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

Author(s): Junsong Chen, Na Niu, Jing Zhang, Lisha Qi, Weiwei Shen, Krishna Vanaja Donkena, Zhenqing Feng, Jinsong Liu*

Journal Name: Current Cancer Drug Targets

Volume 19 , Issue 5 , 2019

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Graphical Abstract:


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.

Keywords: Polyploid giant cancer cells, cancer stem cells, blastomere-like cancer stem cells, endoreplication, reprogramming, cell fusion.

Cronin, K.A.; Lake, A.J.; Scott, S.; Sherman, R.L.; Noone, A.M.; Howlader, N.; Henley, S.J.; Anderson, R.N.; Firth, A.U.; Ma, J.; Kohler, B.A.; Jemal, A. Annual report to the nation on the status of cancer, Part I: National Cancer Statistics. Cancer, 2018.
Weinberg, R.A. Coming full circle-from endless complexity to simplicity and back again. Cell, 2014, 157(1), 267-271.
Davoli, T.; de Lange, T. The causes and consequences of polyploidy in normal development and cancer. Annu. Rev. Cell Dev. Biol., 2011, 27, 585-610.
Fox, D.T.; Duronio, R.J. Endoreplication and polyploidy: Insights into development and disease. Development, 2013, 140(1), 3-12.
Orr-Weaver, T.L. When bigger is better: The role of polyploidy in organogenesis. Trends Genet., 2015, 31(6), 307-315.
Zielke, N.; Edgar, B.A.; DePamphilis, M.L. Endoreplication. Cold Spring Harb. Perspect. Biol., 2013, 5(1), a012948.
Lee, H.O.; Davidson, J.M.; Duronio, R.J. Endoreplication: Polyploidy with purpose. Genes Dev., 2009, 23(21), 2461-2477.
Ganem, N.J.; Pellman, D. Limiting the proliferation of polyploid cells. Cell, 2007, 131(3), 437-440.
Athayde Wirka, K.; Chen, A.A.; Conaghan, J.; Ivani, K.; Gvakharia, M.; Behr, B.; Suraj, V.; Tan, L.; Shen, S. Atypical embryo phenotypes identified by time-lapse microscopy: High prevalence and association with embryo development. Fertil. Steril., 2014, 101(6), 1637-1648.
Chavez, S.L.; Loewke, K.E.; Han, J.; Moussavi, F.; Colls, P.; Munne, S.; Behr, B.; Reijo, P.R.A. Dynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage. Nat. Commun., 2012, 3, 1251.
Hardy, K.; Winston, R.M.; Handyside, A.H. Binucleate blastomeres in preimplantation human embryos in vitro: Failure of cytokinesis during early cleavage. J. Reprod. Fertil., 1993, 98(2), 549-558.
Iwata, K.; Yumoto, K.; Sugishima, M.; Mizoguchi, C.; Kai, Y.; Iba, Y.; Mio, Y. Analysis of compaction initiation in human embryos by using time-lapse cinematography. J. Assist. Reprod. Genet., 2014, 31(4), 421-426.
Kligman, I.; Benadiva, C.; Alikani, M.; Munne, S. The presence of multinucleated blastomeres in human embryos is correlated with chromosomal abnormalities. Hum. Reprod., 1996, 11(7), 1492-1498.
Van Royen, E.; Mangelschots, K.; Vercruyssen, M.; De Neubourg, D.; Valkenburg, M.; Ryckaert, G.; Gerris, J. Multinucleation in cleavage stage embryos. Hum. Reprod., 2003, 18(5), 1062-1069.
Voet, T.; Vanneste, E.; Van der Aa, N.; Melotte, C.; Jackmaert, S.; Vandendael, T.; Declercq, M.; Debrock, S.; Fryns, J.P.; Moreau, Y.; D’Hooghe, T.; Vermeesch, J.R. Breakage-fusion-bridge cycles leading to inv dup del occur in human cleavage stage embryos. Hum. Mutat., 2011, 32(7), 783-793.
