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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

Cytotoxic agents impact the Bcl-2 rheostat. The pro- and anti-apoptotic BCL-2 family proteins closely interact at the mitochondrial membrane and regulate the intrinsic apoptosis pathway. Cellular stress causes activation of pro-apoptotic BCL-2 proteins from the BH3-only sub-group (BIM, PUMA etc.). These bind to and inhibit their anti-apoptotic antagonists (BCL-2, MCL-1 etc.), thus releasing and activating the downstream effectors BAK and BAX. Mitochondrial membrane permeabilization (MOMP) is triggered, and pro-apoptotic molecules released into the cytoplasm activate caspases (in more detail reviewed by Labi et al.120). Conventional cytotoxic agents interfere with upstream signaling pathways converging at the BCL-2 family level. In contrast, BH3-mimetics directly inhibit pro-survival BCL-2 proteins
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fig1: Cytotoxic agents impact the Bcl-2 rheostat. The pro- and anti-apoptotic BCL-2 family proteins closely interact at the mitochondrial membrane and regulate the intrinsic apoptosis pathway. Cellular stress causes activation of pro-apoptotic BCL-2 proteins from the BH3-only sub-group (BIM, PUMA etc.). These bind to and inhibit their anti-apoptotic antagonists (BCL-2, MCL-1 etc.), thus releasing and activating the downstream effectors BAK and BAX. Mitochondrial membrane permeabilization (MOMP) is triggered, and pro-apoptotic molecules released into the cytoplasm activate caspases (in more detail reviewed by Labi et al.120). Conventional cytotoxic agents interfere with upstream signaling pathways converging at the BCL-2 family level. In contrast, BH3-mimetics directly inhibit pro-survival BCL-2 proteins

Mentions: Though cells can commit suicide by multiple ways, most cell death in vertebrates is mediated by the mitochondrial (intrinsic) pathway that is initiated by a plethora of signals, such as DNA damage, growth factor deprivation, developmental cues as well as many standard anti-cancer therapies. The initiators of this pathway belong to the BCL-2 family (Figure 1) and the balance between anti- and pro-apoptotic family members, the so-called 'Bcl-2 rheostat' determines whether a cell will live or die an apoptotic death.


How cell death shapes cancer.

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

Cytotoxic agents impact the Bcl-2 rheostat. The pro- and anti-apoptotic BCL-2 family proteins closely interact at the mitochondrial membrane and regulate the intrinsic apoptosis pathway. Cellular stress causes activation of pro-apoptotic BCL-2 proteins from the BH3-only sub-group (BIM, PUMA etc.). These bind to and inhibit their anti-apoptotic antagonists (BCL-2, MCL-1 etc.), thus releasing and activating the downstream effectors BAK and BAX. Mitochondrial membrane permeabilization (MOMP) is triggered, and pro-apoptotic molecules released into the cytoplasm activate caspases (in more detail reviewed by Labi et al.120). Conventional cytotoxic agents interfere with upstream signaling pathways converging at the BCL-2 family level. In contrast, BH3-mimetics directly inhibit pro-survival BCL-2 proteins
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Cytotoxic agents impact the Bcl-2 rheostat. The pro- and anti-apoptotic BCL-2 family proteins closely interact at the mitochondrial membrane and regulate the intrinsic apoptosis pathway. Cellular stress causes activation of pro-apoptotic BCL-2 proteins from the BH3-only sub-group (BIM, PUMA etc.). These bind to and inhibit their anti-apoptotic antagonists (BCL-2, MCL-1 etc.), thus releasing and activating the downstream effectors BAK and BAX. Mitochondrial membrane permeabilization (MOMP) is triggered, and pro-apoptotic molecules released into the cytoplasm activate caspases (in more detail reviewed by Labi et al.120). Conventional cytotoxic agents interfere with upstream signaling pathways converging at the BCL-2 family level. In contrast, BH3-mimetics directly inhibit pro-survival BCL-2 proteins
Mentions: Though cells can commit suicide by multiple ways, most cell death in vertebrates is mediated by the mitochondrial (intrinsic) pathway that is initiated by a plethora of signals, such as DNA damage, growth factor deprivation, developmental cues as well as many standard anti-cancer therapies. The initiators of this pathway belong to the BCL-2 family (Figure 1) and the balance between anti- and pro-apoptotic family members, the so-called 'Bcl-2 rheostat' determines whether a cell will live or die an apoptotic death.

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