Lung Adenocarcinoma Cells Promote Self-Migration and Self-Invasion by Activating Neutrophils to Upregulate Notch3 Expression of Cancer Cells

Abstract

Background: Invasion and migration of cancer cells play a key role in lung cancer progression and metastasis. Tumor-associated neutrophils (TANs) are related to poor prognosis in many types of cancer. However, the role of TANs in lung cancer is controversial. In this study, we investigated the effect of TANs on the invasion and migration of lung adenocarcinoma.Methods: Immunohistochemistry was performed to detect the density of infiltrating TANs and the expression of Notch3 in 100 lung adenocarcinoma tissues. Flow cytometry was used to observe the viability of neutrophils, which were isolated from healthy peripheral blood and then exposed to the supernatant of cultured lung adenocarcinoma cell lines. After treating with tumor-associated neutrophils culture supernatant, NeuCS (supernatant of cultured neutrophils), tumor cells culture supernatant, Medium (serum-free medium), respectively, the migration and invasion of the lung cancer cells before and after transfected by si-Notch3 were detected by transwell assay and wound healing assay. Kaplan-Meier plotter (http://kmplot.com/analysis/index.php?p) was used to analyze the prognostic role of the density of TANs on lung adenocarcinoma and TIMER ((http://cistrome.dfci.harvard.edu/TIMER/) was used to detect the expression of Notch3 on lung adenocarcinoma.Results: The infiltration of TANs was observed in the parenchyma and stroma of the lung adenocarcinoma, the density of TANs was positively related to the TNM stage and negatively related to the differentiation and prognosis. Notch3 expression of cancer cells was negatively related to the tumor differentiation and prognosis. Compared to quiescent neutrophils, the viability of TCCS-activated neutrophils was enhanced. Both migration and invasion of A549 and PC9 cells were significantly promoted by TANs, while after knocking down Notch3, the migration and invasion of the cancer cells were not affected by TANs. Bioinformatics analysis showed that the density of TANs and the expression of Notch3 were related to the poor prognosis.Conclusion: The results indicated that lung adenocarcinoma cells promote self-invasion and self-migration by activating neutrophils to upregulate the Notch3 expression of cancer cells. The density of infiltrating TANs may be a novel marker for the poor prognosis of lung adenocarcinoma. Targeting TANs might be a potential therapeutic strategy for lung cancer treatment.

Relationship Between Infiltration of CD163+ TAMs, FoxP3+ Tregs, or CD66b+ TANs and Cell Differentiation in Colorectal Cancer Tissues

“…The density of infiltrating TANs is negatively related to the tumor differentiation in the lung adenocarcinoma. 34 High infiltration of CD66b + TANs is obviously associated with well differentiations in gastric cancer. 18 Whether the low-level TANs in poorly differentiated tissues in this study is related to the anti-immunity and immune tolerance caused by CD163 + TAMs and FoxP3 + Tregs still needs further research to determine.…”

Huaier suppresses cell viability, migration and invasion in human non-small cell lung cancer via lncRNA DLEU2/miR-212-5p/ELF3 axis

“…The protein kinase C iota activates the level of Notch3 via phosphorylating the transcription factor ELF3 and subsequent occupancy of ELF3 on the Notch3 promoter in lung adenocarcinoma 42 . The Notch3 upregulation facilitates the autologous invasion and migration of lung adenocarcinoma cells 43 . The modulation of Notch3 signaling is a pivotal factor in the progression and pathogenesis of lung cancer 44 , 45 .…”

The dual role of autophagy in the regulation of cancer treatment

“…Previous studies have demonstrated that immune cells infiltrating tumors can be influenced by interactions in the tumor microenvironment to support tumor progression (Kwantwi 2023b , 2023c ; Sheng et al 2023 ; Peng et al 2021 ; Cai et al 2020 ; Kwantwi et al 2021a ; Li et al 2021 ). Notably, autophagy induction can shape immune cells to gain protumor functions leading to therapeutic resistance and tumor progression (Bustos et al 2020 ; Ishimwe et al 2020 ; Jiang et al 2019 ; Janji et al 2018 ).…”