Dataset Information

TGFβ1 in Cancer-Associated Fibroblasts Is Associated With Progression and Radiosensitivity in Small-Cell Lung Cancer.

ABSTRACT:

Objective

Small-cell lung cancer (SCLC) is aggressive, with early metastasis. Cytokines secreted by cancer-associated fibroblasts (CAFs) within various tumors influences these features, but the function in particular of TGFβ1 (transforming growth factor beta 1) is controversial and unknown in SCLC. This study explored the influence of TGFβ1 in CAFs on the development, immune microenvironment, and radiotherapy sensitivity of SCLC.

Methods

SCLC specimens were collected from 90 patients who had received no treatment before surgery. Tumor and tumor stroma were subjected to multiplex immunohistochemistry to quantitate TGFβ1 and other immune factors in CAFs. Cell proliferation and flow cytometry apoptosis assays were used to investigate associations between TGFβ1 and proliferation and radiotherapy sensitivity. The immune factors in tumors were detected by immunohistochemistry in vitro and in vivo (mice).

Results

TGFβ1 levels on CAFs lower or higher than the median were found, respectively, in 52.2 and 47.8% of patients; overall survival of patients with TGFβ1-high levels (53.9 mo) was significantly longer than that of the TGFβ1-low group (26.9 mo; P = 0.037). The univariate and multivariate analyses indicated that a TGFβ1-high level was an independent predictor of increased survival time. TGFβ1-high levels in CAFs were associated with inhibition of growth, proliferation, antitumor immunity, and enhanced radiotherapeutic sensitivity and tumor immunity of tumor. TGFβ1-low levels promoted tumor cell growth and radiotherapy sensitivity in vivo and in vitro.

Conclusion

High levels of TGFβ1 in CAFs were associated with longer overall survival in patients with SCLC and enhanced radiotherapy sensitivity.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8172974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRadioresistance of thoracic radiotherapy is a major bottleneck in the treatment of non-small cell lung cancer (NSCLC). Until now, there have been no effective biomarkers to predict the radiosensitivity.PurposesBased on miRNA profile screened from NSCLC cell lines with different radiosensitivity, this study was conducted to explore the correlation between plasma miRNAs and radiotherapy response in NSCLC patients, and to identify biomarkers of the radiosensitivity in NSCLC.MethodsDifferentially expressed genes were acquired from time-series gene expression profiles of radioresistant H1299 and radiosensitive H460 lung cancer cells (GSE20549). Potential miRNAs were screened from these differentially expressed genes by combining bioinformatics with GO analysis, pathway analysis, and miRNA prediction. A clinical observational study was performed to explore the correlation between candidate miRNAs and radiotherapy response. Stage IIIa-IV NSCLC patients who received two to four cycles of previous chemotherapy and underwent thoracic radiotherapy alone were included. Total RNA was purified from peripheral blood before radiotherapy, and plasma miRNAs were detected by real-time PCR (qRT-PCR). Then, tumor response, progression-free survival (PFS), and overall survival (OS) were acquired. Four miRNAs significantly different between effective and ineffective groups were further analyzed to obtain cutpoints from receiver operating characteristic (ROC) curves and the predictive value of radiosensitivity.ResultsCandidate miRNAs included 14 miRNAs screened from radioresistant genes and five from radiosensitive genes. From Jan., 2013 to Dec., 2014, 54 eligible patients were enrolled with a median follow-up of 15.3 months (range 4.6 to 31.4) by the deadline of Aug. 31, 2015. Totally, there were no case of complete response (CR), 15 of partial response (PR), 35 of stable disease (SD), and 4 of progressive disease (PD). Eight patients had no progression and 19 patients were still alive. The median PFS and OS were 6.6 months (range 2.3 to 29.3) and 15.3 months (range 4.6 to 31.4), respectively. Four miRNAs (hsa-miR-98-5p, hsa-miR-302e, hsa-miR-495-3p, and hsa-miR-613) demonstrated a higher expression in effective group (CR + PR, 15 cases) than in ineffective group (SD + PD, 39 cases). Based on each cutpoint, objective response rate (ORR) was higher in miR-high group than in miR-low group. No miRNA showed correlation with median PFS or OS.ConclusionBioinformatical analysis and clinical verification reveal the correlation between plasma miRNAs and radiosensitivity in NSCLC patients. Plasma miRNAs represent novel biomarkers to predict radiotherapy response clinically.