Abstract

Simple SummaryIn the tumor microenvironment, interaction among tumor cells, immune cells, stromal cells, and the extracellular matrix is vital to support pro-tumor mechanisms such as drug resistance and metastases. Malignant pleural mesothelioma has a unique and complex tumor microenvironment. Several reports underlined the key role of immune and stromal cells in tumorigenesis and progression of mesothelioma. These non-cancer cells, via a reciprocal informational exchange with tumor cells, established a chronic inflammatory microenvironment that support the malignancy and the chemoresistant phenotype of the tumor. The knowledge of the cellular and molecular mechanisms underlying tumor microenvironment interconnection was recently considered a crucial point for the design of more effective therapeutic strategies. In this review, we summarize the molecular mechanisms by which stroma and immune cells support the malignancy of mesothelioma and their potential therapeutic targeting.Several studies have reported that cellular and soluble components of the tumor microenvironment (TME) play a key role in cancer-initiation and progression. Considering the relevance and the complexity of TME in cancer biology, recent research has focused on the investigation of the TME content, in terms of players and informational exchange. Understanding the crosstalk between tumor and non-tumor cells is crucial to design more beneficial anti-cancer therapeutic strategies. Malignant pleural mesothelioma (MPM) is a complex and heterogenous tumor mainly caused by asbestos exposure with few treatment options and low life expectancy after standard therapy. MPM leukocyte infiltration is rich in macrophages. Given the failure of macrophages to eliminate asbestos fibers, these immune cells accumulate in pleural cavity leading to the establishment of a unique inflammatory environment and to the malignant transformation of mesothelial cells. In this inflammatory landscape, stromal and immune cells play a driven role to support tumor development and progression via a bidirectional communication with tumor cells. Characterization of the MPM microenvironment (MPM-ME) may be useful to understand the complexity of mesothelioma biology, such as to identify new molecular druggable targets, with the aim to improve the outcome of the disease. In this review, we summarize the known evidence about the MPM-ME network, including its prognostic and therapeutic relevance.

Highlights

  • Malignant pleural mesothelioma is the main cancer affecting the pleural membranes covering the lungs

  • Biochemical analysis has shown that spheroid-derived mesothelioma stem-cells (MSCs), expressing increased levels of the cancer cell survival-related protein transaglutaminase (TG2), had more invasive and migratory capabilities compared with monolayer-derived mesothelioma cells

  • Cekic et al [120] reported that A2A expression on myeloid cells, tumor-associated macrophages (TAMs), indirectly mediated suppression of T cells and Natural killer (NK) cells in the tumor microenvironment. Extracellular ATP (eATP) hydrolytic activity to produce ADO has been documented in exosomes isolated from Malignant pleural mesothelioma (MPM) pleural effusion (PE) estimated to contribute for 20% of the total ATP-hydrolytic activity in MPM PE [121]

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Summary

Introduction

Malignant pleural mesothelioma is the main cancer affecting the pleural membranes covering the lungs. Tumor-associated macrophages (TAMs), T regulatory cells (Treg), such as cancer-associated fibroblasts (CAFs), are the most abundant population of MPM infiltration, that, in response to pro-tumoral signals, acquire malignant and immunosuppressive properties, influencing the progression of the tumor [32] (Figure 1). High incidence of CD8+ T cells was associated with a better prognosis and favorable outcome; on the contrary, the presence of M2-like macrophages that represent the most abundant immune population in MPM-TME, was correlated with a worse prognosis and no improvement in the overall survival [36,37]. Up-regulation of ABCB-5 drug transporter was observed in MM CSCs as necessary for the acquisition and maintenance of a stemness and chemoresistant phenotype Intrinsic mechanisms, such as increased expression of the autocrine loops Wnt/GSK3β/β-catenin/c-myc in MM CSCs support the over-activation of ABCB-5 as well as drug resistance of these cells [48]. A better characterization of MM CSCs biology is required to fight drug resistance and improve MM treatment

Mesothelioma Stem Cells Malignancy and TME
Mesothelioma Microenvironment Crosstalk
Macrophages in Mesothelioma
Adenosine Pathway and Mesothelioma Microenvironment
Therapeutic Approach Targeting TME
Findings
Conclusions
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