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The significance of spread through air spaces in the prognostic assessment model of stage I lung adenocarcinoma and the exploration of its invasion mechanism

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Abstract

Purpose

Spread through air spaces (STAS) is a crucial invasive mode of lung cancer and has been shown to be associated with early recurrence and metastasis. We aimed to develop a prognostic risk assessment model for stage I lung adenocarcinoma based on STAS and other pathological features and to explore the potential relationship between CXCL-8, Smad2, Snail, and STAS.

Methods

312 patients who underwent surgery at Harbin Medical University Cancer Hospital with pathologically diagnosed stage I lung adenocarcinoma were reviewed in the study. STAS and other pathological features were identified by H&E staining, and a prognostic risk assessment model was established. The expression levels of CXCL8, Smad2, and Snail were determined by immunohistochemistry.

Results

The nomogram was established based on age, smoking history, STAS, tumor lymphocyte infiltration, tissue subtype, nuclear grade, and tumor size. The C-index for DFS was (training set 0.84 vs validation set 0.77) and for OS was (training set 0.83 vs validation set 0.78). Decision curve analysis showed that the model constructed has a better net benefit than traditional reporting. The prognostic risk score validated the risk stratification value for stage I lung adenocarcinoma. STAS was an important prognostic factor associated with stronger invasiveness and higher expression of CXCL8, Smad2, and Snail. CXCL8 was associated with poorer DFS and OS.

Conclusions

We developed and validated a survival risk assessment model and the prognostic risk score formula for stage I lung adenocarcinoma. Additionally, we found that CXCL8 could be used as a potential biomarker for STAS and poor prognosis, and its mechanism may be related to EMT.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  • Alassaf E, Mueller A (2020) The role of PKC in CXCL8 and CXCL10 directed prostate, breast and leukemic cancer cell migration. Eur J Pharmacol 886:173453

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y, Ma XL, Wei YQ, Wei XW (2019) Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer 1871(2):289–312

    Article  CAS  PubMed  Google Scholar 

  • David JM, Dominguez C, Hamilton DH, Palena C (2016) The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines 4:22

    Article  PubMed  PubMed Central  Google Scholar 

  • ErenKupik G, Altundağ K (2022) The clinicopathological characteristics of pure and mixed invasive micropapillary breast carcinomas: a single center experience. Balkan Med J 39(4):275–281

    Article  Google Scholar 

  • Fang QI, Wang X, Luo G, Yu M, Zhang X, Xu N (2017) Increased CXCL8 expression is negatively correlated with the overall survival of patients with ER-negative breast cancer. Anticancer Res 37(9):4845–4852

    CAS  PubMed  Google Scholar 

  • Fauvet R, Demblocque E, Morice P, Querleu D, Daraï E (2012) Behavior of serous borderline ovarian tumors with and without micropapillary patterns: results of a French multicenter study. Ann Surg Oncol 19(3):941–947

    Article  CAS  PubMed  Google Scholar 

  • Fousek K, Horn LA, Palena C (2021) Interleukin-8: a chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol Ther 219:107692

    Article  CAS  PubMed  Google Scholar 

  • Gutierrez-Sainz L, López-Muñoz S, Cruz-Castellanos P, Higuera O, Esteban-Rodríguez MI, Losantos-García I, De Castro-Carpeño J (2022) Retrospective analysis of the prognostic implications of tumor spread through air spaces in lung adenocarcinoma patients treated with surgery. ESMO Open 7(5):100568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu X, Yuan L, Ma T (2020) Mechanisms of JAK-STAT signaling pathway mediated by CXCL8 gene silencing on epithelial-mesenchymal transition of human cutaneous melanoma cells. Oncol Lett 20(2):1973–1981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hung JJ, Jeng WJ, Hsu WH et al (2012) Predictors of death, local recurrence, and distant metastasis in completely resected pathological stage-I non-small-cell lung cancer. J Thorac Oncol 7(7):1115–1123

    Article  PubMed  Google Scholar 

  • Hwang WL, Yang MH, Tsai ML, Lan HY, Su SH, Chang SC, Teng HW, Yang SH, Lan YT, Chiou SH, Wang HW (2011) SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 141(1):279-91-291.e1-5

    Article  PubMed  Google Scholar 

  • Jia L, Li F, Shao M, Zhang W, Zhang C, Zhao X, Luan H, Qi Y, Zhang P, Liang L, Jia X, Zhang K, Lu Y, Yang Z, Zhu X, Zhang Q, Du J, Wang W (2018) IL-8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells. Oncol Lett 15(1):1350–1356

    PubMed  Google Scholar 

  • Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR et al (2015) Tumor spread through air spaces is an important pattern of invasion and impacts the frequency and location of recurrences after limited resection for small stage I lung adenocarcinomas. J Thorac Oncol 10(5):806–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kadota K, Kushida Y, Kagawa S et al (2019) Limited resection is associated with a higher risk of locoregional recurrence than lobectomy in stage I lung adenocarcinoma with tumor spread through air spaces. Am J Surg Pathol 43:1033–1041

