Journal
SURGERY
Volume 152, Issue 3, Pages 449-454Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.surg.2012.06.011
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Funding
- NIH [R01 GM065113-A2, UL1 RR024128, T32 CA093245-09, T32 GM069331]
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Background. The microenviranments of neoplasms influence both mesenchymal stem cell differentiation into cancer-associated fibroblasts (CAF) and tumor cell line differentiation to mesenchymal phenotypes via epithelial-to-mesenchymal transition (EMT). Using direct cell-cell contact approximating the microenvironment of a neoplasm, we investigated the role of this interaction in human mesenchymal stem cells (hMSCs) and epithelial hepatic carcinoma SK-Hep1 cells by evaluating CAF differentiation and EMT. Methods. hMSCs and SK-Hep1 cells were homogenausly cultured for 12 hours with media only, OPN-R3 aptamer blockade of OPN, or RGD peptide blockade of integrin receptor, negative control mutant OPN-R3 aptamer, and RGE peptide blockade. mRNA was isolated from each subpopulation, and real-time-polymerase chain reaction was performed for CAF markers and EMT transcription factors and structural proteins. Results. SK-Hep1 cells in admixture with hMSCs showed increased EMT marker vimentin expression that was ablated with OPN-R3 aptamer or RGD blockade. SK-Hep1 cells when cultured with hMSC admixture increased Snail and Slug expression that was hindered with OPN-R3 aptamer hMSCs acquired CAF markers tenascin-c and SDF-1 in admixture that was ablated with either OPN-R3 aptamer or RGD blockade. All SK-Hepl and hMSC negative control subpopulations were statistically equivalent to media-only groups. Fluorescence photography exhibited the critical cell-cell interfaces and acquired EMT traits of SK-Hep1. Conclusion. We conclude that direct interaction of cell lines closely replicates the native neoplasm microenvironment. Our experiments reveal soluble OPN or integrin receptor blockade independently prevents progression to metastatic phenotype by acquisition of CAF and EMT markers. (Surgery 2012; 152:449-54.)
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