Mismatch repair deficiencies transforming stem cells into cancer stem cells and therapeutic implications

Abstract

For the exceptional self-renewal capacity, regulated cell proliferation and differential potential to a wide variety of cell types, the stem cells must maintain the intact genome. The cells under continuous exogenous and endogenous genotoxic stress accumulate DNA errors, drive proliferative expansion and transform into cancer stem cells with a heterogeneous population of tumor cells. These cells are a common phenomenon for the hematological malignancies and solid tumors. In response to DNA damage, the complex cellular mechanisms including cell cycle arrest, transcription induction and DNA repair are activated. The cells when exposed to cytotoxic agents, the apoptosis lead to cell death. However, the absence of repair machinery makes the cells resistant to tumor sensitizing agents and result in malignant transformation. Mismatch repair gene defects are recently identified in hematopoietic malignancies, leukemia and lymphoma cell lines. This review emphasizes the importance of MMR systems in maintaining the stem cell functioning and its therapeutic implications in the eradication of cancer stem cells and differentiated tumor cells as well. The understanding of the biological functions of mismatch repair in the stem cells and its malignant counterparts could help in developing an effective novel therapies leaving residual nontumorigenic population of cells resulting in potential cancer cures.

A variant of the Cockayne syndrome B geneERCC6 confers risk of lung cancer

“…However, once the balance is uneven, such that DNA damage surpasses the DNA repair capacity, accumulation of multiple mutations may introduce carcinogenesis/tumorigenesis [Jackson et al, 2001]. Insufficient capacity of the DNA repair gene was evidently related to the increased susceptibility to cancers [Vaish, 2007;Gologan et al, 2005]. Therefore, decreased expression of ERCC6 by polymorphisms may cause a certain level of insufficient DNA repair that was not corrected by other DNA repair enzymes somehow, resulting in a higher susceptibility to lung cancer for these variant carriers.…”

Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies

“…In this regard, a growing body of evidence suggests that the most cancers may arise from the accumulation of different genetic and/or epigenetic alterations in multipotent tissue-resident adult stem/progenitor cells or their early progenies endowed with a high self-renewal capacity concomitant with the changes in their local microenvironment, niches (Hanahan and Weinberg, 2011; Kim et al, 2005; Mimeault et al, 2007b; Mimeault et al, 2012; Mimeault and Batra, 2010b; Mimeault and Batra, 2011; Mimeault and Batra, 2013; Nijhof et al, 2007; Shiras et al, 2007; Sugiarto et al, 2011; Vaish, 2007). Particularly, cancer initiation and development is often accompanied by a down-regulation of specific tumor suppressor gene products such as p16 INK4A , phosphatase and tensin homolog deleted on chromosome 10 (PTEN), p53 and/or retinoblastoma (pRb) combined with the overexpression of different oncogenic products, including chromosomal translocations generating oncogenic fusion proteins in cancer-initiating cells (Chen et al, 2007; Clement et al, 2007; Mimeault and Batra, 2009; Mimeault and Batra, 2010b; Mimeault and Batra, 2011; Mimeault and Batra, 2013; Motohara et al, 2011; Sengupta et al, 2007; Wang et al, 2007a).…”

Human Adipose Stromal Cells (ASC) for the Regeneration of Injured Cartilage Display Genetic Stability after In Vitro Culture Expansion

“…The MisMatch Repair (MMR) System is the main post-replicative correction pathway whose efficiency can be monitored by MSI analysis. The rationale to evaluate this repair system lies in its fundamental role for genomic stability maintenance [41]–[43] in actively replicating cells such as those being studied. In addition, both oxidative stress (known to be induced by culture conditions) [44]–[46] and in vitro / in vivo aging [47]–[50] were shown to be capable of altering MMR system efficiency, thus leading to genetic instability.…”