Acidosis promotes the metastatic colonization of lung cancer via remodeling of the extracellular matrix and vasculogenic mimicry

Shie,Wan-Yi; Chu,Pin-Hsuan; Kuo,Mark Yen-Ping; Chen,Huei-Wen; Lin,Meng-Tie; Su,Xuan-Jie; Hong,Yi-Ling; Chou,Han-Yi Elizabeth

doi:10.3892/ijo.2023.5584

Acidosis promotes the metastatic colonization of lung cancer via remodeling of the extracellular matrix and vasculogenic mimicry

Authors:
- Wan-Yi Shie
- Pin-Hsuan Chu
- Mark Yen-Ping Kuo
- Huei-Wen Chen
- Meng-Tie Lin
- Xuan-Jie Su
- Yi-Ling Hong
- Han-Yi Elizabeth Chou
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Affiliations: Graduate Institute of Oral Biology, National Taiwan University, Taipei 100, Taiwan, R.O.C., Department of Dentistry, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C., Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C.
Published online on: October 26, 2023 https://doi.org/10.3892/ijo.2023.5584
Article Number: 136
Copyright: © Shie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acidosis is a hallmark of the tumor microenvironment caused by the metabolic switch from glucose oxidative phosphorylation to glycolysis. It has been associated with tumor growth and progression; however, the precise mechanism governing how acidosis promotes metastatic dissemination has yet to be elucidated. In the present study, a long‑term acidosis model was established using patient‑derived lung cancer cells, to identify critical components of metastatic colonization via transcriptome profiling combined with both in vitro and in vivo functional assays, and association analysis using clinical samples. Xenograft inoculates of 1 or 10 acidotic cells mimicking circulating tumor cell clusters were shown to exhibit increased tumor incidence compared with their physiological pH counterparts. Transcriptomics revealed that profound remodeling of the extracellular matrix (ECM) occurred in the acidotic cells, including upregulation of the integrin subunit α‑4 (ITGA4) gene. In clinical lung cancer, ITGA4 expression was found to be upregulated in primary tumors with metastatic capability, and this trait was retained in the corresponding secondary tumors. Expression of ITGA4 was markedly upregulated around the vasculogenic mimicry structures of the acidotic tumors, while acidotic cells exhibited a higher ability of vasculogenic mimicry in vitro. Acidosis was also found to induce the enrichment of side population cells, suggesting an enhanced resistance to noxious attacks of the tumor microenvironment. Taken together, these results demonstrated that acidosis actively contributed to tumor metastatic colonization, and novel mechanistic insights into the therapeutic management and prognosis of lung cancer were discussed.

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