Tumor microenvironment pathways: Cross regulation in breast cancer metastasis

The tumor microenvironment (TME) is heterogeneous and contains a multiple cell population with surrounded immune cells, which plays a major role in regulating metastasis. The multifunctional pathways, Hedgehog (Hh), Wnt, Notch, and NF-kB, cross-regulates metastasis in breast cancer. This review presents substantial evidence for cross-regulation of TME components and signaling pathways, which makes breast TME more heterogeneous and complex, promoting breast cancer progression and metastasis as a highly aggressive form. We discoursed the importance of stromal and immune cells as well as their crosstalk in bridging the metastasis. We also discussed the role of Hh and Notch pathways in the intervention between breast cancer cells and macrophages to support TME; Notch signaling in the bidirectional communication between cancer cells and components of TME; Wnt signal pathway in controlling the factors responsible for EMT and NF-kappa B pathway in the regulation of genes controlling the inflammatory response. We also present the role of exosomes and their miRNAs in the cross-regulation of TME cells as well as pathways in the reprogramming of breast TME to support metastasis. Finally, we examined and discussed the targeted small molecule inhibitors and natural compounds targeting developmental pathways and proposed small molecule natural compounds as potential therapeutics of TME based on the multitargeting ability. In conclusion, the understanding of the molecular basis of the cross-regulation of TME pathways and their inhibitors helps identify molecular targets for rational drug discovery to treat breast cancers. Copyright (C) 2020, Chongqing Medical University. Production and hosting by Elsevier B.V.

Automated summary

This review discusses the heterogeneous and complex nature of the tumor microenvironment (TME) in breast cancer metastasis. The cross-regulation of signaling pathways such as Hedgehog, Wnt, Notch, and NF-kB is crucial in promoting breast cancer progression and metastasis. The importance of stromal and immune cells, as well as their interaction, in bridging the metastasis is highlighted. The role of Hh, Notch, Wnt, and NF-kappa B pathways in supporting TME and controlling various aspects of breast cancer progression is also discussed. Additionally, the involvement of exosomes and miRNAs in the cross-regulation of TME cells and pathways is explored. The review concludes with an examination of targeted small molecule inhibitors and natural compounds as potential therapeutics targeting TME.