Abstract
Sarcomatoid mesothelioma (SM) is a devastating cancer associated with one of the poorest outcome. Therefore, representative preclinical models reproducing different tumor microenvironments (TME) observed in patients would open up new prospects for the identification of markers and evaluation of innovative therapies. Histological analyses of four original models of rat SM revealed their increasing infiltrative and metastatic potential were associated with differences in Ki67 index, blood-vessel density, and T-lymphocyte and macrophage infiltration. In comparison with the noninvasive tumor M5-T2, proteomic analysis demonstrated the three invasive tumors F4-T2, F5-T1 and M5-T1 shared in common a very significant increase in the abundance of the multifunctional proteins galectin-3, prohibitin and annexin A5, and a decrease in proteins involved in cell adhesion, tumor suppression, or epithelial differentiation. The increased metastatic potential of the F5-T1 tumor, relative to F4-T2, was associated with an increased macrophage vs T-cell infiltrate, changes in the levels of expression of a panel of cytokine genes, an increased content of proteins involved in chromatin organization, ribosome structure, splicing, or presenting anti-adhesive properties, and a decreased content of proteins involved in protection against oxidative stress, normoxia and intracellular trafficking. The most invasive tumor, M5-T1, was characterized by a pattern of specific phenotypic and molecular features affecting the presentation of MHC class I-mediated antigens and immune cell infiltration, or involved in the reorganization of the cytoskeleton and composition of the extracellular matrix. These four preclinical models and data represent a new resource available to the cancer research community to catalyze further investigations on invasiveness.
Highlights
For cancers located in deep cavities, early symptoms are often absent, and the majority of patients are diagnosed late in the disease, leading to very low five-year survival rates
The most significant change shared in common by the three invasive MM concerned galectin-3, a multifunctional protein distributed both www.oncotarget.com intracellularly and in the tumor stroma, which is involved in the development, progression, invasion and metastasis of many cancers [18]
NCAM belongs to the same category of proteins involved in cell adhesion, as both upregulation and downregulation have been reported in cancers, inactivation of the Ncam gene in vivo has indicated a key role for this adhesion molecule in governing the interplay between tumor cells and their microenvironment [28]
Summary
For cancers located in deep cavities, early symptoms are often absent, and the majority of patients are diagnosed late in the disease, leading to very low five-year survival rates For such patients, a better understanding of the crosstalk between tumor cells and components of the tumor microenvironment (TME) (stromal cells including www.oncotarget.com immune cells, blood vessels, extracellular matrix (ECM), and associated signaling molecules) [1] is critical. Antitumor effector T-cell quantity or quality may not be the key, as the TME can confer profound resistance to lymphocyteinduced cell death [4] Recent findings in this field have demonstrated that CD8+ T cells recognizing tumorspecific antigens detected in patients are dysfunctional early in the tumorigenic process [6], while the TME contributes to the exclusion of T cells from the vicinity of cancer cells, leading to their concentration outside the tumor field [7]
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