Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan.
J Immunother. 2010 Jan;33(1):73-82. doi: 10.1097/CJI.0b013e3181b7a0a4.
Chronic inflammation is a potential risk factor for tumor progression. The molecular mechanisms linking chronic inflammation and tumor growth have proven elusive. Herein, we describe a new role for Toll-like receptor 4 (TLR4) in tumor-associated macrophages (TAMs) in promoting tumor growth. TAMs can remodel tumor microenvironment and promote tumor growth. With the use of mice lacking TLR4 signaling, we show that TLR4 signaling influences tumor growth and that TLR4 signaling is a critical upstream activator of nuclear factor-kappa B (NF-kappaB) in TAMs. TLR4-deficient TAMs produce neither proinflammatory cytokines nor angiogenic factors, and activate no NF-kappaB activity in tumor cells. Furthermore, using macrophage/tumor cell coculture system and adoptive transfer of macrophages with functional TLR4 macrophages to TLR4-deficient mice bearing tumors, we demonstrate an essential role for TLR4 signaling in inducing NF-kappaB activity in tumor cells and enhancing tumor growth. Antibody neutralization experiments reveal that TAMs are stimulated by heat shock proteins derived from tumor cells through TLR4, leading to production of growth factors, which may in turn promote tumor growth via NF-kappaB signal pathway. Therefore, this signaling cascade may represent a therapeutic target in cancer.
慢性炎症是肿瘤进展的一个潜在风险因素。将慢性炎症与肿瘤生长联系起来的分子机制一直难以捉摸。在此，我们描述了 Toll 样受体 4（TLR4）在肿瘤相关巨噬细胞（TAMs）中促进肿瘤生长的新作用。TAMs 可以重塑肿瘤微环境并促进肿瘤生长。利用缺乏 TLR4 信号的小鼠，我们表明 TLR4 信号影响肿瘤生长，并且 TLR4 信号是 TAMs 中核因子-κB（NF-κB）的关键上游激活剂。TLR4 缺陷型 TAMs 既不产生促炎细胞因子也不产生血管生成因子，并且不能激活肿瘤细胞中的 NF-κB 活性。此外，通过巨噬细胞/肿瘤细胞共培养系统和用具有功能性 TLR4 的巨噬细胞过继转移到携带肿瘤的 TLR4 缺陷型小鼠，我们证明了 TLR4 信号在诱导肿瘤细胞中 NF-κB 活性和增强肿瘤生长方面的重要作用。抗体中和实验表明，TAMs 通过 TLR4 被源自肿瘤细胞的热休克蛋白刺激，导致生长因子的产生，这可能通过 NF-κB 信号通路进而促进肿瘤生长。因此，该信号级联可能代表癌症的治疗靶点。
