Extracellular Vesicles: Messengers of p53 in Tumor–Stroma Communication and Cancer Metastasis

Abstract

Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor–stroma crosstalk is instructed by the genetic alterations of the tumor cells—the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor–stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor–host communication within the entire organism so as to promote metastatic tumor cell dissemination.

Opposing Roles of Wild-type and Mutant p53 in the Process of Epithelial to Mesenchymal Transition

“…The fact that p53 can change its cellular functions depending on the acquisition of missense mutations makes the mutant p53 protein even more important regulator of EMT. For example, mutant p53 was shown to facilitate the production of exosomes, suggesting that mutant p53 may regulate the microenvironment of metastatic niches ( Pavlakis et al, 2020 ). Furthermore, since metastasizing is a multi-step process that involves EMT, intravasation into the blood vessel followed by extravasation and Mesenchymal-to-Epithelial Transition (a process, opposite to EMT), it would be interesting to see whether mutant p53 can affect all these steps ( Giacomelli et al, 2018 ).…”

Changing Perspectives from Oxidative Stress to Redox Signaling—Extracellular Redox Control in Translational Medicine

“…The extracellular space is gaining increasing recognition as a key compartment determining cancer cell survival and evolution [124,125]. Despite this, redox proteins' role in cancer cells has been mostly investigated intracellularly and less attention has been paid to extracellular redox changes.…”

Dying to Survive—The p53 Paradox

“…p53 has also been shown to play a role in the release of extracellular vesicles, and in particular exosomes, is gaining significant interest in cancer research and immunology owing to the increasing importance of the complex interplay between cancer cells and the tumour microenvironment [150,151]. This includes effects on adjacent cancer cells, resident immune cells as well as cancer associated fibroblasts (CAFs) and the ECM which together determine cancer initiation, progression, and response to treatment.…”

“…This includes effects on adjacent cancer cells, resident immune cells as well as cancer associated fibroblasts (CAFs) and the ECM which together determine cancer initiation, progression, and response to treatment. In response to stress, p53 has been shown to transcriptionally regulate TSAP6, a multi-pass transmembrane protein that facilitates exosome secretion [150]. Exosome size and cargo are also modulated by p53 activity with multiple anti-tumorigenic effects described.…”