Abstract
p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization.
Highlights
Discovered at the highpoint of tumor virus research and initially classified as an oncogene, the tumor suppressor p53 is considered one of the most critical protectors of the human genome and a central component of a multiplex molecular network of signaling cascades [1,2,3,4]
Similar as observed for the transcriptional activities of wild-type and mutant p53, mutant p53 proteins. These tumor‐associated macrophages (TAMs) are a chief component of the vast majority of solid tumors and strategic players in cancer progression, as they are responsible for constructing an immunosuppressive and pro‐metastatic microenvironment through the production of chemokines, cytokines, and growth factors [188,189]. It is still unknown whether other stromal cells are affected, this study revealed an intriguing cell nonautonomous pro‐tumorigenic role of mutant Bipom5o3leicnulems 2ic0r2o0,e1n0v, 3ir0o7nmental reprogramming mediated by altered cargo loading of exosomes. 13 of 24
Mutant p53 is recognized as an important driver of the epithelial-mesenchymal transition (EMT) by controlling TGF-β signaling and by regulating expression of various epithelial-to-mesenchymal transition (EMT) TFs (ZEB1, ZEB2, Snail, and Slug) or EMT-miRNAs [23]
Summary
Discovered at the highpoint of tumor virus research and initially classified as an oncogene, the tumor suppressor p53 is considered one of the most critical protectors of the human genome and a central component of a multiplex molecular network of signaling cascades [1,2,3,4]. Mutant p53 has been shown to control several tumor cell-autonomous processes beneficial for tumor cell survival under adverse conditions, including regulation of energy metabolism, response to proapoptotic signals, and adaptation to oxidative stress [21,24]. Apart from these well-known functions within tumor cells, TP53 mutations affect how tumor cells interact with their surroundings, i.e., the various types of stroma cells in the microenvironment and the extracellular matrix in which tumor and stroma cells are embedded. For the purpose of this review, we will focus on secreted proteins and discuss how TP53 mutations affect the protein secretome of tumor cells and thereby shape the local and distant microenvironment to foster invasion, metastasis, and drive tumor progression to a more aggressive and therapy-refractory state
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