EMT and Acquisition of Stem Cell-Like Properties Are Involved in Spontaneous Formation of Tumorigenic Hybrids

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, a-smooth muscle actin (a-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 subpopulation