p53 Signaling on Microenvironment and Its Contribution to Tissue Chemoresistance

Membranes

Mariana Paranhos Stelling¹  Helena Lobo Borges²  Carla Pires Veríssimo²  Anderson Faletti²  Leonel Cardozo de Menezes e Souza² 

[1] Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro 20260-100, Brazil;Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;

关键词: tumor microenvironment;    p53 signaling;    secretome;    extracellular vesicles;    drug resistance;    mutant p53;   

DOI  :  10.3390/membranes12020202

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown