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

Vaish M - Mol. Cancer (2007)

Bottom Line: These cells are a common phenomenon for the hematological malignancies and solid tumors.The cells when exposed to cytotoxic agents, the apoptosis lead to cell death.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 non-tumorigenic population of cells resulting in potential cancer cures.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, University of Lucknow-226007, UP, India. minal14@yahoo.com

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 non-tumorigenic population of cells resulting in potential cancer cures.

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Development of cancer stem cells from the normal stem cells and progenitor cells. Accumulation of DNA errors in normal stem cells or progenitor cells are activated to generate a cancer stem cells (CSCs) that further generate a primary tumor constituting CSCs and other tumor cells.
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Figure 1: Development of cancer stem cells from the normal stem cells and progenitor cells. Accumulation of DNA errors in normal stem cells or progenitor cells are activated to generate a cancer stem cells (CSCs) that further generate a primary tumor constituting CSCs and other tumor cells.

Mentions: The multipotency of stem cells to maintain tissue homeostasis and its differentiation into mature cell types is under a tightly controlled system and is associated with restricted expression profile. The expression of transport proteins – ABC (ATP-binding cassette) transporter proteins and multidrug resistant proteins that protect cells against toxins and are associated with the efflux of xenobiotic toxins, low rate of cell division and active DNA repair are the innate properties of normal development of stem cells. Besides hormonal stimulation, DNA damage is one of the key factors for stem cell activation. DNA accumulates errors either from environmental factors, which could be the exposure to radiation, chemicals or drugs, viruses and bacteria or DNA replication errors [4]. This would result in complex cellular responses that include loss of cell cycle regulation, transcription induction and DNA repair mechanisms for maintaining genomic and chromosomal stability. But in absence of efficient DNA repair machinery, the stem cells accumulate harmful mutations and become resistant to apoptosis resulting in the loss of genome or instability, which ultimately lead to malignant transformation of stem cells [5]. Table 1 features the stem cell activation types, which transforms them into different cancer types [4,6]. Each stem cell activation type is exemplified with a single cancer type in the Table 1, however many could be associated. The progenitor cells also known as transit – amplifying cells arise from normal stem cells have replicative ability but not self-renewal capacity. Mutations in these progenitor cells help in regaining self-renewal property and become cancerous (Fig 1).


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

Vaish M - Mol. Cancer (2007)

Development of cancer stem cells from the normal stem cells and progenitor cells. Accumulation of DNA errors in normal stem cells or progenitor cells are activated to generate a cancer stem cells (CSCs) that further generate a primary tumor constituting CSCs and other tumor cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851711&req=5

Figure 1: Development of cancer stem cells from the normal stem cells and progenitor cells. Accumulation of DNA errors in normal stem cells or progenitor cells are activated to generate a cancer stem cells (CSCs) that further generate a primary tumor constituting CSCs and other tumor cells.
Mentions: The multipotency of stem cells to maintain tissue homeostasis and its differentiation into mature cell types is under a tightly controlled system and is associated with restricted expression profile. The expression of transport proteins – ABC (ATP-binding cassette) transporter proteins and multidrug resistant proteins that protect cells against toxins and are associated with the efflux of xenobiotic toxins, low rate of cell division and active DNA repair are the innate properties of normal development of stem cells. Besides hormonal stimulation, DNA damage is one of the key factors for stem cell activation. DNA accumulates errors either from environmental factors, which could be the exposure to radiation, chemicals or drugs, viruses and bacteria or DNA replication errors [4]. This would result in complex cellular responses that include loss of cell cycle regulation, transcription induction and DNA repair mechanisms for maintaining genomic and chromosomal stability. But in absence of efficient DNA repair machinery, the stem cells accumulate harmful mutations and become resistant to apoptosis resulting in the loss of genome or instability, which ultimately lead to malignant transformation of stem cells [5]. Table 1 features the stem cell activation types, which transforms them into different cancer types [4,6]. Each stem cell activation type is exemplified with a single cancer type in the Table 1, however many could be associated. The progenitor cells also known as transit – amplifying cells arise from normal stem cells have replicative ability but not self-renewal capacity. Mutations in these progenitor cells help in regaining self-renewal property and become cancerous (Fig 1).

Bottom Line: These cells are a common phenomenon for the hematological malignancies and solid tumors.The cells when exposed to cytotoxic agents, the apoptosis lead to cell death.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 non-tumorigenic population of cells resulting in potential cancer cures.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, University of Lucknow-226007, UP, India. minal14@yahoo.com

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 non-tumorigenic population of cells resulting in potential cancer cures.

Show MeSH
Related in: MedlinePlus