Department of Dermatology and Venerology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
Int J Mol Sci. 2021 Apr 10;22(8):3912. doi: 10.3390/ijms22083912.
Chitinase 3-like 1 (CHI3L1) is an enzymatically inactive mammalian chitinase that is associated with tumor inflammation. Previous research indicated that CHI3L1 is able to interact with different extracellular matrix components, such as heparan sulfate. In the present work, we investigated whether the interaction of CHI3L1 with the extracellular matrix of melanoma cells can trigger an inflammatory activation of endothelial cells. The analysis of the melanoma cell secretome indicated that CHI3L1 increases the abundance of various cytokines, such as CC-chemokine ligand 2 (CCL2), and growth factors, such as vascular endothelial growth factor A (VEGF-A). Using a solid-phase binding assay, we found that heparan sulfate-bound VEGF-A and CCL2 were displaced by recombinant CHI3L1 in a dose-dependent manner. Microfluidic experiments indicated that the CHI3L1 altered melanoma cell secretome promoted immune cell recruitment to the vascular endothelium. In line with the elevated VEGF-A levels, CHI3L1 was also able to promote angiogenesis through the release of extracellular matrix-bound pro-angiogenic factors. In conclusion, we showed that CHI3L1 is able to affect the tumor cell secretome, which in turn can regulate immune cell recruitment and blood vessel formation. Accordingly, our data suggest that the molecular targeting of CHI3L1 in the course of cancer immunotherapies can tune patients' response and antitumoral inflammation.
几丁质酶 3 样蛋白 1（CHI3L1）是一种无酶活性的哺乳动物几丁质酶，与肿瘤炎症有关。先前的研究表明，CHI3L1 能够与不同的细胞外基质成分相互作用，如硫酸乙酰肝素。在本工作中，我们研究了 CHI3L1 与黑色素瘤细胞细胞外基质的相互作用是否能够触发内皮细胞的炎症激活。对黑色素瘤细胞分泌组的分析表明，CHI3L1 增加了各种细胞因子的丰度，如趋化因子配体 2（CCL2），和生长因子，如血管内皮生长因子 A（VEGF-A）。使用固相结合测定法，我们发现硫酸乙酰肝素结合的 VEGF-A 和 CCL2 被重组 CHI3L1 以剂量依赖的方式置换。微流控实验表明，CHI3L1 改变的黑色素瘤细胞分泌组促进免疫细胞募集到血管内皮。与升高的 VEGF-A 水平一致，CHI3L1 还能够通过释放细胞外基质结合的促血管生成因子来促进血管生成。总之，我们表明 CHI3L1 能够影响肿瘤细胞的分泌组，进而调节免疫细胞的募集和血管形成。因此，我们的数据表明，在癌症免疫治疗过程中靶向 CHI3L1 的分子可以调节患者的反应和抗肿瘤炎症。
