The role of autophagy in escaping therapy-induced polyploidy/senescence

Dudkowska, Magdalena; Staniak, Karolina; Bojko, Agnieszka; Sikora, Ewa

doi:10.1016/bs.acr.2021.01.004

Cited by 17 publications

(14 citation statements)

References 159 publications

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“…Although described over a century ago, it was not until the late 1950’s when Puck and Marcus reported that giant cells that developed in cultures of the HeLa cervical carcinoma cell line, following exposure to ionizing radiation, remain viable and secrete growth promoting factors (reviewed in [ 50 ]). Since then, the basis for the creation of giant cancer cells with massive nuclear contents and their impact on therapy resistance and disease relapse has been clearly established and extensively reviewed (e.g., [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]).…”

Section: Well Established and Yet Widely Overlooked Therapy-induced C...mentioning

confidence: 99%

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

Mirzayans

Murray

2022

IJMS

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Over 50 years of cancer research has resulted in the generation of massive amounts of information, but relatively little progress has been made in the treatment of patients with solid tumors, except for extending their survival for a few months at best. Here, we will briefly discuss some of the reasons for this failure, focusing on the limitations and sometimes misunderstanding of the clinical relevance of preclinical assays that are widely used to identify novel anticancer drugs and treatment strategies (e.g., “synthetic lethality”). These include colony formation, apoptosis (e.g., caspase-3 activation), immunoblotting, and high-content multiwell plate cell-based assays, as well as tumor growth studies in animal models. A major limitation is that such assays are rarely designed to recapitulate the tumor repopulating properties associated with therapy-induced cancer cell dormancy (durable proliferation arrest) reflecting, for example, premature senescence, polyploidy and/or multinucleation. Furthermore, pro-survival properties of apoptotic cancer cells through phoenix rising, failed apoptosis, and/or anastasis (return from the brink of death), as well as cancer immunoediting and the impact of therapeutic agents on interactions between cancer and immune cells are often overlooked in preclinical studies. A brief review of the history of cancer research makes one wonder if modern strategies for treating patients with solid tumors may sometimes cause more harm than benefit.

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Section: Well Established and Yet Widely Overlooked Therapy-induced C...mentioning

confidence: 99%

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

Mirzayans

Murray

2022

IJMS

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“…This process can generate a high level of fatty acids and energy for the cells. PACCs that enter quiescence due to chemotherapy treatment are under high levels of stress and are hypothesized to have increased autophagy levels (Dudkowska et al, 2021). High levels of autophagy could give PACCs a metabolic advantage during quiescence by slowly breaking down cellular components for energy instead of importing nutrients from the toxic environment.…”

Section: Discussion: Understanding Different Types Of Dormancy Provides Insight Into Dormant Pacc Metabolismmentioning

confidence: 99%

Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla

2021

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Dormancy is a key survival strategy in many organisms across the tree of life. Organisms that utilize some type of dormancy (hibernation, aestivation, brumation, diapause, and quiescence) are able to survive in habitats that would otherwise be uninhabitable. Induction into dormant states is typically caused by environmental stress. While organisms are dormant, their physical activity is minimal, and their metabolic rates are severely depressed (hypometabolism). These metabolic reductions allow for the conservation and distribution of energy while conditions in the environment are poor. When conditions are more favorable, the organisms are then able to come out of dormancy and reengage in their environment. Polyaneuploid cancer cells (PACCs), proposed mediators of cancer metastasis and resistance, access evolutionary programs and employ dormancy as a survival mechanism in response to stress. Quiescence, the type of dormancy observed in PACCs, allows these cells the ability to survive stressful conditions (e.g., hypoxia in the microenvironment, transiting the bloodstream during metastasis, and exposure to chemotherapy) by downregulating and altering metabolic function, but then increasing metabolic activities again once stress has passed. We can gain insights regarding the mechanisms underlying PACC dormancy by looking to the evolution of dormancy in different organisms.

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“…Such escape was related to overexpression of CDC2 and its downstream effector survivin, conferring increased viability of the escaped cells [60,78,102]. In addition, CDK1 upregulation has been found to promote polyploidy and subsequent escape from TIS, while there is also evidence for senescence escape mediated by autophagic activation [99,100]. Similarly, polyploid features were also evident in cells escaping from OIS during a cancer evolution experiment [79].…”

Section: The Senescence Escape Phenomenon: Mechanistic Insightsmentioning

confidence: 99%

“…Additionally, doxorubicin-treated cancer cells were found to display high levels of glutamate following escape from TIS [98]. Polyploidy is a common trait of senescent cells and has been extensively demonstrated in tumour cells following TIS [61,99]. Polyploidy is linked to chromatin reorganisation, stemness, and drug-resistant properties along with enhanced metabolic energy.…”

Section: K Evangelou K Belogiannis Et Almentioning

confidence: 99%

Escape from senescence: molecular basis and therapeutic ramifications

Evangelou

Belogiannis

Papaspyropoulos

et al. 2023

The Journal of Pathology

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Cellular senescence constitutes a stress response mechanism in reaction to a plethora of stimuli. Senescent cells exhibit cell‐cycle arrest and altered function. While cell‐cycle withdrawal has been perceived as permanent, recent evidence in cancer research introduced the so‐called escape‐from‐senescence concept. In particular, under certain conditions, senescent cells may resume proliferation, acquiring highly aggressive features. As such, they have been associated with tumour relapse, rendering senescence less effective in inhibiting cancer progression. Thus, conventional cancer treatments, incapable of eliminating senescence, may benefit if revisited to include senolytic agents. To this end, it is anticipated that the assessment of the senescence burden in everyday clinical material by pathologists will play a crucial role in the near future, laying the foundation for more personalised approaches. Here, we provide an overview of the investigations that introduced the escape‐from‐senescence phenomenon, the identified mechanisms, as well as the major implications for pathology and therapy. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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The role of autophagy in escaping therapy-induced polyploidy/senescence

Cited by 17 publications

References 159 publications

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla

Escape from senescence: molecular basis and therapeutic ramifications

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