Daughtry, B.L.; Chavez, S.L. Chromosomal instability in mammalian pre-implantation embryos: Potential causes, detection methods, and clinical consequences. Cell Tissue Res., 2016, 363(1), 201-225.
Eakin, G.S.; Hadjantonakis, A.K.; Papaioannou, V.E.; Behringer, R.R. Developmental potential and behavior of tetraploid cells in the mouse embryo. Dev. Biol., 2005, 288(1), 150-159.
Zhang, S.; Mercado-Uribe, I.; Xing, Z.; Sun, B.; Kuang, J.; Liu, J. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene, 2014, 33(1), 116-128.
Lv, H.; Shi, Y.; Zhang, L.; Zhang, D.; Liu, G.; Yang, Z.; Li, Y.; Fei, F.; Zhang, S. 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. BMC Cancer, 2014, 14, 576.
Kondorosi, E.; Roudier, F.; Gendreau, E. Plant cell-size control: Growing by ploidy? Curr. Opin. Plant Biol., 2000, 3(6), 488-492.
Chen, S.; Stout, J.R.; Dharmaiah, S.; Yde, S.; Calvi, B.R.; Walczak, C.E. Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability. Mol. Biol. Cell, 2016, 27(19), 2911-2923.
Erenpreisa, J.; Kalejs, M.; Cragg, M.S. Mitotic catastrophe and endomitosis in tumour cells: An evolutionary key to a molecular solution. Cell Biol. Int., 2005, 29(12), 1012-1018.
Niu, N.; Zhang, J.; Zhang, N.; Mercado-Uribe, I.; Tao, F.; Han, Z.; Pathak, S.; Multani, A.S.; Kuang, J.; Yao, J.; Bast, R.C.; Sood, A.K.; Hung, M.C.; Liu, J. Linking genomic reorganization to tumor initiation via the giant cell cycle. Oncogenesis, 2016, 5(12), e281.
Erenpreisa, J.A.; Cragg, M.S.; Fringes, B.; Sharakhov, I.; Illidge, T.M. Release of mitotic descendants by giant cells from irradiated Burkitt’s lymphoma cell line. Cell Biol. Int., 2000, 24(9), 635-648.
Sundaram, M.; Guernsey, D.L.; Rajaraman, M.M.; Rajaraman, R. Neosis: A novel type of cell division in cancer. Cancer Biol. Ther., 2004, 3(2), 207-218.
Walen, K.H. The origin of transformed cells. studies of spontaneous and induced cell transformation in cell cultures from marsupials, a snail, and human amniocytes. Cancer Genet. Cytogenet., 2002, 133(1), 45-54.
Rohnalter, V.; Roth, K.; Finkernagel, F.; Adhikary, T.; Obert, J.; Dorzweiler, K.; Bensberg, M.; Muller-Brusselbach, S.; Muller, R. 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. Oncotarget, 2015, 6(37), 40005-40025.
Zack, T.I.; Schumacher, S.E.; Carter, S.L.; Cherniack, A.D.; Saksena, G.; Tabak, B.; Lawrence, M.S.; Zhsng, C.Z.; Wala, J.; Mermel, C.H.; Sougnez, C.; Gabriel, S.B.; Hernandez, B.; Shen, H.; Laird, P.W.; Getz, G.; Meyerson, M.; Beroukhim, R. Pan-cancer patterns of somatic copy number alteration. Nat. Genet., 2013, 45(10), 1134-1140.
Dikovskaya, D.; Cole, J.J.; Mason, S.M.; Nixon, C.; Karim, S.A.; McGarry, L.; Clark, W.; Hewitt, R.N.; Sammons, M.A.; Zhu, J.; Athineos, D.; Leach, J.D.; Marchesi, F.; van Tuyn, J.; Tait, S.W.; Brock, C.; Morton, J.P.; Wu, H.; Berger, S.L.; Blyth, K.; Adams, P.D. Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest. Cell Reports, 2015, 12(9), 1483-1496.
Mirzayans, R.; Andrais, B.; Scott, A.; Wang, Y.W.; Kumar, P.; Murray, D. Multinucleated giant cancer cells produced in response to ionizing radiation retain viability and replicate their genome. Int. J. Mol. Sci., 2017, 18(2), 360.
