Abstract
Recent evidences indicate that a small subpopulation of cancer cells called cancer stem cells (CSCs) is possible to initiate tumor growth, drive tumor metastasis and lead to drug resistance. In addition, some reports suggest that EMT (epitheli-al-mesenchymal transition), playing an important role in the cancer invasion and me-tastasis, can induce cancer cell to acquire stem-like phenotype. An innovative concept is that the niche has a profound influence on the cancer progression. The niche is a specific microenvironment that regulates cancer cell survival, self-renewal, and dif-ferentiation. In particular, studies have shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited into tumors and considered regulating cancer metastasis by several signal pathways, including IL6/STAT3 signal. However, the ex-act network of CSC niche created by BM-MSCs is poorly understood. In this study, human bone marrows (hBMs) were obtained from volunteers, without the history of cancer, undergoing joint arthroplasty surgeries. After isolating hBM-MSCs, we identified the characteristics of isolated BM-MSCs by flow cytome-try. Then, we collected MSC-conditional medium (MSC-CM) to investigate if MSCs help the establishment of CSC niche and promote the CSC properties. The RT-PCR and Western blotting showed that paracrine factors in MSC-CM secreted by BM-MSCs would upregulate mesenchymal markers in epithelial-type cells (LM cells). We also found the ABC transporter genes, related to the ability of drug resistance, were distinctly upregulated (including ABCA1, ABCB1, and ABCG1) after MSC-CM treatment. In the functional assays, we suggested MSC-CM treatment ob-viously promoted migration abilities and sphere forming abilities in LM cells. Taken together, we demonstrate that MSC-CM treatment can elicit the CSC phenotype. Furthermore, according to the microarray data, the target genes of JAK/STAT3 signal pathway were upregulated in LM cells treated with MSC-CM. Therefore, we hypoth-esized paracrine factors secreted by MSCs might establish the CSC niche to promote cancer progression via STAT3 signal pathway. Here, we illustrated that MSC-CM treatment predominantly activated STAT3 transcriptional activity through enhancing phosphorylation of STAT3 (Tyr705). Surprisingly, the EMT and CSC properties in-duced by MSC-CM would be eliminated, after the transfection of mutant STAT3 (Y705F) in LM cells. In conclusion, BM-MSCs can trigger STAT3-elicited promotion of the CSC phenotype. Based on these findings, we look forward to developing new strategies and drugs, such as antibodies and pharmacologic inhibitors, directly target-ing CSCs to improve tumor therapies.