Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Cells. 2022 Aug 22;11(16):2618. doi: 10.3390/cells11162618.
Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity.
自 19 世纪鲁道夫·魏尔啸（Rudolf Virchow）时代以来，人们已经熟知癌症相关炎症有助于肿瘤的发生和进展。然而，尚不清楚是否是抗肿瘤免疫反应（通过免疫监视系统）与癌症相关炎症引起的促肿瘤免疫之间的平衡崩溃导致了癌症的恶性程度。大多数炎症信号通过激活信号转导和转录激活因子 3（STAT3）和核因子-κB 来影响肿瘤发生。恶性癌细胞中持续的 STAT3 激活介导了极其广泛的功能，包括细胞生长、存活、血管生成和侵袭，并导致与炎症相关的肿瘤发生增加。此外，免疫细胞内的 STAT3 激活会对抗肿瘤免疫产生抑制作用，并导致未成熟髓样衍生细胞和肿瘤相关巨噬细胞的分化和动员。在许多癌症类型中，STAT3 并不直接依赖于其致癌突变的激活，而是在肿瘤微环境（TME）中的肿瘤和基质细胞中具有重要的致癌和恶性转化相关功能。我们已经报告了一系列旨在了解涉及信号转导衔接蛋白-2 的各种类型肿瘤增殖的分子机制的研究，作为调节 STAT3 活性的衔接分子，我们最近发现富含 AT 的相互作用域蛋白 5a 作为一种 mRNA 稳定剂，协调恶性间充质肿瘤中的免疫抑制性 TME。在这篇综述中，我们总结了我们对 STAT3 在肿瘤进展中的功能作用的最新理解，并介绍了迄今为止我们发现的涉及 STAT3 激活的癌症发展和恶性转化的新分子机制。最后，我们讨论了针对靶向信号通路以增强 STAT3 活性的癌症的潜在治疗策略。
