Compartmental exchange between cells through extracellular vesicles (EVs), including exosomes and microvesicles, has emerged as a central mechanism that coordinates the complex communication between malignant and stromal cells during tumor initiation and evolution. Some of the most critical processes of EV-mediated communication, including EV biogenesis and EV uptake, can be mediated by heparan sulfate proteoglycans (HSPGs) that reside on the surface of producer and recipient cells as well as on EVs. With interestingly similar, HSPG-dependent, pathways as the ones exploited by some viruses, EVs may, in an evolutionary perspective, be viewed as endogenous counterparts of viral particles. Cancer cell-derived EVs exert their protumorigenic effects by direct interactions of biologically active surface molecules, by transfer of proteins and nucleic acids into recipient cells or by transfer of metabolites that can be utilized as an energy source by the recipient cell. Here, we discuss the pleiotropic role of the HSPG family in these different contexts of EV communication with a specific focus on tumor development. We propose EV-associated PGs as dynamic reservoirs and chaperones of signaling molecules with potential implications in ligand exchange between EVs and tumor target cells. The protumorigenic consequences of EV mediated communication through HSPG should motivate the development of therapeutic approaches targeting EV-HSPG interactions as a novel strategy in cancer treatment.

通过细胞外囊泡（EVs），包括外泌体和微囊泡，细胞之间的隔室交换已经成为协调肿瘤起始和进化过程中恶性和基质细胞之间复杂交流的重要机制。EV介导的交流中一些最关键的过程，包括EV生物发生和EV摄取，可以通过位于生产者和受体细胞表面以及EV上的硫酸乙酰肝素蛋白聚糖（HSPG）来介导。有趣的是，与某些病毒所利用的HSPG依赖性途径相似，从进化的角度来看，电动汽车可被视为病毒颗粒的内源性对应物。癌细胞衍生的电动汽车通过生物活性表面分子的直接相互作用发挥其促肿瘤作用，通过将蛋白质和核酸转移到受体细胞中或通过代谢物的转移，这些代谢物可以被受体细胞用作能源。在这里，我们讨论HSPG家族在这些不同的EV交流环境中的多效性作用，并特别关注肿瘤的发展。我们提出了与电动汽车相关的PGs作为信号分子的动态储库和分子伴侣，对电动汽车与肿瘤靶细胞之间的配体交换具有潜在的影响。通过HSPG介导的EV介导的沟通的致瘤作用应激发针对EV-HSPG相互作用的治疗方法的开发，作为癌症治疗中的一种新策略。我们讨论了HSPG家族在这些不同的EV交流环境中的多效性作用，特别关注肿瘤的发展。我们提出了与电动汽车相关的PGs作为信号分子的动态储库和分子伴侣，对电动汽车与肿瘤靶细胞之间的配体交换具有潜在的影响。通过HSPG介导的EV介导的沟通的致瘤作用应激发针对EV-HSPG相互作用的治疗方法的开发，作为癌症治疗中的一种新策略。我们讨论了HSPG家族在这些不同的EV交流环境中的多效性作用，特别关注肿瘤的发展。我们提出了与电动汽车相关的PGs作为信号分子的动态储库和分子伴侣，对电动汽车与肿瘤靶细胞之间的配体交换具有潜在的影响。通过HSPG介导的EV介导的沟通的致瘤作用应激发针对EV-HSPG相互作用的治疗方法的开发，作为癌症治疗中的一种新策略。