Coagulation proteases and the generation of thrombin are increased in tumors. In addition, chemotherapeutic agents commonly used to treat malignant cancers can exacerbate cancer-associated thromboses. Thrombin can modify tumor cell behavior directly through the activation of protease-activated receptors (PAR) or indirectly by generating fibrin matrices. In addition to its role in generating fibrin to promote hemostasis, thrombin acts directly on multiple effector cells of the immune system impacting both acute and chronic inflammatory processes. Thrombin-mediated release of interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 leads to the accumulation of multiple tumor-infiltrating immunosuppressive cell populations including myeloid derived suppresser cells, M2-like macrophages, and T regulatory cells. Ablation of PAR-1 from the tumor microenvironment, but not the tumor, has been shown to dramatically reduce tumor growth and metastasis in multiple tumor models. Thrombin-activated platelets release immunosuppressive cytokines including transforming growth factor-β that can inhibit natural killer cell activity, helping tumor cells to evade host immunosurveillance. Taken together, there is strong evidence that thrombin influences cancer progression via multiple mechanisms, including the tumor immune response, with thrombin emerging as a target for novel therapeutic strategies for cancer.

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凝血酶在癌症进展中的免疫调节作用

凝血酶和凝血酶的产生在肿瘤中增加。此外，通常用于治疗恶性癌症的化学治疗剂会加剧癌症相关的血栓形成。凝血酶可以直接通过激活蛋白酶激活受体 (PAR) 或通过生成纤维蛋白基质间接改变肿瘤细胞行为。除了在生成纤维蛋白以促进止血方面的作用外，凝血酶还直接作用于免疫系统的多个效应细胞，影响急性和慢性炎症过程。凝血酶介导的白细胞介素 6、肿瘤坏死因子 α 和单核细胞趋化蛋白 1 的释放导致多种肿瘤浸润性免疫抑制细胞群的积累，包括骨髓来源的抑制细胞、M2 样巨噬细胞和 T 调节细胞。在多种肿瘤模型中，从肿瘤微环境而非肿瘤中消融 PAR-1 已被证明可显着减少肿瘤生长和转移。凝血酶激活的血小板释放免疫抑制细胞因子，包括可以抑制自然杀伤细胞活性的转化生长因子-β，帮助肿瘤细胞逃避宿主免疫监视。总之，有强有力的证据表明凝血酶通过多种机制影响癌症进展，包括肿瘤免疫反应，凝血酶成为癌症新治疗策略的靶点。凝血酶激活的血小板释放免疫抑制细胞因子，包括可以抑制自然杀伤细胞活性的转化生长因子-β，帮助肿瘤细胞逃避宿主免疫监视。总之，有强有力的证据表明凝血酶通过多种机制影响癌症进展，包括肿瘤免疫反应，凝血酶成为癌症新治疗策略的靶点。凝血酶激活的血小板释放免疫抑制细胞因子，包括可以抑制自然杀伤细胞活性的转化生长因子-β，帮助肿瘤细胞逃避宿主免疫监视。总之，有强有力的证据表明凝血酶通过多种机制影响癌症进展，包括肿瘤免疫反应，凝血酶成为癌症新治疗策略的靶点。