Augimeri Giuseppina, Bonofiglio Daniela
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Cosenza, Italy.
Biomedicines. 2021 May 13;9(5):543. doi: 10.3390/biomedicines9050543.
Over the last decades, the breast tumor microenvironment (TME) has been increasingly recognized as a key player in tumor development and progression and as a promising prognostic and therapeutic target for breast cancer patients. The breast TME, representing a complex network of cellular signaling-deriving from different stromal cell types as well as extracellular matrix components, extracellular vesicles, and soluble growth factors-establishes a crosstalk with cancer cells sustaining tumor progression. A significant emphasis derives from the tumor surrounding inflammation responsible for the failure of the immune system to effectively restrain breast cancer growth. Thus, effective therapeutic strategies require a deeper understanding of the interplay between tumor and stroma, aimed at targeting both the intrinsic neoplastic cells and the extrinsic surrounding stroma. In this scenario, peroxisome proliferator-activated receptor (PPAR) γ, primarily known as a metabolic regulator, emerged as a potential target for breast cancer treatment since it functions in breast cancer cells and several components of the breast TME. In particular, the activation of PPARγ by natural and synthetic ligands inhibits breast cancer cell growth, motility, and invasiveness. Moreover, activated PPARγ may educate altered stromal cells, counteracting the pro-inflammatory milieu that drive breast cancer progression. Interestingly, using Kaplan-Meier survival curves, PPARγ also emerges as a prognostically favorable factor in breast cancer patients. In this perspective, we briefly discuss the mechanisms by which PPARγ is implicated in tumor biology as well as in the complex regulatory networks within the breast TME. This may help to profile approaches that provide a simultaneous inhibition of epithelial cells and TME components, offering a more efficient way to treat breast cancer.
在过去几十年中，乳腺肿瘤微环境（TME）日益被认为是肿瘤发生和发展的关键因素，也是乳腺癌患者有前景的预后和治疗靶点。乳腺TME是一个复杂的细胞信号网络，源自不同的基质细胞类型以及细胞外基质成分、细胞外囊泡和可溶性生长因子，它与癌细胞建立了相互作用，维持肿瘤进展。一个重要的关注点来自肿瘤周围的炎症，这种炎症导致免疫系统无法有效抑制乳腺癌的生长。因此，有效的治疗策略需要更深入地了解肿瘤与基质之间的相互作用，旨在同时靶向内在的肿瘤细胞和外在的周围基质。在这种情况下，过氧化物酶体增殖物激活受体（PPAR）γ，主要作为一种代谢调节因子为人所知，由于它在乳腺癌细胞和乳腺TME的几个成分中发挥作用，已成为乳腺癌治疗的潜在靶点。特别是，天然和合成配体对PPARγ的激活可抑制乳腺癌细胞的生长、运动和侵袭。此外，激活的PPARγ可能会重塑改变的基质细胞，对抗驱动乳腺癌进展的促炎环境。有趣的是，使用Kaplan-Meier生存曲线分析，PPARγ在乳腺癌患者中也是一个预后良好的因素。从这个角度来看，我们简要讨论PPARγ参与肿瘤生物学以及乳腺TME内复杂调控网络的机制。这可能有助于勾勒出同时抑制上皮细胞和TME成分的方法，为治疗乳腺癌提供更有效的途径。
