Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation

Our plain-English summary of Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation, by M. Cioce, C. Canino, C. Goparaju, et al (Cell Death & Disease, 2014).

The study

• Authors: M. Cioce, C. Canino, C. Goparaju, H. Yang, M. Carbone, H.I. Pass
• Journal: Cell Death & Disease
• Published: 2014;5(4):e1167
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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-1R(pos) 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 CSF1R(pos) 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.

In plain English

This laboratory study examined CSF-1R (macrophage colony-stimulating-factor-1 receptor) in malignant pleural mesothelioma (MPM). Microarray analysis of 34 matched normal peritoneal and mesothelioma samples showed higher CSF-1R mRNA in tumour tissue (P less than 0.001). In seven primary MPM cultures, CSF-1R-positive cells persisted in long-term culture and many co-expressed calretinin. CSF-1 was found in 7 of 7 and IL-34 in 6 of 7 primary culture media. All mesothelioma cell lines contained a small CSF-1R-positive fraction (2-13%), versus under 1.5% of LP9 mesothelial cells. CSF-1R-positive cells survived pemetrexed in cell lines and primary cultures. Silencing CSF-1R reduced viability and colony formation of vehicle- and pemetrexed-treated cells, more strongly in the pemetrexed-treated cells. A CSF-1R ligand decoy reduced colony formation of H-2595 cells and viability of purified primary CSF-1R-positive cells, further reduced by pemetrexed. Sorted CSF-1R-positive cells were enriched for pluripotency, EMT and detoxifying genes and phospho-AKT. Expressing a constitutively active CSF-1R in LP9 cells conferred clonogenicity and pemetrexed resistance, reversed by the AKT inhibitor LY294002.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study: tumour tissue gene-expression microarray plus experiments in mesothelioma primary cultures, mesothelioma cell lines and an immortalized mesothelial cell line, including RNA interference, ligand trapping, drug inhibitors and expression of a constitutively active receptor
• Who was studied: mRNA from 34 snap-frozen matched peritoneal versus MPM operative specimens (Karmanos Cancer Institute, Detroit, and NYU Langone Medical Center, New York); 7 mesothelioma primary cultures from pleural effusions and solid specimens of MPM patients; 7 human MPM cell lines and the immortalized mesothelial line LP9
• Exposure: Not an asbestos exposure study; the 'exposures' were laboratory ones: CSF-1 and IL-34 (25 ng/ml), a truncated CSF-1R extracellular domain decoy, CSF-1R-targeting shRNA and siRNA, the chemotherapy drug pemetrexed, and inhibitors parthenolide, butein, LY294002 (PI3K/AKT) and U0126 (MEK1/2-ERK1/2)
• Main results:
  • CSF-1R mRNA was higher in mesothelioma tissue than in matched normal peritoneal tissue from the 34 matched pairs (reported as P less than 0.001)
  • All seven mesothelioma primary cultures contained CSF-1R-positive cells shortly after harvesting, and the percentage was almost unchanged or slightly increased after an average 2.2 plus or minus 1.1 months of culture
  • In the primary cultures, CSF-1 was detected in the conditioned medium of 7 of 7 cultures and IL-34 in 6 of 7
  • All mesothelioma cell lines contained a small CSF-1R-positive sub-population (range 2-13%), while under 1.5% of untransformed mesothelial LP9 cells were CSF-1R-positive
  • Among the cell lines, 7 of 7 mesothelioma cell lines secreted IL-34 and 6 of 7 secreted CSF-1
  • The untransformed mesothelial LP9 cells produced no detectable IL-34 and very little CSF-1
  • Treating H-2595 cells with a truncated CSF-1R extracellular domain (ECD), which sequesters CSF-1 and IL-34, reduced colony formation dose-dependently (colony assay without pemetrexed); control BSA treatment had no effect
  • In two representative primary cultures, viability of purified CSF-1R-positive cells was affected by the CSF-1R decoy (ECD) and further reduced by pemetrexed
  • CSF-1R-positive cells persisted after pemetrexed treatment in the mesothelioma cell lines, which was not seen in pemetrexed-treated mesothelial LP9 cells (P less than 0.05); in all seven primary cultures CSF-1R-positive cells survived pemetrexed without significant change in number
  • shRNA knockdown of CSF-1R in H-2595 and H-2373 cells reduced viability and clonogenicity of both vehicle- and pemetrexed-treated cells, with a stronger effect in the pemetrexed-treated cells, interpreted by the authors as chemosensitizing
  • Sorted CSF-1R-positive cells were enriched for pluripotency, EMT and chemoresistance transcripts and for phospho-STAT3, phospho-NF-kB p65 and phospho-AKT, with no difference in phospho-ERK1/2 compared with unsorted cells
  • Expression of a constitutively active CSF-1R in untransformed LP9 mesothelial cells produced morphological change, faster growth, clonogenicity and pemetrexed resistance; the AKT inhibitor LY294002 reversed this resistance and increased senescent cells
• The authors' conclusion: The authors concluded that CSF-1R expression identifies a precursor-like, clonogenic, chemoresistant mesothelioma cell sub-population dependent on autocrine CSF-1/IL-34 signalling and AKT activation, and suggested that CSF-1R and AKT inhibition may be relevant tools to overcome mesothelioma chemoresistance
• Limitations the authors state:
  • The authors noted that the tissue microarray result alone did not rule out that tumour-associated macrophages or bone marrow-derived cells contributed to the higher CSF-1R expression measured in tumour tissue
  • The authors noted that the degree to which inhibiting CSF-1R-positive cells reduced chemoresistance exceeded what targeting that small fraction alone would predict, and offered a possible but unproven explanation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Chemotherapy, Macrophage, Mesothelial Cells, Pemetrexed (Alimta), Inflammation.

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