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.
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics. CA Cancer J Clin 71(1):7–33
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
Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741
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
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
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
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
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).
Author information
Authors and Affiliations
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
Ethics declarations
Conflict of interest
The authors declare that they have no potential conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-04619-z