    Article  PubMed  Google Scholar 

  • Kim A, Lee SJ, Ahn J, Park WY, Shin DH, Lee CH, Kwon H, Jeong YJ, Ahn HY, Hoseok I, Kim YD, Cho JS (2019) The prognostic significance of tumor-infiltrating lymphocytes assessment with hematoxylin and eosin sections in resected primary lung adenocarcinoma. PLoS ONE 14(11):e0224430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Li A, Yu S, Qin S, Han N, Pestell RG, Han X, Wu K (2018a) DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis. J Hematol Oncol 11(1):53

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Chen D, Qiu X, Duan S, Zhang Y, Li F, Chen C, Zhou Y, Chen Y (2018b) Relationship between MTA1 and spread through air space and their joint influence on prognosis of patients with stage I-III lung adenocarcinoma. Lung Cancer 124:211–218

    Article  PubMed  Google Scholar 

  • Liu A, Sun X, Xu J, Xuan Y, Zhao Y, Qiu T, Hou F, Qin Y, Wang Y, Lu T, Wo Y, Li Y, Xing X, Jiao W (2020) Relevance and prognostic ability of twist, slug and tumor spread through air spaces in lung adenocarcinoma. Cancer Med 9(6):1986–1998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Masai K, Sakurai H, Sukeda A, Suzuki S, Asakura K, Nakagawa K et al (2017) Prognostic impact of margin distance and tumor spread through air spaces in limited resection for primary lung cancer. J Thorac Oncol 12(12):1788–1797

    Article  PubMed  Google Scholar 

  • Meng L, Zhao Y, Bu W, Li X, Liu X, Zhou D, Chen Y, Zheng S, Lin Q, Liu Q, Sun H (2020) Bone mesenchymal stem cells are recruited via CXCL8-CXCR2 and promote EMT through TGF-β signal pathways in oral squamous carcinoma. Cell Prolif 53(8):e12859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • National Comprehensive Cancer Network (2021) NCCN clinical practice guidelines in oncology. In: Non-small cell lung cancer (Version 5.2021). Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

  • Palena C, Hamilton DH, Fernando RI (2012) Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment. Future Oncol 8:713–722

    Article  CAS  PubMed  Google Scholar 

  • Schuchert MJ, Normolle DP, Awais O et al (2019) Factors influencing recurrence following anatomic lung resection for clinical stage I non-small cell lung cancer. Lung Cancer 128:145–151

    Article  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics. CA Cancer J Clin 71(1):7–33

    Article  PubMed  Google Scholar 

  • Varlotto JM, Yao AN, Decamp MM et al (2015) Nodal stage of surgically resected non-small cell lung cancer and its effect on recurrence patterns and overall survival. Int J Radiat Oncol Biol Phys 91(4):765–773

    Article  PubMed  Google Scholar 

  • Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741

    Article  CAS  PubMed  Google Scholar 

  • Wu S, Singh S, Varney ML, Kindle S, Singh RK (2012) Modulation of CXCL-8 expression in human melanoma cells regulates tumor growth, angiogenesis, invasion, and metastasis. Cancer Med 1(3):306–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao YC, Yang ZB, Cheng XS, Fang XB, Shen T, Xia CF, Liu P, Qian HH, Sun B, Yin ZF, Li YF (2015) CXCL8, overexpressed in colorectal cancer, enhances the resistance of colorectal cancer cells to anoikis. Cancer Lett 361(1):22–32

    Article  CAS  PubMed  Google Scholar 

  • Yang S, Wang H, Qin C, Sun H, Han Y (2020) Up-regulation of CXCL8 expression is associated with a poor prognosis and enhances tumor cell malignant behaviors in liver cancer. Biosci Rep 40(8):BSR20201169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng Y, Zhou L, Jia D, Pan B, Li X, Yu Y (2022) Comprehensive analysis for clarifying transcriptomics landscapes of spread through air spaces in lung adenocarcinoma. Front Genet 13:900864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank everyone who participated in this study.

Funding

This study was funded by the Haiyan Foundation of Harbin Medical University Cancer Hospital (JJZD2020-14).

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Authors

Contributions

All authors contributed to the study's conception and design. YYN, YZ, and XHH collected and analyzed the data in the study. YYN, YZ, XHH, NA, QB, SNG, YLH, YY, QJZ and XML discussed the results and contributed to the final manuscript. YYN, YZ, and XHH drafted the manuscript. YY, QJZ and XML conceived of the presented idea and completed the critical revision of the article. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yan Yu, QiuJu Zhang or XiaoMei Li.

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Niu, Y., Han, X., Zeng, Y. et al. The significance of spread through air spaces in the prognostic assessment model of stage I lung adenocarcinoma and the exploration of its invasion mechanism. J Cancer Res Clin Oncol 149, 7125–7138 (2023). https://doi.org/10.1007/s00432-023-04619-z

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  • DOI: https://doi.org/10.1007/s00432-023-04619-z

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