The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized, encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here, we focused on the cross-talk between macrophages, chemotherapy, and heparanase and the combined effect on tumor progression. Macrophages were markedly activated by chemotherapeutics paclitaxel and cisplatin, evidenced by increased expression of proinflammatory cytokines, supporting recent studies indicating that chemotherapy may promote rather than suppress tumor regrowth and spread. Strikingly, cytokine induction by chemotherapy was not observed in macrophages isolated from heparanase-knockout mice, suggesting macrophage activation by chemotherapy is heparanase dependent. paclitaxel-treated macrophages enhanced the growth of Lewis lung carcinoma tumors that was attenuated by a CXCR2 inhibitor. Mechanistically, paclitaxel and cisplatin activated methylation of histone H3 on lysine 4 (H3K4) in wild-type but not in heparanase-knockout macrophages. Furthermore, the H3K4 presenter WDR5 functioned as a molecular determinant that mediated cytokine induction by paclitaxel. This epigenetic, heparanase-dependent host-response mechanism adds a new perspective to the tumor-promoting functions of chemotherapy, and offers new treatment modalities to optimize chemotherapeutics. Significance: Chemotherapy-treated macrophages are activated to produce proinflammatory cytokines, which are blunted in the absence of heparanase.

中文翻译：

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乙酰肝素酶和化学疗法协同作用以驱动巨噬细胞活化并增强肿瘤生长

乙酰肝素酶在肿瘤发生，生长，转移和化学耐药中的新兴作用已得到公认，这鼓励了乙酰肝素酶抑制剂作为抗癌药的发展。与乙酰肝素酶在癌细胞中的功能不同，很少关注由组成肿瘤微环境的细胞贡献的乙酰肝素酶。在这里，我们集中于巨噬细胞，化学疗法和乙酰肝素酶之间的相互影响以及对肿瘤进展的综合影响。巨噬细胞被化疗药物紫杉醇和顺铂显着激活，促炎性细胞因子的表达增加证明了这一点，支持最近的研究表明化学疗法可以促进而不是抑制肿瘤的再生和扩散。令人惊讶的是，在从乙酰肝素敲除小鼠中分离出的巨噬细胞中未观察到化学疗法诱导的细胞因子，提示化学疗法激活巨噬细胞是乙酰肝素酶依赖性的。紫杉醇处理的巨噬细胞增强了Lewis肺癌肿瘤的生长，这种肿瘤被CXCR2抑制剂减弱了。从机制上讲，紫杉醇和顺铂在野生型中激活组蛋白H3在赖氨酸4（H3K4）上的甲基化，而在乙酰肝素酶敲除巨噬细胞中则没有。此外，H3K4呈递者WDR5充当分子决定簇，可通过紫杉醇介导细胞因子的诱导。这种表观遗传的，依赖乙酰肝素酶的宿主反应机制为化学疗法的肿瘤促进功能增加了新的视角，并为优化化学疗法提供了新的治疗方式。意义：激活经化学疗法处理的巨噬细胞以产生促炎性细胞因子，在缺乏乙酰肝素酶的情况下，该因子会变钝。