The possibility that endocrine factors may influence the clinical course of malignant melanoma is suggested by the superior survival data of women. In preclinical models we observed a higher rate of colony formation by human melanoma cells in male compared to female SCID mice, but only in the case of the liver and not in other organs. The gender difference could be seen at an early phase of colony formation. On the other hand, in our human melanoma cell lines we failed to detect steroid receptor protein expression, and treatment with sex hormones did not considerably influence their in vitro behavior. Investigating the possible contribution of host cells to the observed gender difference, we performed in vivo blocking experiments applying pretreatment of the animals with Kupffer cell inhibitor gadolinium chloride and the NK cell inhibitor anti-asialo GM1 antibody. While Kupffer cell blockade enhanced melanoma liver colonization equally in the two sexes, a more prominent increase was observed in female than in male mice in the case of NK cell inhibition. Further supporting the importance of NK cells in the lower liver colonization efficiency of melanoma cells in females, gender difference in colony formation was lost in NSG mice lacking NK activity. Although in humans no organ selectivity of gender difference in melanoma progression has been observed according to data in the literature, our results possibly indicate a contribution of natural host defense mechanisms to gender difference in survival of patients with melanoma or other tumor types as well.

译文

女性的优越生存数据表明内分泌因素可能会影响恶性黑色素瘤的临床进程。在临床前模型中,与雌性SCID小鼠相比,我们观察到雄性黑素瘤细胞的集落形成率更高,但仅在肝脏而不是其他器官的情况下。性别差异可以在菌落形成的早期阶段看到。另一方面,在我们的人类黑素瘤细胞系中,我们未能检测到类固醇受体蛋白的表达,并且用性激素治疗不会显着影响其体外行为。研究宿主细胞对观察到的性别差异的可能贡献,我们进行了体内阻断实验,应用了Kupffer细胞抑制剂氯化g和NK细胞抑制剂抗asialo GM1抗体对动物进行预处理。尽管Kupffer细胞阻滞在两种性别中平等地增强了黑素瘤的肝脏定植,但在NK细胞抑制的情况下,雌性小鼠的增加比雄性小鼠的增加更为明显。进一步支持NK细胞在雌性黑色素瘤细胞较低的肝脏定植效率中的重要性,在缺乏NK活性的NSG小鼠中,集落形成的性别差异消失了。尽管根据文献中的数据,在人类中没有观察到黑素瘤进展中性别差异的器官选择性,但我们的结果可能表明自然宿主防御机制对黑素瘤或其他肿瘤类型患者生存中的性别差异也有贡献。

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