Apoptosis Reversal Promotes Cancer Stem Cell-Like Cell Formation

Xu, Yiyue; So, Chi‐Chiu; Lam, Hon‐Ming; Fung, Ming-Chiu; Tsang, Suk Ying

doi:10.1016/j.neo.2018.01.005

Cited by 42 publications

(47 citation statements)

References 40 publications

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“…However, most metastatic cancers, including lung, brain, skin and pancreatic cancers, inevitably recur, leading to treatment failure [ 185 – 189 ]. Anastasis has been observed in various cultured human cancer cell lines including cervical cancer, small cell lung carcinoma, neuroblastoma, skin cancer, testicular cancer, liver cancer, breast cancer and prostate cancer [ 21 , 26 , 28 , 29 , 31 – 33 , 85 ], thereby suggesting that this process could be a common occurrence in cancers. Furthermore, upregulation of genes involved in cell migration (MMP9, MMP10 and MMP13) and angiogenesis (ANGPTL4, ANGPT2 and VEGFA) during anastasis [ 29 ] suggests a plausible connection between anastasis and cancer metastasis during a recurrence.…”

Section: Looking Forwardmentioning

confidence: 99%

Anastasis: recovery from the brink of cell death

Tang

2018

R. Soc. open sci.

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Anastasis is a natural cell recovery phenomenon that rescues cells from the brink of death. Programmed cell death such as apoptosis has been traditionally assumed to be an intrinsically irreversible cascade that commits cells to a rapid and massive demolition. Interestingly, recent studies have demonstrated recovery of dying cells even at the late stages generally considered immutable. Here, we examine the evidence for anastasis in cultured cells and in animals, review findings illuminating the potential mechanisms of action, discuss the challenges of studying anastasis and explore new strategies to uncover the function and regulation of anastasis, the identification of which has wide-ranging physiological, pathological and therapeutic implications.

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Section: Looking Forwardmentioning

confidence: 99%

Anastasis: recovery from the brink of cell death

Tang

2018

R. Soc. open sci.

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“…Time-lapse live cell microscopy has demonstrated that cancer cell fragments resulting from the formation of apoptotic bodies can coalesce to give rise to cells with apparently normal morphology, often displaying an increased number of micronuclei and chromosomal abnormalities that can lead to increased aneuploidy [125,127]. Consistent with these observations, studies have revealed that anastatic cancer cells acquire stem cell-like properties that can promote tumor progression, therapy resistance, and disease recurrence [125][126][127]130].…”

Section: Recovery Of Apoptotic Cancer Cells From the Brink Of Deathmentioning

confidence: 88%

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Mirzayans

Murray

2020

IJMS

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A major challenge in treating cancer is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes. These include therapy-induced dormancy (durable proliferation arrest through, e.g., polyploidy, multinucleation, or senescence), apoptosis reversal (anastasis), and cell fusion. Unfortunately, such responses are often overlooked or misinterpreted as “death” in commonly used preclinical assays, including the in vitro colony-forming assay and multiwell plate “viability” or “cytotoxicity” assays. Although these assays predominantly determine the ability of a test agent to convert dangerous (proliferating) cancer cells to potentially even more dangerous (dormant) cancer cells, the results are often assumed to reflect loss of cancer cell viability (death). In this article we briefly discuss the dark sides of dormancy, apoptosis, and cell fusion in cancer therapy, and underscore the danger of relying on short-term preclinical assays that generate population-based data averaged over a large number of cells. Unveiling the molecular events that underlie intratumor heterogeneity together with more appropriate experimental design and data interpretation will hopefully lead to clinically relevant strategies for treating recurrent/metastatic disease, which remains a major global health issue despite extensive research over the past half century.

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“…Failure to execute apoptosis also seems to impact the emergence of cancer stem cell-like cells (CSCs) in breast cancer. Here the authors found that breast cancer cells surviving non-lethal doses of staurosporine gain in metastatic potential in vivo while some of them acquired CSCs properties 35 .…”

Section: Discussionmentioning

confidence: 99%

“…Even though we used melanoma cancer cells as a proof-of-principle tool to investigate failed apoptosis, we hypothesize that our findings might extend to other types of cancers. In this vein, research conducted in colon or breast cancer cells also highlighted a correlation between increased aggressiveness and non-lethal caspase activation 35,48 .…”

Section: Discussionmentioning

confidence: 99%

Failed apoptosis enhances melanoma cancer cells aggressiveness

Berthenet

Ferrer

Popgeorgiev

et al. 2019

Preprint

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Triggering apoptosis remains an efficient strategy to treat cancer. However, apoptosis is no longer a final destination, since cells can undergo partial apoptosis without dying. Recent evidence shows that partial mitochondrial permeabilization and non-lethal caspase activation occur under certain circumstances, though it remains unclear how failed apoptosis impacts established cancers. Using a cancer cell model to trigger non-lethal caspase activation based on either BH3-only protein expression or chemotherapy treatment, we found that melanoma cancer cells failing to undergo complete apoptosis have a particular transcriptomic signature associated with focal adhesions, transendothelial migration and modifications of actin cytoskeleton.In line with this, cancer cells surviving apoptosis have a gain in migratory and invasive properties both in vitro (random migration, chemotaxis, wound healing and invasion assays) and in vivo (in a model of zebrafish metastasis)We further demonstrate that the failed apoptosis-associated gain in invasiveness is regulated by the c-Jun N-terminal kinase (JNK) pathway while its RNA seq signature is found in metastatic melanoma. These findings are highly significant for understanding how cell death can both cure and promote cancer.3

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Apoptosis Reversal Promotes Cancer Stem Cell-Like Cell Formation

Cited by 42 publications

References 40 publications

Anastasis: recovery from the brink of cell death

Anastasis: recovery from the brink of cell death

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Failed apoptosis enhances melanoma cancer cells aggressiveness

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