Nervous system interactions with nonimmune elements in cancer microenvironment: A missing piece?

An adequate tumor microenvironment is essential for the growth and spread of cancer cells. This microenvironment consists of fibroblasts, endothelial cells, immune cells, and neurons along with other components (Denton et al., Adv Exp Med Biol 1060:99-114, 2018). Recent discoveries have shown the key role of stroma-cancer interactions in shaping the tumor microenvironment. For instance, fibroblasts, found and activated in the tumor microenvironment, are accountable for the epithelial-mesenchymal transition of cancer cells and the formation of the desmoplastic microenvironment in certain cancers (Jurcak and Zheng, Pharmacol Ther 200:126-134, 2019; General Subjects 1861(2):296-306, 2017). Moreover, evidence shows that nerves play a vital role in the development of some cancers (Dwivedi et al., Cell Death Discov 7:364, 2021), supported by the known prognostic value of nerve-cancer interactions, such as neural invasion (Schorn et al., Surg Oncol 26:105-115, 2017). Even though the cancer cell-stroma interactions have been studied in detail, the investigation of the interactions of stromal components with each other, especially of the nerves with other stromal elements, is still at its infancy. This missing piece could be of vital importance in our understanding of the complex puzzle that cancer constitutes and help us overcome cancer-related death. With this review, we aim to shed a light on the nerve-stroma interactions in cancer biology and summarize the recent discoveries in this field.