Sikora, E.; Mosieniak, G.; Sliwinska, M.A. Morphological and functional characteristic of senescent cancer cells. Curr. Drug Targets, 2016, 17(4), 377-387.
Ianzini, F.; Kosmacek, E.A.; Nelson, E.S.; Napoli, E.; Erenpreisa, J.; Kalejs, M.; Mackey, M.A. Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe. Cancer Res., 2009, 69(6), 2296-2304.
Sharma, S.; Zeng, J.Y.; Zhuang, C.M.; Zhou, Y.Q.; Yao, H.P.; Hu, X.; Zhang, R.; Wang, M.H. Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. Mol. Cancer Ther., 2013, 12(5), 725-736.
Lagadec, C.; Vlashi, E.; Della Donna, L.; Dekmezian, C.; Pajonk, F. Radiation-induced reprogramming of breast cancer cells. Stem Cells, 2012, 30(5), 833-844.
Jia, L.; Zhang, S.; Ye, Y.; Li, X.; Mercado-Uribe, I.; Bast, R.C., Jr; Liu, J. Paclitaxel inhibits ovarian tumor growth by inducing epithelial cancer cells to benign fibroblast-like cells. Cancer Lett., 2012, 326(2), 176-182.
Zhang, S.; Mercado-Uribe, I.; Liu, J. Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel. Int. J. Cancer, 2014, 134(3), 508-518.
Ahn, H.J.; Kim, Y.S.; Kim, J.U.; Han, S.M.; Shin, J.W.; Yang, H.O. Mechanism of taxol-induced apoptosis in human SKOV3 ovarian carcinoma cells. J. Cell. Biochem., 2004, 91(5), 1043-1052.
Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer, 2004, 4(4), 253-265.
Ganem, N.J.; Cornils, H.; Chiu, S.Y.; O’Rourke, K.P.; Arnaud, J.; Yimlamai, D.; Thery, M.; Camargo, F.D.; Pellman, D. Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell, 2014, 158(4), 833-848.
Mosieniak, G.; Sikora, E. Polyploidy: The link between senescence and cancer. Curr. Pharm. Des., 2010, 16(6), 734-740.
Mosieniak, G.; Sliwinska, M.A.; Alster, O.; Strzeszewska, A.; Sunderland, P.; Piechota, M.; Was, H.; Sikora, E. Polyploidy formation in doxorubicin-treated cancer cells can favor escape from senescence. Neoplasia, 2015, 17(12), 882-893.
Puig, P.E.; Guilly, M.N.; Bouchot, A.; Droin, N.; Cathelin, D.; Bouyer, F.; Favier, L.; Ghiringhelli, F.; Kroemer, G.; Solary, E.; Martin, F.; Chauffert, B. Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy. Cell Biol. Int., 2008, 32(9), 1031-1043.
Niu, N.; Mercado-Uribe, I.; Liu, J. Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells. Oncogene, 2017, 36(34), 4887.
Lu, X.; Kang, Y. Cell fusion as a hidden force in tumor progression. Cancer Res., 2009, 69(22), 8536-8539.
Rengstl, B.; Newrzela, S.; Heinrich, T.; Weiser, C.; Thalheimer, F.B.; Schmid, F.; Warner, K.; Hartmann, S.; Schroeder, T.; Kuppers, R.; Rieger, M.A.; Hansmann, M.L. Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells. Proc. Natl. Acad. Sci. USA, 2013, 110(51), 20729-20734.
Braune, E.B.; Tsoi, Y.L.; Phoon, Y.P.; Landor, S.; Silva Cascales, H.; Ramskold, D.; Deng, Q.; Lindqvist, A.; Lian, X.; Sahlgren, C.; Jin, S.B.; Lendahl, U. Loss of CSL unlocks a hypoxic response and enhanced tumor growth potential in breast cancer cells. Stem Cell Reports, 2016, 6(5), 643-651.
Mittal, K.; Donthamsetty, S.; Kaur, R.; Yang, C.; Gupta, M.V.; Reid, M.D.; Choi, D.H.; Rida, P.C.G.; Aneja, R. Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer. Br. J. Cancer, 2017, 116(9), 1186-1194.
