LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages.
LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages.
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LL-37有助于黑色素瘤中肿瘤细胞的垂直侵袭。事实上，LL-37表达细胞的比例与T分期严重程度正相关。此外，LL-37在人和小鼠系统中诱导促血管生成因子。我们的研究结果表明，LL-37刺激肿瘤细胞和巨噬细胞，以促进黑色素瘤侵袭的诱导促血管生成因子。LL-37可以刺激各种皮肤驻留细胞，从而促进肿瘤的发展。由于肿瘤（T）分期是由黑色素瘤中肿瘤细胞的垂直侵袭决定的，因此我们假设LL-37表达水平与黑色素瘤患者的T分期相关。在黑素瘤的每个阶段（Tis-T4）中进行LL-37的免疫组织化学染色，表明表达LL-37的细胞的比率与T阶段严重性正相关。接下来，为了检查由LL-37刺激诱导的促血管生成因子，使用B16 F10黑素瘤模型。肿瘤内施用CRAMP（LL-37的小鼠受体）显著增加B16 F10黑素瘤中CXCL 5、IL 23 A、MMP 1a和MMP 9的mRNA表达。为了证实促血管生成因子的诱导，在体外用LL-37刺激A375人黑素瘤细胞。LL-37刺激显著增加CXCL 5、IL 23 A和MMP 9的mRNA表达，但不增加MMP 1。此外，LL-37刺激的A375培养上清液促进了管网，表明这些肿瘤衍生因子促进了对肿瘤发展的促血管生成作用。与黑色素瘤细胞系相反，LL-37体外刺激的M2巨噬细胞显著增加其MMP-1的表达和分泌，但不增加MMP-9的表达。总的来说，这些结果表明，LL-37刺激肿瘤细胞和巨噬细胞通过诱导促血管生成因子促进黑色素瘤侵袭。
LL-37 contributes the vertical invasion of tumor cells in melanoma. Indeed, the ratio of LL-37-expressing cells correlated positively to T stage severity. Moreover, LL-37 induced pro-angiogenic factors in both human and mouse systems. Our results suggested that LL-37 stimulates both tumor cells and macrophages to promote melanoma invasion by the induction of pro-angiogenic factors. LL-37 can stimulate various skin-resident cells to contribute to tumor development. Since tumor (T) stage is determined by the vertical invasion of tumor cells in melanoma, we hypothesized that the LL-37 expression level is correlated with the T stage in melanoma patients. Immunohistochemical staining of LL-37 was performed in each stage of melanoma (Tis-T4), suggesting the ratio of LL-37-expressing cells correlate positively to T stage severity. Next, to examine pro-angiogenetic factors induced by LL-37 stimulation, the B16F10 melanoma model was used. Intra-tumorally administered CRAMP, the mouse ortologe of LL-37, significantly increased the mRNA expression of CXCL5, IL23A, MMP1a, and MMP9 in B16F10 melanoma. To confirm the induction of pro-angiogenic factors, A375 human melanoma cells were stimulated by LL-37 in vitro. The mRNA expression of CXCL5, IL23A, and MMP9, but not MMP1, were significantly increased by LL-37 stimulation. Moreover, LL-37-stimulated A375 culture supernatant promoted tube networks, suggesting that these tumor-derived factors promote the pro-angiogenic effect on tumor development. In contrast to melanoma cell lines, M2 macrophages stimulated by LL-37 in vitro significantly increased their expression and secretion of MMP-1, but not MMP-9 expression. Collectively, these results suggest that LL-37 stimulates both tumor cells and macrophages to promote melanoma invasion by the induction of pro-angiogenic factors.
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作者：
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DOI：
10.1016/j.bbrc.2016.12.048
发表时间：
2017-01-22
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