Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Cancer Metastasis Rev. 2020 Sep;39(3):933-952. doi: 10.1007/s10555-020-09878-7.
Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.
Wnt5a 是典型的非经典 Wnt 通路激活剂，其过表达通过促进细胞迁移、侵袭、上皮间质转化和转移，被认为与几种肿瘤类型的进展有关。最近的证据揭示了 Wnt5a 在癌症细胞中磷酸化 NF-κB 亚基 p65 和激活 NF-κB 通路中的新作用。在本文中，我们综述了定义 Wnt5a/NF-κB 信号通路的分子机制和介质，并提出一些肿瘤中 Wnt5a 的异常表达驱动了 Wnt5a/NF-κB/IL-6/STAT3 正反馈回路，放大了 Wnt5a 的作用。这里讨论的证据表明，Wnt5a 对肿瘤微环境有双重影响。首先，它激活了一个自分泌的 ROR1/Akt/p65 通路，促进了免疫细胞的炎症和趋化作用。然后，Wnt5a 仅在髓样细胞中激活 TLR/MyD88/p50 通路，促进抗炎细胞因子 IL-10 的合成和耐受表型。由于这些机制，Wnt5a 对免疫细胞功能起负作用，有助于免疫抑制的肿瘤微环境，并可能导致对免疫治疗的抵抗。最后，我们总结了针对 Wnt5a 或 Wnt5a 受体 ROR1 的不同策略的发展，这些策略通过有助于产生更具免疫刺激性的肿瘤微环境，有助于癌症治疗。
