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.
Highlights
Drug resistance or chemoresistance is a hallmark of many advanced tumors and one of the main reasons for therapy failure despite developing novel compounds
This concept is known as intratumoral heterogeneity, which contributes to differential drug responses and the selection of resistant subclones during treatment [1,2]
As the tumor microenvironment (TME) dynamically shapes tumor response to therapy, so do tumor cells actively recruit microenvironmental components to support their features, chemoresistance included [17–24]. Such studies demand a shift in scales of our understanding of the acquisition of drug resistance, from cellular to a multicellular/tissue-level process in which the tumor-stroma crosstalk comes into play
Summary
Drug resistance or chemoresistance is a hallmark of many advanced tumors and one of the main reasons for therapy failure despite developing novel compounds. As the TME dynamically shapes tumor response to therapy, so do tumor cells actively recruit microenvironmental components to support their features, chemoresistance included [17–24] Such studies demand a shift in scales of our understanding of the acquisition of drug resistance, from cellular to a multicellular/tissue-level process in which the tumor-stroma crosstalk comes into play. We will propose that, if, on the one hand, mutp promotes the rewiring of intracellular signaling, on the other hand, the consequences extend beyond the plasma membrane and across the tumor tissue where mutant and non-mutant cells coexist In this way, mutp reverses the tide of wtp53-associated tumor suppression with a pro-tumoral, chemoresistance-promoting wave of alternated p53 activity
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