Introduction and objectives

Lung cancer often spreads to the bones in about 50% of lung cancer patients, leading to poor clinical outcomes with standard treatment. Therefore, preventing bone metastasis is crucial for lung cancer patients. Recent research suggests that bone marrow-derived mesenchymal stem cells (BM-MSCs) have the ability to differentiate into osteoblasts and adipocytes. Moreover, these cells can be attracted to primary tumor sites by cancer cells, where they transform into activated myofibroblasts and contribute to the tumor microenvironment, thereby fueling cancer progression.

Methods

Multiple primary BM-MSCs were isolated from patients with fractures. An in vitro cell co-culture system was established using primary BM-MSCs and CL1-0, a low-invasive lung cancer cell line. We evaluated the impact of BM-MSCs on lung cancer cells in vitro by examining proliferation, independent colony formation, migration, invasion, adhesion, and changes in cell morphology. Additionally, we delved into the secretome within the bone niche using a cytokines array. We performed integrated proteomic analyses on tumor cells by LC-MS/MS to unveil the detailed mechanisms behind BM-MSC-induced lung cancer-related bone metastases.

Results and Discussion

The study's findings suggest that BM-MSCs enhance the invasion ability and distal colonization of low-invasive lung cancer cells. CL1-0 cells were co-cultured with BM-MSCs for extended periods to investigate the regulatory mechanisms involved. Cell lysates were then subjected to total proteomic analysis, and the conditioned medium was collected for secretomic dissection. This analysis identified critical pathways, including wound healing and intermediate filament cytoskeleton organization, associated with metastasis and affecting cellular morphology, migration, invasion, and adhesion. The results indicated that low-invasive cancer cells increase their malignancy by regulating epithelial-mesenchymal transition (EMT) within the bone microenvironment.

Conclusion

Low-invasive lung cancer cells' migration and invasion abilities increased after co-culturing with BM-MSCs. These cancer cells tended to adhere to bone cells and exhibited morphological changes towards a mesenchymal-like appearance. Proteomics analysis identified proteins associated with cell migration, cell shape, and cytoskeleton organization, indicating that BM-MSCs enhance the malignancy and metastatic potential of low-invasive lung cancer cells. In summary, the malignancy of low-invasive cancer cells is elevated through EMT regulation within the bone microenvironment. These findings offer insights into the changes occurring in lung cancer cells under the influence of cytokines from bone cells, potentially guiding the development of new treatment strategies to effectively prevent bone metastasis from lung cancer.

Keywords

lung cancer, bone metastasis, bone microenvironment, paracrine