The Mechanism of Mesenchymal Stem Cells Involved in Air Pollution and Cigarette Smoke-Related Lung Cancer Metastasis

Cigarette smoking produces many organic compounds, including the carcinogenic polycyclic aromatic hydrocarbon benzo [α] pyrene, (B[α]P), which is linked to lung cancer. Tumor tissue recruits mesenchymal stem cells (MSCs; undifferentiated multipotent adult stem cells) to increase cancer cell proliferation, invasion and metastasis. We sought to determine the effects of cigarette smoke extract (CSE) and B[α]P stimulation on lung cancer cells and MSCs. We found that CSE and B[α]P increased mRNA and protein expression of osteopontin (OPN), a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family, but had no such effects on any other SIBLING proteins. Our analysis of data from Gene Expression Omnibus (GEO) GSE31210 database at the National Center for Biotechnology Information (NCBI) identified much higher levels of OPN expression in current and ex-cigarette smokers with lung cancer than in levels from lung cancer patients who were nonsmokers. When we stimulated lung cancer cells with CSE and B[α]P, we observed the recruitment of MSCs and their adherence to the cells was dependent upon OPN. We also discovered that recruited MSCs can induce lung cancer cell migration and invasion. Next, we used a set of 12 genes from the BioCarta database to investigate signaling pathways associated with lung cancer. We found that the Ras/MAPK/ELK and JAK/STAT signaling pathways occurred most frequently in lung cancer patients who were cigarette smokers. This research plan will therefore examine whether the Ras/MAPK/ELK and JAK/STAT signaling pathways are involved in CSE- and B[α]P-induced stimulation of OPN expression and MSC recruitment and adhesion. We will also evaluate that by linking with lung cancer cells through OPN receptor on the MSC cell membrane, MSCs can be recruited and thus induce lung cancer cell migration and invasion. Finally, whether CSE and B[α]P-induced OPN mediates MSC recruitment and distant metastasis in vivo will be examined using an orthotopic animal model that we successfully established in our previous research. The results will provide evidence how CSE and B[α]P treatment affects the interaction between lung cancer cells and MSCs. This phenomenon has important implications for our understanding of how lung cancer metastasis is established.