Metastatic melanoma is a fatal disease with a rapid systemic dissemination. The most frequent target sites are the liver, bone, and brain. Melanoma metastases represent a heterogeneous cell population, which associates with genomic instability and resistance to therapy. Interaction of melanoma cells with the hepatic sinusoidal endothelium initiates a signaling cascade involving cytokines, growth factors, bioactive lipids, and reactive oxygen and nitrogen species produced by the cancer cell, the endothelium, and also by different immune cells. Endothelial cell-derived NO and H₂O₂ and the action of immune cells cause the death of most melanoma cells that reach the hepatic microvascularization. Surviving melanoma cells attached to the endothelium of pre-capillary arterioles or sinusoids may follow two mechanisms of extravasation: a) migration through vessel fenestrae or b) intravascular proliferation followed by vessel rupture and microinflammation. Invading melanoma cells first form micrometastases within the normal lobular hepatic architecture via a mechanism regulated by cross-talk with the stroma and multiple microenvironment-related molecular signals. In this review special emphasis is placed on neuroendocrine (systemic) mechanisms as potential promoters of liver metastatic growth. Growing metastatic cells undergo functional and metabolic changes that increase their capacity to withstand oxidative/nitrosative stress, which favors their survival. This adaptive process also involves upregulation of Bcl-2-related antideath mechanisms, which seems to lead to the generation of more resistant cell subclones.

转移性黑色素瘤是一种具有快速全身传播的致命疾病。最常见的目标部位是肝脏、骨骼和大脑。黑色素瘤转移代表异质细胞群，这与基因组不稳定性和对治疗的抗性有关。黑色素瘤细胞与肝窦内皮的相互作用引发了一个信号级联反应，涉及癌细胞、内皮以及不同免疫细胞产生的细胞因子、生长因子、生物活性脂质和活性氧和氮物质。内皮细胞衍生的 NO 和 H ₂ O ₂免疫细胞的作用导致大多数到达肝脏微血管化的黑色素瘤细胞死亡。附着在毛细血管前小动脉或血窦内皮上的存活黑色素瘤细胞可能遵循两种外渗机制：a) 通过血管窗迁移或 b) 血管内增殖，随后血管破裂和微炎症。侵入的黑色素瘤细胞首先通过与基质的串扰和多种微环境相关分子信号调节的机制在正常的小叶肝结构内形成微转移。在这篇综述中，特别强调了神经内分泌（全身）机制作为肝转移生长的潜在促进剂。生长中的转移性细胞经历功能和代谢变化，增加了它们抵抗氧化/亚硝化应激的能力，这有利于他们的生存。这种适应性过程还涉及 Bcl-2 相关抗死亡机制的上调，这似乎导致产生更具抗性的细胞亚克隆。