Cigarette smoke-promoted increases in osteopontin expression attract mesenchymal stem cell recruitment and facilitate lung cancer metastasis

Introduction: Cigarette smoking is the main risk factor for lung cancer. MSCs in the TME promoting tumor angiogenesis, growth, and metastasis. SIBLING proteins enable cancer cells to extend, invade and metas-tasize.Objectives: Cigarette smoke promotes the progression and metastasis of lung cancer, although how this occurs is poorly understood. We evaluated the impact of whether cigarette smoking motivates SIBLING protein expression and is involved in MSC-mediated lung tumor metastasis.Methods: We investigated the expression of OPN in the Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of lung cancer cells and tissues. The effect of OPN on the recruitment and adhesion of mesenchymal stem cells (MSCs) to lung cancer cells and lung cancers metastasis was investigated by Transwell, adhesion assays. A series of in vitro and in vivo experiments were conducted to demonstrate the mechanisms by which OPN modulates recruitment and adhesion of MSCs to lung cancer cells and lung cancer metastasis.Results: Cigarette smoke extract (CSE) and benzo[a]pyrene (B[a]P) increased levels of OPN expression and facilitated the recruitment and adhesion of MSCs to lung cancer cells via JAK2/STAT3 signaling. We also observed that OPN promotes tumor-associated MSC (TA-MSC) formation through the OPN recep-tor (integrins avb1, avb3, avb5 or CD44), inducing lung cancer cell migration and invasion. In an ortho-topic mouse model of lung cancer, increases in OPN expression promoted by cigarette smoke upregulated MSC recruitment and facilitated lung cancer metastasis. Knockdown of OPN expression inhibited cigar-ette smoke-induced lung cancer metastasis in vivo.Conclusion: Cigarette smoke increases OPN expression through the JAK2/STAT3 signaling pathway to attract MSC cell recruitment and promote lung cancer metastasis. Our findings offer important insights into how lung cancer metastasis develops in smokers.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Cigarette smoking, as a main risk factor for lung cancer, increases the expression levels of OPN through the JAK2/STAT3 signaling pathway, thereby promoting the recruitment and adhesion of MSCs to lung cancer cells, and facilitating lung cancer metastasis and invasion.