Linking genomic reorganization to tumor initiation via the giant cell cycle

Niu, Na; Zhang, J.; Zhang, N.; Mercado‐Uribe, Imelda; Tao, Fangfang; Han, Zhenbo; Pathak, Sen; Multani, Asha S.; Kuang, Jian; Yao, Jun; Bast, Robert C.; Sood, Anil K.; Hung, Mien‐Chie; Liu, J.

doi:10.1038/oncsis.2016.75

Cited by 136 publications

(159 citation statements)

References 47 publications

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“…In any case, converging evidences indicated that MNGCs ultimately contribute to the generation of progeny with stem cell-like properties and may have a fundamental role in cancer recurrences and chemoresistance [22,38]. This phenotype was also observed in several studies performed on ovarian cancer models [44][45][46][47][48]. Future studies are, however, necessary to properly clarify the molecular mechanisms underlying the formation of MNGCs and how TP53 MUT contribute to this phenotype.…”

Section: Discussionmentioning

confidence: 73%

Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

Lorenzon

Pellarin

Pellizzari

et al. 2019

Cells

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Platinum-based chemotherapy is the therapy of choice for epithelial ovarian cancer (EOC). Acquired resistance to platinum (PT) is a frequent event that leads to disease progression and predicts poor prognosis. To understand possible mechanisms underlying acquired PT-resistance, we have recently generated and characterized three PT-resistant isogenic EOC cell lines. Here, we more deeply characterize several PT-resistant clones derived from MDAH-2774 cells. We show that, in these cells, the increased PT resistance was accompanied by the presence of a subpopulation of multinucleated giant cells. This phenotype was likely due to an altered progression through the M phase of the cell cycle and accompanied by the deregulated expression of genes involved in M phase progression known to be target of mutant TP53. Interestingly, we found that PT-resistant MDAH cells acquired in the TP53 gene a novel secondary mutation (i.e., S185G) that accompanied the R273H typical of MDAH cells. The double p53 S185G/R273H mutant increases the resistance to PT in a TP53 null EOC cellular model. Overall, we show how the selective pressure of PT is able to induce additional mutation in an already mutant TP53 gene in EOC and how this event could contribute to the acquisition of novel cellular phenotypes.Cells 2020, 9, 36 2 of 18 PT resistance has been linked to alterations in several processes such as drug transport, drug inactivation, DNA damage response, DNA repair, apoptosis, and autophagy [8][9][10][11]. Many studies have been done to identify genes and mechanisms directly associated to resistance to PT therapy. We have recently contributed to this issue reporting the selection and preliminary characterization of three new isogenic models of PT-resistant EOC cell lines-MDAH-2774, TOV-112D and OVSAHO. This work has pointed out a common ability of the three isogenic PT-resistant cells to resolve the PT-induced DNA damage compared to parental cells. Moreover, all PT-resistant cells displayed a change in their morphology and a higher ability to grow on mesothelium [12].In the present work, we better characterized MDAH-2774 PT-resistant (PT-res) cells reporting the appearance of a novel mutation in TP53 induced by platinum pressure that is linked to the increased resistance to PT and an altered mitotic division observed in PT-res cells. Materials and Methods Cell CultureMDAH-2774 (CRL-10303) parental and SKOV-3 (HTB-77) cells are from ATCC. Cisplatin-resistant (PT-res) isogenic cells were generated as described [12]. All cell lines were maintained in RPMI-1640 medium (Sigma-Aldrich Co., St. Louis, MO, USA) containing 10% heat-inactivated FBS, 100 U/mL penicillin and streptomycin (Sigma-Aldrich Co., St. Louis, MO, USA) at 37 • C in a 5% CO 2 atmosphere. After the selection process, PT-res cells were kept in PT-free medium. MDAH-2774 PT-res clones were obtained from PT-res pools by plating them at 0.7 cell/well dilution in a 96-multiwell plate. All cell lines were authenticated in our lab using the Cell ID TM System (Promega, Madison, WI, USA) ...

