Promotion of gastric tumor initiating cells in a 3D collagen gel culture model via YBX1/SPP1/NF-\u03baB signaling

Shuangya Deng,Xiaobo Wang,Tong Han,Shu Xu,Lun Li

doi:10.1186/s12935-021-02307-x

Abstract

BackgroundThe high potential for tumor recurrence and chemoresistance is a major challenge of clinical gastric cancer treatment. Increasing evidence suggests that the presence of tumor initiating cells (TICs) is the principal cause of tumor recurrence and chemoresistance. However, the underlying mechanism of TIC development remains controversial.MethodsTo identify novel molecular pathways in gastric cancer, we screened the genomic expression profile of 155 gastric cancer patients from the TCGA database. We then described an improved 3D collagen I gels and tested the effects of collagen on the TIC phenotype of gastric cells using colony formation assay, transwell assay, and nude mouse models. Additionally, cell apoptosis assay was performed to examine the cytotoxicity of 5-fluorine and paclitaxel on gastric cancer cells cultured in 3D collagen I gels.ResultsElevated expression of type I collagen was observed in tumor tissues from high stage patients (stage T3–T4) when compared to the low stage group (n=10, stage T1–T2). Furthermore, tumor cells seeded in a low concentration of collagen gels acquired TIC-like phenotypes and revealed enhanced resistance to chemotherapeutic agents, which was dependent on an integrin β1 (ITGB1)/Y-box Binding Protein 1 (YBX1)/Secreted Phosphoprotein 1 (SPP1)/NF-κB signaling pathway. Importantly, inhibition of ITGB1/NF-κB signaling efficiently reversed the chemoresistance induced by collagen and promoted anticancer effects in vivo.ConclusionsOur findings demonstrated that type I collagen promoted TIC-like phenotypes and chemoresistance through ITGB1/YBX1/SPP1/NF-κB pathway, which may provide novel insights into gastric cancer therapy.

Highlights

The high potential for tumor recurrence and chemoresistance is a major challenge of clinical gastric cancer treatment
Compelling studies have implicated that 3D gel culture, such as fibrin gels and Matrigel, can promote the tumor initiating cells (TICs) phenotype, in which 100–1000 3D cultured TICs were capable of forming tumors in vivo [21,22,23]
To assess whether our 3D collagen gels could promote TIC proliferation, we examined the colony formation capability of cancer cells seeded in collagen gels

Summary

Introduction

The high potential for tumor recurrence and chemoresistance is a major challenge of clinical gastric cancer treatment. TICs, called cancer stem cells or tumor repopulating cells, are a small fraction of cells within tumor tissues, which largely contribute to both tumor recurrence as well as drug resistance in cancer-associated disease [3]. Specific environmental cues, such as 3D fibrin culture or serum-free suspension culture, could equip differentiated tumor cells with stem-like characteristics and facilitate tumorigenicity of cancer cells in nude mice [13]. These findings infer that tumor cells might be able to obtain the TIC phenotype under specific conditions and there is a dynamic conversation between TICs and bulk tumor cells [14]

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Discussion

Conclusion