Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer.

Polyploidy is associated with increased cell size and is commonly found in a subset of adult organs and blastomere stage of the human embryo. The polyploidy is formed through endoreplication or cell fusion to support the specific need of development including earliest embryogenesis. Recent data demonstrated that Polyploid Giant Cancer Cells (PGCCs) may have acquired an activated early embryonic-like program in response to oncogenic and therapeutic stress to generate reprogrammed cancer cells for drug resistance and metastasis. Targeting PGCCs may open up new opportunities for cancer therapy.

[1]  T. V. Bykova,et al.  Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers , 2014, Cell cycle.

[2]  M. Alikani,et al.  The presence of multinucleated blastomeres in human embryos is correlated with chromosomal abnormalities. , 1996, Human reproduction.

[3]  F. Camargo,et al.  Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation , 2014, Cell.

[4]  Jean M. Davidson,et al.  Endoreplication: polyploidy with purpose. , 2009, Genes & development.

[5]  Jinsong Liu,et al.  A Fraction of CD133+ CNE2 Cells Is Made of Giant Cancer Cells with Morphological Evidence of Asymmetric Mitosis , 2015, Journal of Cancer.

[6]  R. Weinberg.  Coming Full Circle—From Endless Complexity to Simplicity and Back Again , 2014, Cell.

[7]  H. Scherthan,et al.  Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells. , 2010, Experimental Cell Research.

[8]  K. Iwata,et al.  Analysis of compaction initiation in human embryos by using time-lapse cinematography , 2014, Journal of Assisted Reproduction and Genetics.

[9]  M. Jordan,et al.  Microtubules as a target for anticancer drugs , 2004, Nature Reviews Cancer.

[10]  S. Hanash,et al.  iTRAQ-Based Proteomic Analysis of Polyploid Giant Cancer Cells and Budding Progeny Cells Reveals Several Distinct Pathways for Ovarian Cancer Development , 2013, PloS one.

[11]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[12]  I. Mercado-uribe,et al.  Generation of erythroid cells from fibroblasts and cancer cells in vitro and in vivo. , 2013, Cancer letters.

[13]  K. Walen.  The origin of transformed cells. studies of spontaneous and induced cell transformation in cell cultures from marsupials, a snail, and human amniocytes. , 2002, Cancer genetics and cytogenetics.

[14]  Jan Gerris,et al.  Multinucleation in cleavage stage embryos. , 2003, Human reproduction.

[15]  F. Finkernagel,et al.  A multi-stage process including transient polyploidization and EMT precedes the emergence of chemoresistent ovarian carcinoma cells with a dedifferentiated and pro-inflammatory secretory phenotype , 2015, Oncotarget.

[16]  R. Behringer,et al.  Developmental potential and behavior of tetraploid cells in the mouse embryo. , 2005, Developmental biology.

[17]  Y. Li,et al.  Role of cancer stem cells in the development of giant cell tumor of bone , 2020, Cancer Cell International.

[18]  Kathleen A Cronin,et al.  Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics , 2018, Cancer.

[19]  A. Krešo,et al.  Evolution of the cancer stem cell model. , 2014, Cell stem cell.

[20]  T. Illidge,et al.  RELEASE OF MITOTIC DESCENDANTS BY GIANT CELLS FROM IRRADIATED BURKITT'S LYMPHOMA CELL LINES , 2000, Cell biology international.

[21]  D. Guernsey,et al.  Neosis: A Novel Type of Cell Division in Cancer , 2004, Cancer biology & therapy.

[22]  Farshid Moussavi,et al.  Dynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage , 2012, Nature Communications.

[23]  I. Mercado-uribe,et al.  Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel , 2014, International journal of cancer.

[24]  S. Gabriel,et al.  Pan-cancer patterns of somatic copy-number alteration , 2013, Nature Genetics.

[25]  E. Sikora,et al.  Polyploidy Formation in Doxorubicin-Treated Cancer Cells Can Favor Escape from Senescence1 , 2015, Neoplasia.

[26]  B. Calvi,et al.  Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability , 2016, Molecular biology of the cell.

[27]  E. Kondorosi,et al.  Plant cell-size control: growing by ploidy? , 2000, Current opinion in plant biology.

[28]  Ruiwen Zhang,et al.  Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents , 2013, Molecular Cancer Therapeutics.

[29]  R. Bast,et al.  Linking genomic reorganization to tumor initiation via the giant cell cycle , 2016, Oncogenesis.

