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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

How apoptosis shapes cancer. (a) In proliferative tissues, injury is followed by rapid regeneration and restoration of normally sized and shaped structures. In the Drosophila wing imaginal disc, apoptotic cells induce competitive proliferation by secretion of mitogenic factors in a caspase-dependent manner. (b) In tissues with aberrant cells, tissue injury (e.g. caused by DNA damage in MDS patients) and consecutive proliferation enables outgrowth of more aggressive clones. This fosters malignant transformation. (c) Within established tumors, chemo- or radiotherapy induces apoptosis but leads to death-induced proliferation of therapy-surviving cells. Following the generation of space, proliferation is mediated by mitogens derived from apoptotic cells (such as PGE2). As proposed in mathematical models, this results in increased sub-clonal variability with a higher risk of tumor progression, chemoresistance and relapse
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fig2: How apoptosis shapes cancer. (a) In proliferative tissues, injury is followed by rapid regeneration and restoration of normally sized and shaped structures. In the Drosophila wing imaginal disc, apoptotic cells induce competitive proliferation by secretion of mitogenic factors in a caspase-dependent manner. (b) In tissues with aberrant cells, tissue injury (e.g. caused by DNA damage in MDS patients) and consecutive proliferation enables outgrowth of more aggressive clones. This fosters malignant transformation. (c) Within established tumors, chemo- or radiotherapy induces apoptosis but leads to death-induced proliferation of therapy-surviving cells. Following the generation of space, proliferation is mediated by mitogens derived from apoptotic cells (such as PGE2). As proposed in mathematical models, this results in increased sub-clonal variability with a higher risk of tumor progression, chemoresistance and relapse

Mentions: How could apoptosis promote tumorigenesis? Cancer development can be viewed as a Darwinistic process of somatic cell evolution, whereby initially 'healthy' cells acquire multiple (epi)genetic lesions driving clonal selection. This process is facilitated by the acquisition of mutations in oncogenes and tumor suppressors and by the selection for cells with superior fitness. Under continuous selection pressure, apoptosis could be a major driver of clonal expansion by generating vacant niches (Figure 2). These niches become repopulated by more aggressive sub-clones with certain competitive advantages. In that respect, apoptosis would be a driver of tumor evolution and a hallmark of aggressive disease. This could be especially relevant during early steps of tumorigenesis. Pre-malignant lesions can stably persist for an extended period of time while still too small to be clinically relevant.


How cell death shapes cancer.

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

How apoptosis shapes cancer. (a) In proliferative tissues, injury is followed by rapid regeneration and restoration of normally sized and shaped structures. In the Drosophila wing imaginal disc, apoptotic cells induce competitive proliferation by secretion of mitogenic factors in a caspase-dependent manner. (b) In tissues with aberrant cells, tissue injury (e.g. caused by DNA damage in MDS patients) and consecutive proliferation enables outgrowth of more aggressive clones. This fosters malignant transformation. (c) Within established tumors, chemo- or radiotherapy induces apoptosis but leads to death-induced proliferation of therapy-surviving cells. Following the generation of space, proliferation is mediated by mitogens derived from apoptotic cells (such as PGE2). As proposed in mathematical models, this results in increased sub-clonal variability with a higher risk of tumor progression, chemoresistance and relapse
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: How apoptosis shapes cancer. (a) In proliferative tissues, injury is followed by rapid regeneration and restoration of normally sized and shaped structures. In the Drosophila wing imaginal disc, apoptotic cells induce competitive proliferation by secretion of mitogenic factors in a caspase-dependent manner. (b) In tissues with aberrant cells, tissue injury (e.g. caused by DNA damage in MDS patients) and consecutive proliferation enables outgrowth of more aggressive clones. This fosters malignant transformation. (c) Within established tumors, chemo- or radiotherapy induces apoptosis but leads to death-induced proliferation of therapy-surviving cells. Following the generation of space, proliferation is mediated by mitogens derived from apoptotic cells (such as PGE2). As proposed in mathematical models, this results in increased sub-clonal variability with a higher risk of tumor progression, chemoresistance and relapse
Mentions: How could apoptosis promote tumorigenesis? Cancer development can be viewed as a Darwinistic process of somatic cell evolution, whereby initially 'healthy' cells acquire multiple (epi)genetic lesions driving clonal selection. This process is facilitated by the acquisition of mutations in oncogenes and tumor suppressors and by the selection for cells with superior fitness. Under continuous selection pressure, apoptosis could be a major driver of clonal expansion by generating vacant niches (Figure 2). These niches become repopulated by more aggressive sub-clones with certain competitive advantages. In that respect, apoptosis would be a driver of tumor evolution and a hallmark of aggressive disease. This could be especially relevant during early steps of tumorigenesis. Pre-malignant lesions can stably persist for an extended period of time while still too small to be clinically relevant.

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