Acidosis promotes the metastatic colonization of lung cancer via remodeling of the extracellular matrix and vasculogenic mimicry
Wan-Yi Shie, Pin-Hsuan Chu, Mark Kuo, Huei‐Wen Chen, Meng-Tie Lin, Xuan-Jie Su, Yiling Hong, Han‐Yi Chou
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 <em>in vitro</em> and <em>in vivo</em> 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 (<em>ITGA4</em>) gene. In clinical lung cancer, <em>ITGA4</em> 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 <em>in vitro</em>. 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.