[30]  R. Mirzayans,et al.  Multinucleated Giant Cancer Cells Produced in Response to Ionizing Radiation Retain Viability and Replicate Their Genome , 2017, International journal of molecular sciences.

[31]  Shiwu Zhang,et al.  Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer , 2020, Frontiers in Oncology.

[32]  U. Lendahl,et al.  Loss of CSL Unlocks a Hypoxic Response and Enhanced Tumor Growth Potential in Breast Cancer Cells , 2016, Stem cell reports.

[33]  R. Bast,et al.  Paclitaxel inhibits ovarian tumor growth by inducing epithelial cancer cells to benign fibroblast-like cells. , 2012, Cancer letters.

[34]  R. Duronio,et al.  Endoreplication and polyploidy: insights into development and disease , 2013, Development.

[35]  Joel s. Brown,et al.  Convergent Evolution, Evolving Evolvability, and the Origins of Lethal Cancer , 2020, Molecular Cancer Research.

[36]  D. Pellman,et al.  Limiting the Proliferation of Polyploid Cells , 2007, Cell.

[37]  K. Walen.  Mitosis is not the only distributor of mutated cells: Non‐mitotic endopolyploid cells produce reproductive genome‐reduced cells , 2010, Cell biology international.

[38]  M. Kalējs,et al.  Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe. , 2009, Cancer research.

[39]  T. Davoli,et al.  The causes and consequences of polyploidy in normal development and cancer. , 2011, Annual review of cell and developmental biology.

[40]  E. Sikora,et al.  Morphological and Functional Characteristic of Senescent Cancer Cells. , 2016, Current drug targets.

[41]  Xin Lu,et al.  Cell fusion as a hidden force in tumor progression. , 2009, Cancer research.

[42]  I. Mercado-uribe,et al.  Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells , 2017, Oncogene.

[43]  T. Orr-Weaver.  When bigger is better: the role of polyploidy in organogenesis. , 2015, Trends in genetics : TIG.

[44]  B. Chauffert,et al.  Tumor cells can escape DNA‐damaging cisplatin through DNA endoreduplication and reversible polyploidy , 2008, Cell biology international.

[45]  R. Kaur,et al.  Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer , 2017, British Journal of Cancer.

[46]  John J. Cole,et al.  Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest , 2015, Cell reports.

[47]  A. Tannapfel,et al.  A Distinct Oncogenerative Multinucleated Cancer Cell Serves as a Source of Stemness and Tumor Heterogeneity. , 2018, Cancer research.

[48]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[49]  M. Kalējs,et al.  Mitotic catastrophe and endomitosis in tumour cells: An evolutionary key to a molecular solution , 2005, Cell biology international.

[50]  David Pellman,et al.  Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells , 2005, Nature.

[51]  Shiwu Zhang,et al.  Polyploid giant cancer cells with budding and the expression of cyclin E, S-phase kinase-associated protein 2, stathmin associated with the grading and metastasis in serous ovarian tumor , 2014, BMC Cancer.

[52]  Baocun Sun,et al.  Generation of cancer stem-like cells through the formation of polyploid giant cancer cells , 2014, Oncogene.

[53]  S. Chavez,et al.  Chromosomal instability in mammalian pre-implantation embryos: potential causes, detection methods, and clinical consequences , 2015, Cell and Tissue Research.

[54]  E. Sikora,et al.  Polyploidy: the link between senescence and cancer. , 2010, Current pharmaceutical design.

[55]  J. Erenpreisa,et al.  “Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres , 2020, International journal of molecular sciences.

[56]  Y. Moreau,et al.  Breakage–fusion–bridge cycles leading to inv dup del occur in human cleavage stage embryos , 2011, Human mutation.

[57]  Hyun-Ok Yang,et al.  Mechanism of taxol‐induced apoptosis in human SKOV3 ovarian carcinoma cells , 2004, Journal of cellular biochemistry.

[58]  C. Weiser,et al.  Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells , 2013, Proceedings of the National Academy of Sciences.

[59]  R. Bast,et al.  Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells , 2016, Genes & cancer.

[60]  I. Fidler,et al.  Formation of solid tumors by a single multinucleated cancer cell , 2011, Cancer.

[61]  Alice A. Chen,et al.  Atypical embryo phenotypes identified by time-lapse microscopy: high prevalence and association with embryo development. , 2014, Fertility and sterility.

[62]  T. Davoli,et al.  Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. , 2012, Cancer cell.

[63]  R. Mirzayans,et al.  Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence , 2020, International journal of molecular sciences.

[64]  S. Haferkamp,et al.  In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells , 2015, Cell Death and Disease.