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Review
. 2022 Feb 9;12(2):202.
doi: 10.3390/membranes12020202.

p53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance

Leonel Cardozo de Menezes E Souza  1 , Anderson Faletti  1 , Carla Pires Veríssimo  1 , Mariana Paranhos Stelling  2 , Helena Lobo Borges  1
Affiliations
Review

p53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance

Leonel Cardozo de Menezes E Souza et al. Membranes (Basel). .

Abstract

Chemoresistance persists as a significant, unresolved clinical challenge in many cancer types. The tumor microenvironment, in which cancer cells reside and interact with non-cancer cells and tissue structures, has a known role in promoting every aspect of tumor progression, including chemoresistance. However, the molecular determinants of microenvironment-driven chemoresistance are mainly unknown. In this review, we propose that the TP53 tumor suppressor, found mutant in over half of human cancers, is a crucial regulator of cancer cell-microenvironment crosstalk and a prime candidate for the investigation of microenvironment-specific modulators of chemoresistance. Wild-type p53 controls the secretion of factors that inhibit the tumor microenvironment, whereas altered secretion or mutant p53 interfere with p53 function to promote chemoresistance. We highlight resistance mechanisms promoted by mutant p53 and enforced by the microenvironment, such as extracellular matrix remodeling and adaptation to hypoxia. Alterations of wild-type p53 extracellular function may create a cascade of spatial amplification loops in the tumor tissue that can influence cellular behavior far from the initial oncogenic mutation. We discuss the concept of chemoresistance as a multicellular/tissue-level process rather than intrinsically cellular. Targeting p53-dependent crosstalk mechanisms between cancer cells and components of the tumor environment might disrupt the waves of chemoresistance that spread across the tumor tissue, increasing the efficacy of chemotherapeutic agents.

Keywords: cell-nonautonomous function; drug resistance; extracellular vesicles; mutant p53; p53 signaling; secretome; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of TME-driven chemoresistance promoted by p53 loss. Tumor tissue-level chemoresistance is the result of complex interactions between cancer cells and their TME, with p53 acting as a key regulator. Functional loss of normal p53 can happen in tumor-associated stromal cells, such as fibroblasts, epithelial cells and tissue-resident cells, which cooperates with GOF p53 mutations in cancer cells to enforce a chemoresistant microenvironment, while also augmenting resistant and invasive phenotypes. CAF, cancer-associated fibroblast; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; IL-6, interleukin-6; IL-8, interleukin-8; mutp53, mutant p53; SASP, senescence-associated secretory phenotype; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; wtp53, wild-type p53.
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