Abstract
Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1Rpos cells exhibit a complex repertoire of pluripotency, epithelial–mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1Rpos cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention.
Highlights
Receptor tyrosine kinase primarily reported as responsible for the proliferation, differentiation and survival of the monocyte– macrophage cell lineage, as well as their recruitment.[1]
To investigate whether CSF-1R is expressed in mesothelioma tissues and if its levels are correlated to the tumor state, we performed a microarray expression analysis of 34 matched pair samples of normal peritoneal tissue versus mesotheliomas (Figure 1a)
Enzyme-linked immunosorbent assay (ELISA) assay revealed that both CSF-1R ligands were represented in the medium of the primary cultures (Figure 1d)
Summary
Receptor tyrosine kinase primarily reported as responsible for the proliferation, differentiation and survival of the monocyte– macrophage cell lineage, as well as their recruitment.[1] The two known ligands of CSF-1R are CSF-1 and the structurally unrelated sibling IL-34 (interleukin-34). Both CSF-1 and IL-34 function through non-competitive binding to CSF-1R by triggering auto- and transphosphorylation of tyrosine residues in the cytoplasmic domain of the receptor,[2] which results in the activation of both phosphatidylinositol 3-kinase (PI3K)-. MPM is a clinically relevant model to study the relationships between chronic inflammation and chemoresistance, as asbestos exposure of pleural mesothelial cells induces sustained nuclear factor-kB (NF-kB) activation[15]
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