The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced. These chemotherapy-induced exosomes (chemoexosomes) have a proteome profile distinct from cells not exposed to drug including a dramatic elevation in the level of heparanase present as exosome cargo. The chemoexosome heparanase was not found inside the chemoexosome, but was present on the exosome surface where it was capable of degrading heparan sulfate embedded within an extracellular matrix. When exposed to myeloma cells, chemoexosomes transferred their heparanase cargo to those cells, enhancing their heparan sulfate degrading activity and leading to activation of ERK signaling and an increase in shedding of the syndecan-1 proteoglycan. Exposure of chemoexosomes to macrophages enhanced their secretion of TNF-α, an important myeloma growth factor. Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that anti-myeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels extracellular matrix and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse. SUMMARY We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression.

中文翻译：

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化学疗法诱导分泌了乙酰肝素酶的外泌体分泌，降解了细胞外基质并影响肿瘤和宿主细胞的行为。

硫酸乙酰肝素降解酶乙酰肝素酶通过驱动肿瘤细胞增殖，转移和血管生成来促进许多癌症的进展。乙酰肝素酶通过多种机制来实现此目的，包括最近描述的增强肿瘤外泌体生物发生的作用。由于我们最近发现乙酰肝素酶的表达在能幸免于化疗的骨髓瘤细胞中被上调，因此提示我们研究抗骨髓瘤药物对外泌体生物发生的影响。当骨髓瘤细胞暴露于常用的抗骨髓瘤药物硼替佐米，卡非佐米或美法仑时，细胞的外泌体分泌显着增强。这些化学疗法诱导的外泌体（chemoexosome）的蛋白质组谱不同于未暴露于药物的细胞，包括作为外泌体货物的乙酰肝素水平急剧升高。化学外泌体乙酰肝素酶未在化学外泌体内部发现，但存在于外泌体表面，在那里它能够降解嵌入细胞外基质中的硫酸乙酰肝素。当暴露于骨髓瘤细胞时，化学外来体将其乙酰肝素酶货物转移至那些细胞，增强了其硫酸乙酰肝素的降解活性，并导致ERK信号的活化和syndecan-1蛋白聚糖脱落的增加。将化学外泌体暴露于巨噬细胞可增强其分泌TNF-α（一种重要的骨髓瘤生长因子）的能力。此外，化学外泌体刺激巨噬细胞迁移，而H1023阻止了这种作用，抑制乙酰肝素酶活性的单克隆抗体。这些数据表明，抗骨髓瘤治疗会触发一连串具有高水平乙酰肝素酶的外来体，从而重塑细胞外基质并改变肿瘤和宿主细胞的行为，从而可能导致化学耐药性和最终患者复发。发明内容我们发现抗骨髓瘤化学疗法极大地刺激了外泌体的分泌并改变了外泌体的组成。治疗期间分泌的外泌体表面含有高水平的乙酰肝素酶，可以降解ECM，并且还可以转移到肿瘤和宿主细胞中，从而改变其行为，从而增强肿瘤的存活和发展。这些数据表明，抗骨髓瘤治疗会触发一连串具有高水平乙酰肝素酶的外来体，从而重塑细胞外基质并改变肿瘤和宿主细胞的行为，从而可能导致化学耐药性和最终患者复发。发明内容我们发现抗骨髓瘤化学疗法极大地刺激了外泌体的分泌并改变了外泌体的组成。治疗期间分泌的外泌体表面含有高水平的乙酰肝素酶，可以降解ECM，并且还可以转移到肿瘤和宿主细胞中，从而改变其行为，从而增强肿瘤的存活和发展。这些数据表明，抗骨髓瘤治疗会触发一连串具有高水平乙酰肝素酶的外来体，从而重塑细胞外基质并改变肿瘤和宿主细胞的行为，从而可能导致化学耐药性和最终患者复发。发明内容我们发现抗骨髓瘤化学疗法极大地刺激了外泌体的分泌并改变了外泌体的组成。治疗期间分泌的外泌体表面含有高水平的乙酰肝素酶，可以降解ECM，并且还可以转移到肿瘤和宿主细胞中，从而改变其行为，从而增强肿瘤的存活和发展。发明内容我们发现抗骨髓瘤化学疗法极大地刺激了外泌体的分泌并改变了外泌体的组成。治疗期间分泌的外泌体表面含有高水平的乙酰肝素酶，可以降解ECM，并且还可以转移到肿瘤和宿主细胞中，从而改变其行为，从而增强肿瘤的存活和发展。发明内容我们发现抗骨髓瘤化学疗法极大地刺激了外泌体的分泌并改变了外泌体的组成。治疗期间分泌的外泌体表面含有高水平的乙酰肝素酶，可以降解ECM，并且还可以转移到肿瘤和宿主细胞中，从而改变其行为，从而增强肿瘤的存活和发展。