Cancer regeneration: Polyploid cells are the key drivers of tumor progression

Moein, Shiva; Adibi, Rezvan; Meirelles, Lindolfo da Silva; Nardi, Nance Beyer; Gheisari, Yousof

doi:10.1016/j.bbcan.2020.188408

Cited by 54 publications

(60 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…| PNAS Pienta et al https://doi.org/10.1073/pnas.2020838118 Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cellsPACCs form in response to many different natural and synthetic environmental stimuli such as hypoxia, lack of nutrients, changes in pH, or chemotherapy38). Within a multicellular organism, somatic cells that demonstrate chromosomal anomalies are commonly shunted to apoptosis.…”

mentioning

confidence: 99%

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Pienta¹,

Hammarlund

Brown

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

show abstract

mentioning

confidence: 99%

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Pienta¹,

Hammarlund

Brown

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Today, cellular polyploidy is no longer considered an exclusively pathological process but also a physiological mechanism for tissue homeostasis, that is conserved and subverted in tumour pathogenesis and progression[ 277 ]. Between 0.1%-20% of solid tumour volumes consist of polyploid cancer cells that increase in percentage with malignancy, contributing to tumour initiation, heterogeneity, EMT, invasion, metastasis, therapeutic resistance and the generation of CSC-like cells[ 278 - 281 ]. Previously, polyploid cancer cells were presumed to be non-dividing but recent observations confirm that these cells express genes involved in cell cycle regulation, in addition to expressing hypoxia-inducible, stem cell-regulating, chromatin remodelling, and invasion and metastasis promoting genes[ 278 , 280 - 282 ].…”

Section: Molecules and Mechanisms That Promote Select And Maintain Nb Cscsmentioning

confidence: 99%

“…Most polyploid cells die but others survive initially in a quiescent G0 pseudo-senescent state but then escape this state to undergo asymmetrical division by blebbing and/or bursting to yield aneuploid progeny that go on to generate novel tumourigenic and therapy-resistant CSC-like cells by mitosis[ 283 ]. Polyploid tumour cells are generated by tumour microenvironmental stress, within a context of survival adapted cellular ER-stress responses and immunosuppression[ 279 , 280 , 284 , 285 ], and are induced by: gene overexpression and oncogene expression that increase centrosome numbers[ 149 , 279 , 280 ]; replication stress; genotoxic chemotherapeutic agents that induce abortive cell cycles[ 286 - 288 ], and by loss of tumour suppressor function[ 279 , 281 , 289 , 290 ]. Tumour cell polyploidy induced by hypoxia is associated with CSC and EMT gene expression patterns, resulting in a more adaptable, less disruptive phenotype within stressful and hypoxic microenvironments, with multiple gene copies lessening the need for chromosome segregation, promoting survival and facilitating tumour evolution and therapeutic resistance.…”

Section: Molecules and Mechanisms That Promote Select And Maintain Nb Cscsmentioning

confidence: 99%

“…Tumour cell polyploidy induced by hypoxia is associated with CSC and EMT gene expression patterns, resulting in a more adaptable, less disruptive phenotype within stressful and hypoxic microenvironments, with multiple gene copies lessening the need for chromosome segregation, promoting survival and facilitating tumour evolution and therapeutic resistance. Polyploid giant cancer cells evolve complex karyotypes and exhibit enhanced tumourigenic activity in vitro and in vivo implicating tumour cell polyploidy as a basis of aneuploidy[ 279 , 281 ]. Within the somatic context, long term passage of induced polyploid somatic cells eventually leads to transformation and tumourigenesis, in a cellular transformation process characterised by transition from diploid to aneuploid states via tetraploidy.…”

Section: Molecules and Mechanisms That Promote Select And Maintain Nb Cscsmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting

Farina¹,

Cappabianca²,

Zelli³

et al. 2021

WJSC

View full text Add to dashboard Cite

Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.

show abstract

“…Formation of PGCCs can be induced by either natural tensions such as hypoxia, acidic condition, and mechanical pressures or by chemotherapy and radiotherapy [6][7][8][9]. The survived polyploid cells then serve as a source for the generation of new tumor cells and hence "tumor regeneration" [10]. Despite various reports on the association of these cells with tumor resistance and relapse, little is known about the molecular pathways related to cell polyploidy.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin resistant ovarian cancer cells reveal a polyploid phenotype with remarkable activation of nuclear processes

Adibi

Moein

Gheisari

2021

Preprint

Self Cite

View full text Add to dashboard Cite

Background Tumor recurrence as a main cause of cancer death is a big barrier in cancer complete treatment. Various studies denote for the possible role of therapeutics in tumor relapse. Cisplatin as one of the generally-used chemotherapy agents is supposed to be the source of therapy-resistance through formation of polyploid giant cancer cells (PGCCs). Nevertheless, the mechanisms by which PGCCs promote tumor relapse are not fully understood.Methods In this study we performed experimental and bioinformatic investigations to recognize the mechanisms related to cisplatin resistance. A2780 and SCOV-3 cell lines were treated with cisplatin for 72 hours and were evaluated for their morphology by fluorescent microscopy and DNA content analysis. Furthermore, a microarray dataset of cisplatin-resistant ovarian cancer cells was reanalyzed to determine the significantly altered genes and signaling pathways.Result Although cisplatin led to death of considerable fraction of cells in both cell lines, a significant number of survived cells became polyploid. On the other hand, our high throughput analysis determined significant change in expression of 1930 genes which mainly related to gene regulatory mechanisms and nuclear processes. Besides, mTOR, hypoxia, Hippo and 14-3-3 signaling pathways previously shown to have role in PGCCs were determined.Conclusion Taken together, results of this study demonstrated some key biological mechanisms related to cisplatin-resistant polyploid cancer cells.

show abstract

Cancer regeneration: Polyploid cells are the key drivers of tumor progression

Cited by 54 publications

References 153 publications

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting

Cisplatin resistant ovarian cancer cells reveal a polyploid phenotype with remarkable activation of nuclear processes

Contact Info

Product

Resources

About