Tumor cell escape from therapy-induced senescence

Saleh, Tareq; Tyutyunyk‐Massey, Liliya; Murray, Graeme; Alotaibi, Moureq R.; Kawale, Ajinkya S.; Elsayed, Zeinab; Henderson, Scott C.; Yakovlev, Vasily A.; Elmore, Lynne W.; Toor, Amir A.; Harada, Hisashi; Reed, Jason; Landry, Joseph W.; Gewirtz, David A.

doi:10.1016/j.bcp.2018.12.013

Cited by 116 publications

(125 citation statements)

References 53 publications

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“…Enriched, SA-β-gal-positive tumor cells were shown to resume proliferation, marked by real-time live cell imaging which revealed the ability of a subpopulation of tumor cells to undergo spontaneous mitoses. These outcomes were confirmed using advanced High-Speed Live Cell Interferometry (HSLCI) technology [27].…”

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 85%

“…These senescent tumor cells underwent a state of growth arrest, but failed to maintain features of the senescent phenotype indefinitely; consequently, over a period of 7 days (or more), these chemotherapy-exposed tumor cells were able to resume proliferation. The resolution from senescence was accompanied by an attenuation of the expression of select SASP components [27].…”

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 99%

“…We have recently provided what we believe is direct evidence for the escape from TIS in tumor cells in vitro and in vivo in work that examined the fate of three tumor cell lines (H460 lung, HCT116 colon and 4T1 breast) induced into senescence by exposure to two topoisomerase II inhibitors, etoposide and doxorubicin [27]. Senescence induction in these cell lines was marked by markers of the senescent phenotype, such as morphological alterations (cell flattening and enlargement), increased SA-β-gal activity, upregulation of p21 Cip1 , increased expression of the senescence surrogate BTG1, and formation of DNA damage and heterochromatic foci [27]. These senescent tumor cells underwent a state of growth arrest, but failed to maintain features of the senescent phenotype indefinitely; consequently, over a period of 7 days (or more), these chemotherapy-exposed tumor cells were able to resume proliferation.…”

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 99%

“…In order to confirm that growth resumption was not attributable to non-senescent cells that escape genotoxic stress induced by chemotherapy, enrichment of the senescent H460 and HCT116 cell population was carried out based on the expression of SA-β-gal using fluorescence activated cell sorting, and at different temporal points following senescence induction [27]. Enriched, SA-β-gal-positive tumor cells were shown to resume proliferation, marked by real-time live cell imaging which revealed the ability of a subpopulation of tumor cells to undergo spontaneous mitoses.…”

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 99%

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Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 85%

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 99%

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 99%

Section: Evidence For the Reversibility Of Therapy-induced Senescencementioning

confidence: 99%

See 2 more Smart Citations

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

Self Cite

181

140

View full text Add to dashboard Cite

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“…It is important to note that we do not propose that senescence is actually reversible in the manner of a reversible chemical reaction. Instead, we propose that although the bulk of a "senescent" population is likely to be indefinitely arrested, there will be subpopulation(s) of cells capable of recovering self-renewal capacity, particularly in the context of TIS in tumor cells that inherently harbor genetic derangements (3,7). The results of our own recent studies confirm that only a subpopulation of tumor cells is capable of escaping the growth arrest (3), which likely reflects the heterogeneity of the senescent phenotype that has been established by Demaria and colleagues.…”

Section: Discussionmentioning

confidence: 99%

Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy

2019

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Senescence, a durable form of growth arrest, represents a primary response to numerous anticancer therapies. Although the paradigm that senescence is "irreversible" has largely withstood the findings of tumor cell recovery from what has been termed "pseudo-senescence" or "senescence-like arrest," a review of the literature suggests that therapy-induced senes-cence in tumor cells is not obligatorily a permanent cell fate. Consequently, we propose that senescence represents one avenue whereby tumor cells evade the direct cytotoxic impact of therapy, thereby allowing for prolonged survival in a dormant state, with the potential to recover self-renewal capacity and contribute to disease recurrence.

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Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐X_L–BAX interaction

et al. 2020

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Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT-263 (navitoclax), therefore providing a "two-hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy-induced senescence and ABT-263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL-X L and BAX. The administration of ABT-263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumorbearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.

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Tumor cell escape from therapy-induced senescence

Cited by 116 publications

References 53 publications

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy

Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐X_L–BAX interaction

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Tumor cell escape from therapy-induced senescence

Cited by 116 publications

References 53 publications

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy

Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐XL–BAX interaction

Contact Info

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Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐X_L–BAX interaction