Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany; Department of Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany.
Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany.
Matrix Biol. 2022 Aug;111:76-94. doi: 10.1016/j.matbio.2022.06.002. Epub 2022 Jun 9.
Heparan sulfate (HS), a highly negatively charged glycosaminoglycan, is ubiquitously present in all tissues and also exposed on the surface of mammalian cells. A plethora of molecules such as growth factors, cytokines or coagulation factors bear HS binding sites. Accordingly, HS controls the communication of cells with their environment and therefore numerous physiological and pathophysiological processes such as cell adhesion, migration, and cancer cell metastasis. In the present work, we found that HS exposed by blood circulating melanoma cells recruited considerable amounts of plasmatic von Willebrand factor (vWF) to the cellular surface. Analyses assisted by super-resolution microscopy indicated that HS and vWF formed a tight molecular complex. Enzymatic removal of HS or genetic engineering of the HS biosynthesis showed that a reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF encapsulation. In microfluidic experiments, mimicking a tumor-activated vascular system, we found that vWF-HS complexes prevented vascular adhesion. In line with this, single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall to counteract metastasis. Experiments in wild type and vWF knockout mice confirmed that the HS-vWF complex at the melanoma cell surface attenuated hematogenous metastasis, whereas melanoma cells lacking HS evade the anti-metastatic recognition by vWF. Analysis of tissue samples obtained from melanoma patients validated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlate with metastases and reduced patients' survival. In conclusion, we showed that HS-mediated binding of plasmatic vWF to the cellular surface can reduce the hematogenous spread of melanoma. Cancer cells with low HS levels evade vWF recognition and are thus prone to form metastases. Therefore, therapeutic expansion of the cancer cell exposed HS may prevent tumor progression.
硫酸乙酰肝素（HS）是一种高度带负电荷的糖胺聚糖，广泛存在于所有组织中，也暴露在哺乳动物细胞表面。许多分子，如生长因子、细胞因子或凝血因子，都具有 HS 结合位点。因此，HS 控制着细胞与其环境的交流，从而控制着许多生理和病理生理过程，如细胞黏附、迁移和癌细胞转移。在本工作中，我们发现循环黑色素瘤细胞暴露的 HS 募集了大量的血浆血管性血友病因子（vWF）到细胞表面。借助超分辨率显微镜分析表明，HS 和 vWF 形成了紧密的分子复合物。酶去除 HS 或 HS 生物合成的基因工程表明，HS 链的长度缩短或完全缺乏 HS 与 vWF 的包裹显著减少有关。在微流控实验中，模拟肿瘤激活的血管系统，我们发现 vWF-HS 复合物阻止了血管黏附。与此一致，单分子力谱学表明，vWF-HS 复合物促进了循环癌细胞从血管壁的排斥，以抵抗转移。在野生型和 vWF 敲除小鼠的实验中证实，黑色素瘤细胞表面的 HS-vWF 复合物减弱了血源性转移，而缺乏 HS 的黑色素瘤细胞逃避了 vWF 的抗转移识别。从黑色素瘤患者获得的组织样本分析验证了转移性黑色素瘤细胞产生的 HS 较少。转录组数据进一步表明，HS 相关基因表达减弱与转移和患者生存时间缩短相关。总之，我们表明 HS 介导的血浆 vWF 与细胞表面的结合可以减少黑色素瘤的血行播散。HS 水平低的癌细胞逃避 vWF 识别，因此容易形成转移。因此，癌症细胞暴露的 HS 的治疗性扩张可能会阻止肿瘤的进展。