Walen, K.H. Mitosis is not the only distributor of mutated cells: non-mitotic endopolyploid cells produce reproductive genome-reduced cells. Cell Biol. Int., 2010, 34(8), 867-872.
Fujiwara, T.; Bandi, M.; Nitta, M.; Ivanova, E.V.; Bronson, R.T.; Pellman, D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature, 2005, 437(7061), 1043-1047.
Davoli, T.; de Lange, T. Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. Cancer Cell, 2012, 21(6), 765-776.
Leikam, C.; Hufnagel, A.L.; Otto, C.; Murphy, D.J.; Muhling, B.; Kneitz, S.; Nanda, I.; Schmid, M.; Wagner, T.U.; Haferkamp, S.; Brocker, E.B.; Schartl, M.; Meierjohann, S. In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells. Cell Death Dis., 2015, 6, e1711.
Weihua, Z.; Lin, Q.; Ramoth, A.J.; Fan, D.; Fidler, I.J. Formation of solid tumors by a single multinucleated cancer cell. Cancer, 2011, 117(17), 4092-4099.
Kreso, A.; Dick, J.E. Evolution of the cancer stem cell model. Cell Stem Cell, 2014, 14(3), 275-291.
Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; Campbell, L.L.; Polyak, K.; Brisken, C.; Yang, J.; Weinberg, R.A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008, 133(4), 704-715.
Jiang, Q.; Zhang, Q.; Wang, S.; Xie, S.; Fang, W.; Liu, Z.; Liu, J.; Yao, K. A fraction of CD133+ CNE2 cells is made of giant cancer cells with morphological evidence of asymmetric mitosis. J. Cancer, 2015, 6(12), 1236-1244.
Díaz-Carballo, D.; Saka, S.; Klein, J.; Rennkamp, T.; Acikelli, A.H.; Malak, S.; Jastrow, H.; Wennemuth, G.; Tempfer, C.; Schmitz, I.; Tannapfel, A.; Strumberg, D. A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity. Cancer Res., 2018, 78(9), 2318-2331.
Salmina, K.; Jankevics, E.; Huna, A.; Perminov, D.; Radovica, I.; Klymenko, T.; Ivanov, A.; Jascenko, E.; Scherthan, H.; Cragg, M.; Erenpreisa, J. Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells. Exp. Cell Res., 2010, 316(13), 2099-2112.
Chitikova, Z.V.; Gordeev, S.A.; Bykova, T.V.; Zubova, S.G.; Pospelov, V.A.; Pospelova, T.V. Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers. Cell Cycle, 2014, 13(9), 1424-1439.
Ben-Porath, I.; Thomson, M.W.; Carey, V.J.; Ge, R.; Bell, G.W.; Regev, A.; Weinberg, R.A. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet., 2008, 40(5), 499-507.
Zhang, S.; Mercado-Uribe, I.; Liu, J. Generation of erythroid cells from fibroblasts and cancer cells in vitro and in vivo. Cancer Lett., 2013, 333(2), 205-212.
Zhang, S.; Mercado-Uribe, I.; Sood, A.; Bast, R.C.; Liu, J. Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells. Genes Cancer, 2016, 7(3-4), 60-72.
Zhang, S.; Mercado-Uribe, I.; Hanash, S.; Liu, J. iTRAQ-based proteomic analysis of polyploid giant cancer cells and budding progeny cells reveals several distinct pathways for ovarian cancer development. PLoS One, 2013, 8(11), e80120.

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Article Details

Year: 2019
Published on: 23 April, 2019
Page: [360 - 367]
Pages: 8
DOI: 10.2174/1568009618666180703154233
Price: $65

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