Department of Surgical and Radiological Sciences, University of California Davis School of Medicine, Davis, CA, USA.
Neoplasia. 2010 Feb;12(2):173-82. doi: 10.1593/neo.91604.
The lymphatic system plays a critical role in melanoma metastasis, and yet, virtually no information exists regarding the cellular and molecular mechanisms that take place between melanoma cells and the lymphatic vasculature. Here, we generated B16-F1 melanoma cells that expressed high (B16alpha(4)+) and negligible (B16alpha(4)-) levels of alpha(4) integrin to determine how the expression of alpha(4) integrins affects tumor cell interactions with lymphatic endothelial cells in vitro and how it impacts lymphatic metastasis in vivo. We found a direct correlation between alpha(4) integrin expression on B16-F1 melanoma cells and their ability to form adhesive interactions with monolayers of lymphatic endothelial cells. Adhesion of B16-F1 melanoma cells to lymphatic endothelial cells was mediated by the melanoma cell alpha(4) integrin binding to its counterreceptor, vascular cell adhesion molecule 1 (VCAM-1), that was constitutively expressed on the lymphatic endothelial cells. VCAM-1 was also expressed on the tumor-associated lymphatic vessels of B16-F1 and B16alpha(4)+ tumors growing in the subcutaneous space of C57BL/6J mice. B16-F1 tumors metastasized to lymph nodes in 30% of mice, whereas B16alpha(4)+ tumors generated lymph node metastases in 80% of mice. B16-F1 melanoma cells that were deficient in alpha(4) integrins (B16alpha(4)-) were nontumorigenic. Collectively, these data show that the alpha(4) integrin expressed by melanoma cells contributes to tumorigenesis and may also facilitate metastasis to regional lymph nodes by promoting stable adhesion of melanoma cells to the lymphatic vasculature.
淋巴系统在黑色素瘤转移中起着关键作用，但实际上，关于黑色素瘤细胞与淋巴管之间发生的细胞和分子机制几乎没有任何信息。在这里，我们生成了表达高水平（B16alpha(4)+）和可忽略水平（B16alpha(4)-）α(4)整合素的 B16-F1 黑色素瘤细胞，以确定α(4)整合素的表达如何影响肿瘤细胞与淋巴内皮细胞在体外的相互作用，以及如何影响体内淋巴转移。我们发现 B16-F1 黑色素瘤细胞上α(4)整合素的表达与其与淋巴内皮细胞单层形成粘附相互作用的能力之间存在直接相关性。B16-F1 黑色素瘤细胞与淋巴内皮细胞的粘附是由黑色素瘤细胞α(4)整合素与在淋巴内皮细胞上持续表达的其配体血管细胞粘附分子 1（VCAM-1）结合介导的。VCAM-1 也在皮下空间生长的 C57BL/6J 小鼠中的 B16-F1 和 B16alpha(4)+肿瘤的肿瘤相关淋巴管上表达。B16-F1 肿瘤在 30%的小鼠中转移到淋巴结，而 B16alpha(4)+肿瘤在 80%的小鼠中生成淋巴结转移。缺乏α(4)整合素的 B16-F1 黑色素瘤细胞（B16alpha(4)-）无致瘤性。总的来说，这些数据表明黑色素瘤细胞表达的α(4)整合素有助于肿瘤发生，并且还可以通过促进黑色素瘤细胞与淋巴血管的稳定粘附来促进肿瘤转移到局部淋巴结。
