A Novel Therapeutic Target for Small-Cell Lung Cancer: Tumor-Associated Repair-like Schwann Cells

Abstract

Small-cell lung cancer (SCLC), representing 15–20% of all lung cancers, is an aggressive malignancy with a distinct natural history, poor prognosis, and limited treatment options. We have previously identified Schwann cells (SCs), the main glial cells of the peripheral nervous system, in tumor tissues and demonstrated that they may support tumor spreading and metastasis formation in the in vitro and in vivo models. However, the role of SCs in the progression of SCLC has not been investigated. To clarify this issue, the cell proliferation assay, the annexin V apoptosis assay, and the transwell migration and invasion assay were conducted to elucidate the roles in SCLC of tumor-associated SCs (TA-SCs) in the proliferation, apoptosis, migration, and invasion of SCLC cells in vitro, compared to control group. In addition, the animal models to assess SC action’s effects on SCLC in vivo were also developed. The result confirmed that TA-SCs have a well-established and significant role in facilitating SCLC cell cancer migration and invasion of SCLC in vitro, and we also observed that SC promotes tumor growth of SCLC in vivo and that TA-SCs exhibited an advantage and show a repair-like phenotype, which allowed defining them as tumor-associated repair SCs (TAR-SCs). Potential molecular mechanisms of pro-tumorigenic activity of TAR-SCs were investigated by the screening of differentially expressed genes and constructing networks of messenger-, micro-, and long- non-coding RNA (mRNA-miRNA-lncRNA) using DMS114 cells, a human SCLC, stimulated with media from DMS114-activated SCs, non-stimulated SCs, and appropriate controls. This study improves our understanding of how SCs, especially tumor-activated SCs, may promote SCLC progression. Our results highlight a new functional phenotype of SCs in cancer and bring new insights into the characterization of the nervous system-tumor crosstalk.

Schwann cell‐derived exosomes promote lung cancer progression via miRNA‐21‐5p

“…We recently reported that SCs can promote the proliferation and motility of SCLC cell lines in vitro (Cao et al, 2022). To determine the effect of SCs on NSCLC cells and investigate the involvement of SC‐derived extracellular vesicles, we harvested SC‐conditioned medium (SC‐CM) and obtained exosome‐free SC‐CM by size exclusion chromatography and ultracentrifugation (SC‐CM fraction S150).…”

“…Our previous animal studies revealed that SCs, as the principal glial cells of the PNS securing neuronal survival and function, could accelerate lung adenocarcinoma growth and spreading by inducing macrophage polarization and EMT via chemokine production (Zhou et al, 2018; Zhou et al, 2020). Recently, we reported that tumor‐associated SCs may stimulate the viability and motility of SCLC cells (Cao et al, 2022). However, the mechanisms underlying human SC protumorigenic activity are mostly unknown.…”

Schwann cells in the normal and pathological lung microenvironment

“…SCs were detected in the lung tumors and in the tumor surrounding area both in experimental animals and human specimens ( Silva et al, 2019 ; Cao et al, 2022 ). Furthermore, the retrospective analysis of SC identification in NSCLC tissues comprising 90 cases of adenocarcinoma and 51 cases of squamous cell carcinoma revealed higher levels of SCs in cancerous tissues compared to adjacent tissues ( Zhou et al, 2019 ).…”

“…These results suggest that identified intratumoral SC-associated molecules may be used as systems biomarkers for screening in perineural invasion of lung cancer or for potential therapeutic purposes ( Silva et al, 2019 ). Importantly, new data focusing on the ability of human TA-SCs to regulate the functional activity of human SCLC cell lines in vitro revealed that TA-SCs upregulated longevity, proliferation, migration, and invasiveness of tumor cells ( Cao et al, 2022 ). In vivo studies confirmed these findings by demonstrating that SCs promote the growth of SCLC in mice.…”

“…Investigation of differentially expressed genes in lung cancer-activated repair-like SCs allowed the construction of unique networks of messenger-, micro-, and long non-coding RNA (mRNA-miRNA-lncRNA) that brought new insights into our understanding of potential molecular mechanisms of pro-tumorigenic activity of lung cancer-associated SCs. Furthermore, using the gene ontology (GO) enrichment annotations for the analysis of differentially expressed mRNAs in the SC-treated SCLC cells revealed a series of significant alterations that were categorized in all three common groups: biological process, cellular component, and molecular function ( Cao et al, 2022 ). These new findings identified a new functional phenotype of SCs in cancer and brought new development into a better characterization of the nervous system-tumor crosstalk.…”