Cheng Hong Sheng, Yip Yun Sheng, Lim Eldeen Kai Yi, Wahli Walter, Tan Nguan Soon
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore.
Cancers (Basel). 2021 Apr 29;13(9):2153. doi: 10.3390/cancers13092153.
Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.
过氧化物酶体增殖物激活受体（PPARs）已经被广泛研究了三十多年。这些核受体由三种亚型组成，即PPARα、γ和β/δ，它们被视为主要的代谢调节因子，控制着身体能量稳态和细胞命运的许多方面。它们在恶性肿瘤中的作用也越来越受到认可。随着对肿瘤基质与上皮细胞间相互作用的兴趣日益增加，本综述旨在强调目前关于PPARs在肿瘤微环境中作用的知识。PPARγ在癌症相关成纤维细胞和脂肪细胞的代谢重编程中起关键作用，促使这两种基质细胞成为癌症生长的底物供体。成纤维细胞中的PPARβ/δ可以改变肿瘤起始风险和癌症易感性。在内皮细胞中，PPARβ/δ和PPARα分别具有促血管生成和抗血管生成作用。尽管PPARγ的血管生成作用仍不明确，但它是癌症相关成纤维细胞和肿瘤相关巨噬细胞/免疫细胞自分泌和旁分泌信号传导的关键调节因子。值得注意的是，血管生成素样4（ANGPTL4）是一种由PPARs靶基因编码的分泌蛋白，可触发炎症信号传导、细胞外基质紊乱、失巢凋亡抗性和转移等关键致癌过程，使其成为癌症治疗的潜在药物靶点。总之，肿瘤微环境中的PPARs表现出致癌活性，这极具争议性，且取决于许多因素，如基质细胞类型、癌症类型和肿瘤发生阶段。因此，基于PPAR的抗癌治疗的成功可能依赖于以细胞类型特异性方式调节PPAR活性的创新策略。
