Fusion with mesenchymal stem cells differentially affects tumorigenic and metastatic abilities of lung cancer cells

Abstract

Cell fusion plays a crucial role in cancer progression and leads to massive aberrant changes in chromosome and gene expression involved in tumor metastasis. Cancer cells can fuse with many cell types, including stromal cells, epithelial cells, macrophages, and endothelial cells. Mesenchymal stem cells (MSCs) have been reported to migrate and incorporate into tumor sites during cancer progression. However, the underlying mechanism of stem cell fusion in tumor metastasis has not been fully deciphered. In this research, we established a cell fusion model between lung cancer cells and MSCs in vitro. We found that the hybrid cells showed enhanced metastatic capacity with increased expression of MMP-2 and MMP-9, whereas the proliferation ability was inhibited and cell cycle was blocked in the G 0 /G 1 phase with elevated expression of p21, p27, and p53. Moreover, the hybrid cells lost epithelial morphology and exhibited an epithelial-mesenchymal transition (EMT) change with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin, α-SMA and Fibronectin1. Meanwhile, the expressions of EMT transcription factors, including Snail1, Slug, Twist1, Zeb1, and Zeb2, were also increased in hybrid cells. More important, the fusion hybrids acquired stem cell-like properties, which exhibited increased expression stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1. Taken together, our results suggested that cell fusion between lung cancer cells and MSCs offered enhanced metastatic capacity and characteristics of cancer stem cell by undergoing EMT. This study will contribute to explaning the origin of lung cancer stem cells and to elucidate the role of cell fusion in cancer metastasis. K E Y W O R D S cancer stem cells (CSCs), cell fusion, epithelial-mesenchymal transition (EMT), lung cancer, mesenchymal stem cells (MSCs)

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

“…The exact biological implication of MSC fusion is unclear. However, it is worth mentioning that cell fusion between MSCs and cancer cells enhances metastatic capacity and the characteristics of cancer stem cells by undergoing epithelial-mesenchymal transition, which is considered a key cell event in the process of tumour metastasis and invasion [147,148]. Overall, the engraftment and differentiation efficacy of MSCs post-transplantation is very low which heavily limits their therapeutic effects.…”

Cell Fusion in Human Cancer: The Dark Matter Hypothesis

“…However, cell fusion is not limited to tumor cells and macrophages. It is well known that tumor cells also fuse with other tumor cells [47,53,65,66,67], as well as with fibroblasts [8,25,68] and stem(-like) cells [17,21,48,56,69,70]. Whether such tumor cell × tumor cell (TT)-hybrids or tumor cell × fibroblast/stem-like cell hybrid cells (also called TN-hybrid cells) can be detected will depend on whether they express specific markers.…”

Mesenchymal Stem/Stromal Cell Engulfment Reveals Metastatic Advantage in Breast Cancer

“…Emerging studies support a role for fusion between cancer cells and other cell types, including macrophages (Gast et al, 2018) and MSCs (Zhang et al, 2019), in metastasis. Gast et al (2018) reported that macrophage-cancer cell fusion promotes phenotypic diversity and metastasis of colon cancer and melanoma.…”