Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells

Abstract

Although DNA hypermethylation within promoter CpG islands is highly correlated with tumorigenesis, it has not been established whether DNA hypermethylation within a specific tumor suppressor gene (TSG) is sufficient to fully transform a somatic stem cell. In this study, we addressed this question using a novel targeted DNA methylation technique to methylate the promoters of HIC1 and RassF1A, two well-established TSGs, along with a two-component reporter system to visualize successful targeting of human bone marrow-derived mesenchymal stem cells (MSC) as a model cell system. MSCs harboring targeted promoter methylations of HIC1/RassF1A displayed several features of cancer stem/initiating cells including loss of anchorage dependence, increased colony formation capability, drug resistance, and pluripotency. Notably, inoculation of immunodeficient mice with low numbers of targeted MSC resulted in tumor formation, and subsequent serial xenotransplantation and immunohistochemistry confirmed the presence of stem cell markers and MSC lineage in tumor xenografts. Consistent with the expected mechanism of TSG hypermethylation, treatment of the targeted MSC with a DNA methyltransferase inhibitor reversed their tumorigenic phenotype. To our knowledge, this is the first direct demonstration that aberrant TSG hypermethylation is sufficient to transform a somatic stem cell into a fully malignant cell with cancer stem/initiating properties. Cancer Res; 71(13); 4653-63. Ó2011 AACR.

An Upward Trend in Dna P16ink4a Methylation Pattern and High Risk HPV Infection According to the Severity of the Cervical Lesion

“…This is the best characterized epigenetic change associated with gene transcriptional silencing, thus providing a DNA-based surrogate marker for expression status10. It has been increasingly recognized over the past decade that the CpG islands of a large number of genes which are unmethylated in normal tissue are methylated to varying degrees in multiple types of human neoplasm, including cervical cancer9 21 22.…”

Induced cancer stem cells generated by radiochemotherapy and their therapeutic implications

“…Chemotherapy-induced hypoxia-inducible factors (HIFs) enrich BCSCs through IL-6 and IL-8 signaling and increase expression of multidrug resistance 1 [78]. Tumor microenvironment is also reported as a factor that converts non-stem cancer cells into iCSCs [79, 80]. Under the influence of different environmental niches, malignant cells derived from somatic mesenchymal stem cells (MSCs) could give rise to iCSCs with several stemness features including drug resistance [79].…”

“…Tumor microenvironment is also reported as a factor that converts non-stem cancer cells into iCSCs [79, 80]. Under the influence of different environmental niches, malignant cells derived from somatic mesenchymal stem cells (MSCs) could give rise to iCSCs with several stemness features including drug resistance [79]. Transforming growth factor β1 (TGF-β1) dramatically induces non-stem osteosarcoma cells into iCSCs with chemoresistance and metastatic potential [81].…”

RNA‐directed epigenomic reprogramming—an emerging principle of a more targeted cancer therapy?

“…Genomewide analysis of lncRNA expression with a concomitant monitoring of epigenetic alterations could be performed through differentiation of stem cells into terminally differentiated cells in order to find prominent RNA candidates, which may be employed to partially or completely reverting malignant phenotypes of neoplastic cells. The feasibility of performing this task has already been proven in principle, although by other approaches (Illmensee and Mintz, 1976;Hochedlinger et al, 2004;Carette et al, 2010;Teng et al, 2011). Additionally, technical issues still need to be addressed, such as the development of optimal methods for lncRNA delivery, which are required for a replacement therapy or silencing of over-expressed targets.…”