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Section: Discussionmentioning

confidence: 73%

Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

Lorenzon

Pellarin

Pellizzari

et al. 2019

Cells

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“…There is a small body of literature specifically related to PGCCs (74 PubMed‐listed entries with query: [PGCCs] vs 3,857,567 with query [cancer]; accessed 10 May 2019; Figure ), but this literature, taken holistically, makes a compelling case for defining them as the essential keystone cancer species and actuators of tumorigenesis, therapeutic resistance, and recurrence in metastatic disease. Keystone species are relatively few in number, but have a significant impact on the health and composition of the ecosystem.…”

mentioning

confidence: 99%

Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

et al. 2019

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Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do not know why cancer is lethal, we know that a total tumor burden of 1 kg—equivalent to one trillion cells—is not compatible with life. While localized disease is curable through surgical removal or radiation, once cancer has spread, it is largely incurable. The inability to cure metastatic cancer lies, at least in part, to the fact that cancer is resistant to all known compounds and anticancer drugs. The source of this resistance remains undefined. In fact, the vast majority of metastatic cancers are resistant to all currently available anticancer therapies, including chemotherapy, hormone therapy, immunotherapy, and systemic radiation. Thus, despite decades—even centuries—of research, metastatic cancer remains lethal and incurable. We present historical and contemporary evidence that the key actuators of this process—of tumorigenesis, metastasis, and therapy resistance—are polyploid giant cancer cells.

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“…This model readily accounts for the well-established notion that interruption of the menstrual cycle via either pregnancy or oral contraceptive use has profound protective effects against high-grade serous extra-uterine Müllerian and breast carcinomas not only in the general population, 28,29 but also in BRCA1 mutation carriers. [31][32][33] The molecular events leading to cytokinesis failure and polyploidy, which are discussed here in the context of their role in predisposition to malignant transformation in BRCA1 mutation carriers, most likely continue to operate after malignant transformation has taken place, when they might contribute to the generation of polyploid giant cancer cells, recently shown in Jinsong Liu's laboratory 34,35 to express normal and cancer stem cell markers and to have the ability to increase their viability by reducing their DNA content via asymmetric divisions, budding or bursting. This group suggested that these events, which are related to an early embryological mechanism common in the blastomere stage of preimplantation embryos, may represent important mechanisms for generating cancer stemlike cells and may also contribute to tumor heterogeneity.…”

Section: Discussionmentioning

confidence: 97%

Mechanism of cytokinesis failure in ovarian cystadenomas with defective BRCA1 and P53 pathways

Austria

Marion

et al. 2018

Intl Journal of Cancer

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We previously described an in vitro model in which serous ovarian cystadenomas were transfected with SV40 large T antigen, resulting in loss of RB and P53 functions and thus mimicking genetic defects present in early high-grade serous extra-uterine Müllerian (traditionally called high-grade serous ovarian) carcinomas including those associated with the BRCA1 mutation carrier state. We showed that replicative aging in this cell culture model leads to a mitotic arrest at the spindle assembly checkpoint. Here we show that this arrest is due to a reduction in microtubule anchoring that coincides with decreased expression of the BUB1 kinase and of the phosphorylated form of its substrate, BUB3. The ensuing prolonged mitotic arrest leads to cohesion fatigue resulting in cell death or, in cells that recover from this arrest, in cytokinesis failure and polyploidy. Down-regulation of BRCA1 to levels similar to those present in BRCA1 mutation carriers leads to increased and uncontrolled microtubule anchoring to the kinetochore resulting in overcoming the spindle assembly checkpoint. Progression to anaphase under those conditions is associated with formation of chromatin bridges between chromosomal plates due to abnormal attachments to the kinetochore, significantly increasing the risk of cytokinesis failure. The dependence of this scenario on accelerated replicative aging can, at least in part, account for the site specificity of the cancers associated with the BRCA1 mutation carrier state, as epithelia of the mammary gland and of the reproductive tract are targets of cell-nonautonomous consequences of this carrier state on cellular proliferation associated with menstrual cycle progressions.

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Linking genomic reorganization to tumor initiation via the giant cell cycle

Cited by 136 publications

References 47 publications

Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

Identification and Characterization of a New Platinum-Induced TP53 Mutation in MDAH Ovarian Cancer Cells

Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance

Mechanism of cytokinesis failure in ovarian cystadenomas with defective BRCA1 and P53 pathways

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