Kushiro Kyoko, Chu Randy A, Verma Akanksha, Núñez Nomelí P
Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
Cancer Microenviron. 2012 Apr;5(1):73-82. doi: 10.1007/s12307-011-0087-2. Epub 2011 Sep 3.
Metastatic melanoma is one of the most deadly and evasive types of cancer. On average, cancer patients with metastatic melanoma survive only 6-9 months after diagnosis. Epidemiological and animal studies suggest that obesity increases the metastatic ability of malignant melanoma, though the mechanism is not known. In the present studies, we assessed the ability of 3T3L1 adipocytes to modulate B16BL6 melanoma cell invasion and the Epithelial-to-Mesenchymal Transition (EMT). For this purpose, we induced the differentiation of 3T3L1 fibroblasts to adipocytes. Then, we collected the cell culture media from both fibroblasts and adipocytes and determined their effect on the invasive ability and EMT gene expression of B16BL6 melanoma cells. Results show that adipocyte media increased that ability of B16BL6 cells to invade. The higher invasive ability of B16BL6 melanoma cells was associated with increased expression of EMT genes such as Snai1, MMP9, Twist, and Vimentin. Additionally, the expression of the cell-to-cell adhesion protein E-cadherin and the metastasis suppressor gene Kiss1 were down-regulated in these B16BL6 cells. Also, adipocytes had high levels of the pro-inflammatory cytokine Interleukin 6 (IL-6). Treatment of B16BL6 cells with IL-6 elicited similar effects as the adipocyte media; IL-6 promoted the invasive ability of B16BL6 melanoma cells, increased the expression of Snai1, and decreased Kiss1 expression. IL-6 neutralization, however, did not have a visible effect on adipocyte media-induced invasion and snai1 staining. In summary, adipocytes may increase the invasive ability of B16BL6 melanoma cells by promoting EMT and decreasing the expression of genes such as E-cadherin and Kiss1.
转移性黑色素瘤是最致命且最难对付的癌症类型之一。平均而言，转移性黑色素瘤癌症患者在确诊后仅存活6至9个月。流行病学和动物研究表明，肥胖会增加恶性黑色素瘤的转移能力，但其机制尚不清楚。在本研究中，我们评估了3T3L1脂肪细胞调节B16BL6黑色素瘤细胞侵袭和上皮-间质转化（EMT）的能力。为此，我们诱导3T3L1成纤维细胞分化为脂肪细胞。然后，我们收集了成纤维细胞和脂肪细胞的细胞培养基，并确定它们对B16BL6黑色素瘤细胞侵袭能力和EMT基因表达的影响。结果表明，脂肪细胞培养基增强了B16BL6细胞的侵袭能力。B16BL6黑色素瘤细胞较高的侵袭能力与EMT基因（如Snai1、MMP9、Twist和波形蛋白）表达增加有关。此外，这些B16BL6细胞中细胞间粘附蛋白E-钙粘蛋白和转移抑制基因Kiss1的表达下调。此外，脂肪细胞具有高水平的促炎细胞因子白细胞介素6（IL-6）。用IL-6处理B16BL6细胞产生了与脂肪细胞培养基类似的效果；IL-6促进了B16BL6黑色素瘤细胞的侵袭能力，增加了Snai1的表达，并降低了Kiss1的表达。然而，IL-6中和对脂肪细胞培养基诱导的侵袭和Snai1染色没有明显影响。总之，脂肪细胞可能通过促进EMT和降低E-钙粘蛋白和Kiss1等基因的表达来增加B16BL6黑色素瘤细胞的侵袭能力。
