The paracrine effects of tumor-resident mesenchymal stem/stromal cells in the microenvironment of brain metastases

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Background Tumor-resident mesenchymal stem/stromal cells (MSCs) were identified in several cancers, and were implicated in regulating multiple aspects of tumor progression. However, the role of tumor-resident MSCs in the pathophysiology of brain metastases (BrMs) -the most prevalent type of malignant brain tumor- is currently unknown, and was investigated in this study. Methods Tumor-resident MSCs were isolated from fresh human lung-BrM tissues (n=3) and were phenotypically assessed in FFPE lung-BrM tissues (n=11). The paracrine effects of BrM-MSCs on neutrophil granulocytes and endothelial cells (ECs) were examined in ex vivo models using MSC-derived supernatants (SNs), peripheral blood neutrophils from healthy donors and two different EC models (HUVEC and HCAEC). Results The isolated BrM-MSCs were characterized and validated according to the ISCT ® criteria. Cells with an MSC-like phenotype were also identified in situ , in the majority of the samples analyzed (9 out of 11). The MSC-derived SNs promoted neutrophil chemotaxis, and prolonged their survival. Additionally, BrM-MSC SNs stimulated neutrophils to release significant levels of pro-angiogenic and pro-invasive matrix metalloprotease (MMP) 9. In contrast, BrM-MSC SNs had no direct stimulatory effect on the ECs regarding MMP2 release, migration and proliferation, and even inhibited the tubulogenesis in HUVEC. However, the latter effect could not be validated with the HCAEC cells. Conclusion These results indicate that BrMs harbor tumor-resident MSCs that modulate neutrophil biology and function within the BrM microenvironment. While the direct effects of BrM-MSCs on ECs remain to be further characterized, tumor-resident MSCs may play critical roles in the pathophysiology of this disease.