Abstract
The most deadly phase in cancer progression is metastatic conversion. Epithelial-to-mesenchymal transition (EMT) is a key process by which cancer cells acquire invasive and metastatic phenotypes. In order to spawn macroscopic metastases, disseminated cancer cells would seem to require self-renewal capability. However, the underlying mechanism defining these processes is poorly understood. One possible mechanism underlying metastasis is fusion between myeloid cells and cancer cells. In this study, we found that spontaneously-formed tumorigenic hybrids between bone marrow-derived mesenchymal stem cells (MSCs) and three different non-small cell lung cancer (NSCLC) cell lines contributed to highly malignant subpopulations with both EMT and stem cell-like properties. Hybrids lost their epithelial morphology and assumed a fibroblast-like appearance. Up-regulation of vimentin, α-smooth muscle actin (α-SMA), and fibronectin, and down-regulation of E-cadherin and pancytokeratin were observed in tumorigenic hybrids. These cells also exhibited increased expression of the stem cell marker prominin-1 (CD133) and over-expression of transcription factors OCT4, Nanog, BMI1, Notch1, ALDH1 as well as Sox2, all genes responsible for regulating and maintaining the stem cell phenotype. In addition, in spontaneously-formed tumorigenic hybrids, increased pneumosphere-forming capacity and tumor-forming ability in NOD/SCID mice were detectable. Thus, cell fusion between lung cancer cells and MSCs provides a nonmutational mechanism that could contribute to aberrant gene expression patterns and give rise to highly malignant subpopulations both capable of EMT and with properties of cancer stem cells (CSCs).
Highlights
Lung cancer, especially non-small-cell lung cancer (NSCLC), remains the leading cause of cancer-related mortality worldwide
Spontaneous Formation of mesenchymal stem cells (MSCs)–lung Cancer Hybrids Cultured MSCs exhibited fibroblast-like cell morphology (Figure S1A), typical phenotypes and were positive for CD44, CD105 and negative for CD34 (Figure S1B), and have multipotency to differentiate into osteoblasts, adipocytes and chondrocytes after osteogenic, adipogenic and chondrogenic induction differentiation (Figure S1C-E)
The findings presented here describe an unexpected convergence of epithelial-mesenchymal transition (EMT) and stem cell properties in spontaneously-formed tumorigenic hybrids between lung cancer cells and bone marrowderived MSCs
Summary
Especially non-small-cell lung cancer (NSCLC), remains the leading cause of cancer-related mortality worldwide. Tumor metastasis is the primary cause of death due to NSCLC. The mechanisms involved in tumor metastasis remain poorly understood. EMT has been suggested to be an essential step in cancer cell dissemination and metastasis. During the process of tumor metastasis, which is often enabled by an EMT, disseminated cancer cells would seem to require selfrenewal capability, in order to spawn macroscopic metastases. Recent work revealed that the process of EMT generates cells with stemlike properties in the mammary cell population [4]. The link between EMT and acquisition of stem cell-like properties by cancer cells may explain why EMT induces tumor progression. The mechanisms that induce and maintain this mesenchymal/stem cell state remain unclear
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