The metastatic microenvironment: Brain-residing melanoma metastasis and dormant micrometastasis
The metastatic microenvironment: Brain-residing melanoma metastasis and dormant micrometastasis
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DOI：
10.1002/ijc.27324
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发表时间：
2012-09-01
影响因子：
6.4
通讯作者：
Witz, Isaac P.
中科院分区：
文献类型：
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作者：
Izraely, Sivan;Sagi-Assif, Orit;Witz, Isaac P.
脑转移经常发生在患有晚期疾病的黑色素瘤患者中，因此预后令人沮丧。黑色素瘤脑转移发展的潜在机制还不清楚。我们生成了一个可重复的黑色素瘤脑转移模型，由脑转移变体和源自相同黑色素瘤的局部皮下变体组成，因此具有共同的遗传背景。通过心内接种获得脑转移变体。脑转移瘤的变种，皮下接种时产生自发性脑休眠微转移。自发性脑微转移瘤的培养细胞在体外生长良好，原位接种后产生皮下肿瘤。表达分析表明，脑转移瘤和微转移瘤细胞表达较高水平的血管生成素样4，胰蛋白酶合成酶环氧合酶2，基质金属蛋白酶1和优先表达的抗原在黑色素瘤和低水平的claudin-1和富含半胱氨酸的蛋白61比相应的皮肤变异。人黑色素瘤实验性和自发性转移到脑的可重复模型将有助于鉴定新的生物标志物和治疗靶点，并有助于破译黑色素瘤转移的潜在机制。
Brain metastasis occurs frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, subdermal variants that originate from the same melanomas thus sharing a common genetic background. The brain-metastasizing variants were obtained by intracardiac inoculation. Brain metastasis variants when inoculated subdermally yielded spontaneous brain dormant micrometastasis. Cultured cells from the spontaneous brain micrometastasis grew very well in vitro and generated subdermal tumors after an orthotopic inoculation. Expression analysis assays indicated that the brain metastasis and micrometastasis cells expressed higher levels of angiopoietin-like 4, prostaglandin-synthesizing enzyme cyclooxygenase-2, matrix metalloproteinase-1 and preferentially expressed antigen in melanoma and lower levels of claudin-1 and cysteine-rich protein 61 than the corresponding cutaneous variants. The reproducible models of human melanoma metastasizing experimentally and spontaneously to the brain will facilitate the identification of novel biomarkers and targets for therapy and contribute to the deciphering of mechanisms underlying melanoma metastasis.