Tumorigenic potential is restored during differentiation in fusion-reprogrammed cancer cells

Abstract

Detailed understanding of the mechanistic steps underlying tumor initiation and malignant progression is critical for insights of potentially novel therapeutic modalities. Cellular reprogramming is an approach of particular interest because it can provide a means to reset the differentiation state of the cancer cells and to revert these cells to a state of non-malignancy. Here, we investigated the relationship between cellular differentiation and malignant progression by the fusion of four independent mouse cancer cell lines from different tissues, each with differing developmental potentials, to pluripotent mouse embryonic stem (ES) cells. Fusion was accompanied by loss of differentiated properties of the four parental cancer cell lines and concomitant emergence of pluripotency, demonstrating the feasibility to reprogram the malignant and differentiative properties of cancer cells. However, the original malignant and differentiative phenotypes re-emerge upon withdrawal of the fused cells from the embryonic environment in which they were maintained. cDNA array analysis of the malignant hepatoma progression implicated a role for Foxa1, and silencing Foxa1 prevented the re-emergence of malignant and differentiation-associated gene expression. Our findings support the hypothesis that tumor progression results from deregulation of stem cells, and our approach provides a strategy to analyze possible mechanisms in the cancer initiation.

Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo

“…Markers to identify cancer cell fusion and to isolate cancer hybrid cells include resistance to different antibiotics, or the co-expression of two different fluorescent reporter proteins [31,32,73,123,128,129,133,134,137,138,[140][141][142][143][144][145][147][148][149][150][151][152]154,155,158,161,162,164,167,169,[171][172][173][174]178], or the use of hypoxanthine, aminopterin, or thymidine (HAT) medium [125,160,173,175], respectively.…”

Deciphering two decades of cellular reprogramming in cancer: A bibliometric analysis of evolving trends and research frontiers

“…This exciting area of research is especially important in cancers with unusual growth patterns [ [2] , [3] ]. The possibility that reprogramming could turn cancerous cells back to a non-cancerous state is sparking a lot of interest [ [4] , [5] ]. It shows how the environment around cells, along with their genetic makeup and changes in gene expression [ 6 ], play a role.…”

Nuclear transplantation between allogeneic cells through topological reconnection of plasma membrane in a microfluidic system

“…Previous studies have demonstrated that fusion of embryonic stem cells (ES cells) with somatic cells can initiate reprogramming of somatic cells to pluripotency by acquiring reprogramming factors from the stem cells 1,2 . Consequently, cell fusion-based reprogramming is increasingly being applied toward understanding epigenetic modifications during the initiation of reprogramming or dedifferentiation 3,4 . Conventionally, cell fusion has been achieved using viruses, 5 polyethylene glycol, 6 and various electrical approaches (i.e., electrofusion) 7,8 .…”