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Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation.

ABSTRACT: Cultured human umbilical cord mesenchymal stem cells (hUC-MSCs) are being tested in several clinical trials and encouraging outcomes have been observed. To determine whether in vitro expansion influences the genomic stability of hUC-MSCs, we maintained nine hUC-MSC clones in long-term culture and comparatively analyzed them at early and late passages. All of the clones senesced in culture, exhibiting decreased telomerase activity and shortened telomeres. Two clones showed no DNA copy number variations (CNVs) at passage 30 (P30). Seven clones had ?1 CNVs at P30 compared with P3, and one of these clones appeared trisomic chromosome 10 at the late passage. No tumor developed in immunodeficient mice injected with hUC-MSCs, regardless of whether the cells had CNVs at the late passage. mRNA-Seq analysis indicated that pathways of cell cycle control and DNA damage response were downregulated during in vitro culture in hUC-MSC clones that showed genomic instability, but the same pathways were upregulated in the clones with good genomic stability. These results demonstrated that hUC-MSCs can be cultured for many passages and attain a large number of cells, but most of the cultured hUC-MSCs develop genomic alterations. Although hUC-MSCs with genomic alterations do not undergo malignant transformation, periodic genomic monitoring and donor management focusing on genomic stability are recommended before these cells are used for clinical applications.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3877551 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Project description:Background & aimsMalignant transformation of hepatocellular adenoma (MT-HCA) may occur in up to 5% of tumours. However, the prognostic value of this event remains poorly described. In this study, we aimed to analyse the long-term outcomes of patients undergoing liver resection (LR) for MT-HCA compared to those of patients resected for hepatocellular carcinoma (HCC) occurring on normal liver parenchyma (NP-HCC).MethodsThis single-centre retrospective study included all patients who underwent LR for MT-HCA at Beaujon Hospital between 2001 and 2019. MT-HCAs were classified as small foci of malignant transformation HCA (SF-HCA) and as malignant HCA (M-HCA) in cases of predominant HCC foci. Recurrence-free survival (RFS) of MT-HCA was compared with that of NP-HCC after propensity score matching.ResultsForty patients (24 men, 16 women) underwent LR for MT-HCA, including 23 with SF-HCA and 17 with M-HCA. Of these cases, 16/40 (40%) had β-catenin mutations, 19/40 (47.5%) were inflammatory, 1 was HNF1α-mutated HCA and 4 (10%) were unclassified HCA. Microvascular invasion (12% vs. 0%, p = 0.091) and satellite nodules (25% vs. 4%, p = 0.028) were more frequently observed in M-HCA than in SF-HCA. After a median follow-up of 67 months, 10 (25%) patients with MT-HCA had tumour recurrence, including 9 with M-HCA and 1 with SF-HCA (p = 0.007). M-HCA was linked to significantly poorer 1-, 3-, 5- and 10-year RFS rates than SF-HCA (76%, 63%, 39%, 37% vs. 100%, 100%, 100%, 91%, p = 0.003). Multivariate analysis showed that SF-HCA was independently associated with improved RFS (hazard ratio 0.064; 95% CI 0.008-0.519; p = 0.01). After propensity score matching, NP-HCC was associated with significantly poorer 1-, 3-, 5- and 10-year RFS rates than MT-HCA (p = 0.01).ConclusionsHCA with malignant transformation yields a better long-term prognosis than NP-HCC. Among MT-HCA, SF-HCA is associated with a better prognosis than M-HCA.Lay summaryThe prognostic relevance of malignant transformation of hepatocellular adenoma (HCA) remains unknown. Thus, the aim of our study was to compare the outcomes of patients undergoing liver resection for malignant transformation to those of patients undergoing liver resection for hepatocellular carcinoma (HCC). The main long-term risk after resection for carcinoma is recurrence. In this study, 10/40 patients with malignant transformation of HCA relapsed after resection and we identified age >55 years, presence of satellite nodes, and microvascular invasion as risk factors for long-term recurrence. Compared to patients with HCC, patients who underwent liver resection for HCA with malignant transformation had better long-term survival.

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Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation.

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