发性黑色素瘤的发展。
