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J Cancer 2024; 15(7):1816-1825. doi:10.7150/jca.92192 This issue Cite

Research Paper

Lysyl Oxidase Promotes the Formation of Vasculogenic Mimicry in Gastric Cancer through PDGF-PDGFR Pathway

Yifan Liu^1*, Bojian Sun^1,2*, Yuan Lin¹, Hong Deng¹, Xinyi Wang¹, Chuanhao Xu¹, Kaibo Wang¹, Nan Yu³, Rongqing Liu^3✉, Mei Han^1✉

1. Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, Ningxia, P.R. China.
2. Department of Rheumatology and Immunology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China.
3. Department of Rheumatology and Immunology, The General Hospital of Ningxia Medical University, Ningxia 750004, P.R. China.
*These authors contributed equally to this work.

✉ Corresponding authors: Professor Mei Han, Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, P.R. China. E-mail: hanmei0708com; Dr Rongqing Liu, Department of Rheumatology and Immunology, The General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, Ningxia 750004, P.R. China. E-mail: liurongqing1964com. More

Abstract

Objective: Vasculogenic mimicry (VM) generates an important supplementary form of blood supply in cancer, which many factors regulate. However, the effect of lysyl oxidase (LOX) on VM formation is unclear. In this study, gastric cancer tissues and cells were used to investigate the role of LOX in the formation of VM.

Materials and Methods: The samples were collected from 49 patients with a final diagnosis of gastric cancer. According to metastasis (including lymph node metastases and distant metastases), gastric cancer samples were divided into metastasis and non-metastasis groups. Based on the degree of invasion, gastric cancer specimens were divided into T1 + T2 and T3 + T4 groups. The relative expression of LOX was detected using Western blot. The formation of VM was measured by double staining with CD34 and Periodic acid-Schiff (PAS) in gastric cancer tissue slices, and the correlation between LOX and VM was analyzed with Pearson's correlation analysis. Gastric cancer cell line BGC-803 was treated with LOX, β-aminopropionitrile (BAPN, an inhibitor of LOX), and AG1295 or AG1296 (inhibitors of the platelet-derived growth factor receptor). The formation of VM was then measured using PAS staining. The expression of platelet-derived growth factor receptor (PDGFR)α and PDGFRβ in gastric cancer cells was detected by Western blot.

Results: In gastric cancer samples, the level of LOX was higher in the metastasis group than in the non-metastasis group (P < 0.05) and in the T3 + T4 group than in the T1 + T2 group (P < 0.05). VM formation was greater in the T3+T4 group than in the T1+T2 group (P < 0.05) and in the metastasis group than in the non-metastasis group (P < 0.05). The expression level of LOX was positively correlated with VM formation (P < 0.01). In gastric cancer cells, LOX concentration was positively correlated with the degree of VM, and BAPN concentration was negatively correlated with the degree of VM (P <0.05). PDGFR levels in the T3+T4 and metastasis groups were relatively higher (P <0.01) and positively correlated with LOX levels in gastric cancer specimens (P < 0.01). The relative expression of PDGFRα and PDGFRβ in gastric cancer cells was up-regulated with increasing LOX and downregulated with increasing BAPN (P < 0.05). With inhibition of PDGFRα and PDGFRβ using AG1295 or AG1296, VM formation in gastric cancer cells decreased (P <0.05), but the number of VM structures increased while LOX was added (P < 0.05).

Conclusion: LOX partially promotes the formation of VM in gastric cancer through the PDGF-PDGFR signaling pathway.

Keywords: Lysyl oxidase, Vasculogenic mimicry, Gastric cancer, Platelet-derived growth factor receptor

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