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.
Highlights
Investigations into cancer formation are most often focused on the accumulation of specific genetic and epigenetic alterations that alter the expression of the oncogenes and tumor suppressors regulating cell cycle, apoptosis, DNA repair, cell adhesion and signaling.[1,2,3] Less often considered, the tumorigenic process can be regarded from a standpoint of a dynamic relationship between malignant progression and cellular differentiation.[4]
We observed that H3K27 trimethylation, which was independent of H3K9 dimethylation, was an early event in the silencing of p16INK4a during reemergence of the tumorigenic profile, a finding that was supported by a number of other groups studying the progression mechanisms of hepatocellular carcinoma (HCC).[30,31,32]
Two adult cancer lines and two embryonal cancer (EC) lines were fused with mouse embryonic stem (ES) cells to investigate how tumorigenic potential of cancer cells can be influenced by differentiation status
Summary
Investigations into cancer formation are most often focused on the accumulation of specific genetic and epigenetic alterations that alter the expression of the oncogenes and tumor suppressors regulating cell cycle, apoptosis, DNA repair, cell adhesion and signaling.[1,2,3] Less often considered, the tumorigenic process can be regarded from a standpoint of a dynamic relationship between malignant progression and cellular differentiation.[4]. The nuclear transferred cells regained pluripotent potential, the malignant properties remained, indicating incomplete reprogramming in reproductive and therapeutic cloning with this approach.[10,11] Separately, defined factors OSMK (Oct[4], Sox[2], c-Myc and Klf4) were tested for the ability to reprogram both solid and liquid malignant tumors including chronic myeloid leukemia,[12,13] gastrointestinal cancer,[14] melanoma[15] and sarcoma cells.[16,17] Using the OSMK approach, late-stage cancer cells could revert back to an earlier state, bolstering enthusiasm for the discovery of new insights in cancer initiation and progression. Our observations suggest that cell fusionmediated reprogramming is a novel and potentially useful strategy for the identification and testing of molecules involved in cancer initiation and progression, with exploitable modalities for new cancer therapies
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