Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USA.
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Cells. 2022 Mar 30;11(7):1164. doi: 10.3390/cells11071164.
It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers [e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 "neutralizing" antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered.
三十多年前人们就认识到多功能细胞因子白细胞介素 6（IL-6）几乎总是存在于宿主-肿瘤界面。肿瘤微环境中的 IL-6 可以由癌细胞或宿主基质细胞产生，也可以由肿瘤浸润免疫细胞产生，或者由它们共同产生。在这种情况下，IL-6 的作用包括肿瘤细胞-细胞和细胞-基质黏附的局部变化、增强的迁移能力、上皮间质转化（EMT）以及实体瘤和血液恶性肿瘤中细胞增殖率的变化。局部产生的 IL-6 增强了肿瘤浸润巨噬细胞和免疫细胞的靶向肿瘤功能。此外，某些癌症的性别偏倚表型[例如，肝细胞癌（HCC）在男性中发病率高出 3-5 倍]与雌激素 17β（E2）抑制巨噬细胞衍生的 IL-6 产生有关。在许多情况下，局部产生的 IL-6 到达外周循环并引起全身效应，如恶病质和副肿瘤综合征（包括发热、红细胞沉降率增加、血清 C 反应蛋白水平升高、低白蛋白血症）。这篇综述强调了 IL-6 在癌细胞中产生的 EMT，以及 HCC 性别偏倚的潜在机制，包括 p53 突变导致癌细胞中 IL-6 表达增强、随之而来的 STAT3 转录信号改变，以及在癌症细胞中作为相分离生物分子凝聚物和无膜细胞器（MLO）的新型 STAT3 核体的理解。此外，还讨论了使用不同检测方法在人体循环中测量 IL-6 时出现的令人困惑的差异问题，尤其是在接受免疫治疗的患者中。此外，还考虑了抗 IL-6“中和”抗体在体内对 IL-6 的悖论性伴侣（增强）作用以及使用抗 IL-6 mAb 进行免疫治疗的局限性。
