J Cancer 2019; 10(17):4017-4030. doi:10.7150/jca.28163 This issue

Research Paper

The Role of the Tumor Microenvironment in Neuropilin 1-Induced Radiation Resistance in Lung Cancer Cells

Zhuo Dong1, Haiyang Zhang1,2, Xinkou Gong3, Wei Wei1, Yahui Lv1, Zhiyuan Chen1, Rui Wang1, Junxuan Yi1, Yannan Shen1, Shunzi Jin1✉

1. NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China
2. Department of Prosthodontics Dentistry, The Stomatology Hospital of Jilin University, Changchun, 130021, China
3. Department of Radiology, The 2 nd Hospital of Jilin University, Changchun, 130021, China

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Dong Z, Zhang H, Gong X, Wei W, Lv Y, Chen Z, Wang R, Yi J, Shen Y, Jin S. The Role of the Tumor Microenvironment in Neuropilin 1-Induced Radiation Resistance in Lung Cancer Cells. J Cancer 2019; 10(17):4017-4030. doi:10.7150/jca.28163. Available from https://www.jcancer.org/v10p4017.htm

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Background: Neuropilin 1 (NRP1) is a pleiotropic receptor which can interact with multiple ligands and their receptors. It plays an important role in the process of axonal growth, angiogenesis, tumor metastasis and radiation resistance in endothelial cells and some tumor cells. Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis, and has received considerable attention in recent years.

Material and Methods: In this study, A549 lung cancer cell lines with different NRP1 expression levels were constructed in vitro, a two-dimensional (2D), three-dimensional (3D) co-culture system and tumor-bearing model was established in SCID mice. Western blot, qRT-PCR, immunofluorescence, cytometric bead array and flow cytometry were used to investigate the effect of the tumor microenvironment in NRP1-induced lung cancer cell radiation resistance.

Results: In 2D or 3D co-culture system, NRP1 could be regulated inflammatory factors such as TNF, IL-6 IL-8 and IL-17 and the related chemokines MCP-1, IP-10 and RANTES in the tumor microenvironment, which in turn induced radiation resistance in lung cancer cells. In addition, different expression levels of NRP1 in 2D, 3D culture systems and tumor-bearing models were able to significantly regulate cell phenotype, proliferative capacity, epithelial-mesenchymal transition (EMT) and the radiation resistance of A549 cells.

Conclusion: Our results verified that NRP1, inflammatory factors, chemokines and related signaling pathways, which affect the transformation of related cell components and thus lung cancer cell immune tolerance and migratory ability, all play an important role in radiation resistance.

Keywords: Tumor microenvironment, NRP1, radiation resistance, three-dimensional (3D) culture, epithelial-mesenchymal transition (EMT)