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How cell death shapes cancer.

Labi V, Erlacher M - Cell Death Dis (2015)

Bottom Line: Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host.Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage.Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin 13125, Germany.

ABSTRACT
Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

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Related in: MedlinePlus

The rise and fall of apoptosis during MDS pathogenesis. Therapy-related myelodysplastic syndrom (MDS) is caused by repeated cycles of radio- or chemoradiotherapy (i.e., including alkylating agents) that lead to bone marrow attrition and subsequent regeneration. In children and adolescents, MDS can develop on the basis of congenital bone marrow failure syndrome such as Fanconi anemia and Dyskeratosis congenita. MDS frequently progresses to MDS-related AML (MDR-AML). The stepwise evolution of MDS is reflected by the FAB classification, which distinguishes between refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T) and MDR-AML
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fig3: The rise and fall of apoptosis during MDS pathogenesis. Therapy-related myelodysplastic syndrom (MDS) is caused by repeated cycles of radio- or chemoradiotherapy (i.e., including alkylating agents) that lead to bone marrow attrition and subsequent regeneration. In children and adolescents, MDS can develop on the basis of congenital bone marrow failure syndrome such as Fanconi anemia and Dyskeratosis congenita. MDS frequently progresses to MDS-related AML (MDR-AML). The stepwise evolution of MDS is reflected by the FAB classification, which distinguishes between refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T) and MDR-AML

Mentions: MDS are clonal malignancies originating from defective bone-marrow-derived HSCs, in which critical driver mutations provide them with a selective advantage (Figure 3). This disease is characterized by ineffective hematopoiesis causing peripheral cytopenia(s) and bone marrow dysplasia. Abnormal clonal progenitor cell differentiation and increased susceptibility of immature progenitors to apoptosis underlie these symptoms. The risk to develop MDS increases with age, suggesting that accumulation of genetic damage influences pathogenesis. Exposure to alkylating agents, chemo- or radiotherapy of cancer patients dramatically increases the risk to develop therapy-related MDS (lifetime risk of 2–10%).102 MDS has a high propensity to progress to MDS-related AML (MDR-AML). Disease progression is characterized by an increased percentage of bone marrow blast cells and cytogenetic abnormalities (reviewed by Corey et al.102).


How cell death shapes cancer.

Labi V, Erlacher M - Cell Death Dis (2015)

The rise and fall of apoptosis during MDS pathogenesis. Therapy-related myelodysplastic syndrom (MDS) is caused by repeated cycles of radio- or chemoradiotherapy (i.e., including alkylating agents) that lead to bone marrow attrition and subsequent regeneration. In children and adolescents, MDS can develop on the basis of congenital bone marrow failure syndrome such as Fanconi anemia and Dyskeratosis congenita. MDS frequently progresses to MDS-related AML (MDR-AML). The stepwise evolution of MDS is reflected by the FAB classification, which distinguishes between refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T) and MDR-AML
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385913&req=5

fig3: The rise and fall of apoptosis during MDS pathogenesis. Therapy-related myelodysplastic syndrom (MDS) is caused by repeated cycles of radio- or chemoradiotherapy (i.e., including alkylating agents) that lead to bone marrow attrition and subsequent regeneration. In children and adolescents, MDS can develop on the basis of congenital bone marrow failure syndrome such as Fanconi anemia and Dyskeratosis congenita. MDS frequently progresses to MDS-related AML (MDR-AML). The stepwise evolution of MDS is reflected by the FAB classification, which distinguishes between refractory anemia (RA), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T) and MDR-AML
Mentions: MDS are clonal malignancies originating from defective bone-marrow-derived HSCs, in which critical driver mutations provide them with a selective advantage (Figure 3). This disease is characterized by ineffective hematopoiesis causing peripheral cytopenia(s) and bone marrow dysplasia. Abnormal clonal progenitor cell differentiation and increased susceptibility of immature progenitors to apoptosis underlie these symptoms. The risk to develop MDS increases with age, suggesting that accumulation of genetic damage influences pathogenesis. Exposure to alkylating agents, chemo- or radiotherapy of cancer patients dramatically increases the risk to develop therapy-related MDS (lifetime risk of 2–10%).102 MDS has a high propensity to progress to MDS-related AML (MDR-AML). Disease progression is characterized by an increased percentage of bone marrow blast cells and cytogenetic abnormalities (reviewed by Corey et al.102).

Bottom Line: Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host.Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage.Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin 13125, Germany.

ABSTRACT
Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

Show MeSH
Related in: MedlinePlus