Abstract
Polyploid giant cancer cells (PGCCs) have been observed by pathologists for over a century. PGCCs contribute to solid tumor heterogeneity, but their functions are largely undefined. Little attention has been given to these cells, largely because PGCCs have been generally thought to originate from repeated failure of mitosis/cytokinesis and have no capacity for long-term survival or proliferation. Here we report our successful purification and culture of PGCCs from human ovarian cancer cell lines and primary ovarian cancer. These cells are highly resistant to oxygen deprivation and could form through endoreduplication or cell fusion, generating regular-sized cancer cells quickly through budding or bursting similar to simple organisms like fungi. They express normal and cancer stem cell markers, they divide asymmetrically and they cycle slowly. They can differentiate into adipose, cartilage and bone. A single PGCC formed cancer spheroids in vitro and generated tumors in immunodeficient mice. These PGCC-derived tumors gained a mesenchymal phenotype with increased expression of cancer stem cell markers CD44 and CD133 and become more resistant to treatment with cisplatin. Taken together, our results reveal that PGCCs represent a resistant form of human cancer using an ancient, evolutionarily conserved mechanism in response to hypoxia stress; they can contribute to the generation of cancer stem-like cells, and also play a fundamental role in regulating tumor heterogeneity, tumor growth and chemoresistance in human cancer.
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References
Heppner GH . Tumor heterogeneity. Cancer Res 1984; 44: 2259–2265.
Marusyk A, Almendro V, Polyak K . Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 2012; 12: 323–334.
Kumar V, Abbas AL, Fausto N, Aster JC Robbins and Cotran Pathologic Basis of Disease 2010, 8th edn, Chapter 7: Neoplasia. Elsevier, New York, NY, USA, pp 262–270.
Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 2004; 28: 496–504.
Geigl JB, Obenauf AC, Schwarzbraun T, Speicher MR . Defining ‘chromosomal instability’. Trends Genet 2008; 24: 64–69.
Holland AJ, Cleveland DW . Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 2009; 10: 478–487.
Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN . The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 2009; 8: 3274–3284.
Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A . Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010; 7: 150–161.
Keith B, Simon MC . Hypoxia-inducible factors, stem cells, and cancer. Cell 2007; 129: 465–472.
Konopleva MY, Jordan CT . Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol 2011; 29: 591–599.
Ho VT, Bunn HF . Effects of transition metals on the expression of the erythropoietin gene: further evidence that the oxygen sensor is a heme protein. Biochem Biophys Res Commun 1996; 223: 175–180.
Piret JP, Mottet D, Raes M, Michiels C . CoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce apoptotic cell death in hepatoma cell line HepG2. Ann NY Acad Sci 2002; 973: 443–447.
Lee HO, Davidson JM, Duronio RJ . Endoreplication: polyploidy with purpose. Genes Dev 2009; 23: 2461–2477.
Siller KH, Doe CQ . Spindle orientation during asymmetric cell division. Nat Cell Biol 2009; 11: 365–374.
Kusumbe AP, Bapat SA . Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Res 2009; 69: 9245–9253.
Brodbeck WG, Anderson JM . Giant cell formation and function. Curr Opin Hematol 2009; 16: 53–57.
Gurdon JB, Melton DA . Nuclear reprogramming in cells. Science 2008; 322: 1811–1815.
Lu X, Kang Y . Cell fusion as a hidden force in tumor progression. Cancer Res 2009; 69: 8536–8539.
Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003; 422: 897–901.
Weihua Z, Lin Q, Ramoth AJ, Fan D, Fidler IJ . Formation of solid tumors by a single multinucleated cancer cell. Cancer 2011; 117: 4092–4099.
Glotzer M . The molecular requirements for cytokinesis. Science 2005; 307: 1735–1739.
Alberts BJA, Lewis J, Raff M, Roberts K, Walter P . Molecular Biology of the Cell 4th edn (Garland Science, New York, NY, USA, 2002). http://www.garlandscience.com/textbooks/0815341059.asp.
Erenpreisa J, Cragg MS . Mitotic death: a mechanism of survival? A review. Cancer Cell Int 2001; 1: 1.
Walen KH . Human diploid fibroblast cells in senescence; cycling through polyploidy to mitotic cells. In Vitro Cell Dev Biol Anim 2006; 42: 216–224.
Vakifahmetoglu H, Olsson M, Zhivotovsky B . Death through a tragedy: mitotic catastrophe. Cell Death Differ 2008; 15: 1153–1162.
Erenpreisa J, Kalejs M, Ianzini F, Kosmacek EA, Mackey MA, Emzinsh D et al. Segregation of genomes in polyploid tumour cells following mitotic catastrophe. Cell Biol Int 2005; 29: 1005–1011.
Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R . Neosis: a novel type of cell division in cancer. Cancer Biol Ther 2004; 3: 207–218.
Erenpreisa J, Salmina K, Huna A, Kosmacek EA, Cragg MS, Ianzini F et al. Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation. Cell Biol Int 2011; 35: 687–695.
Erenpreisa J, Cragg MS . Cancer: a matter of life cycle? Cell Biol Int 2007; 31: 1507–1510.
Rajaraman R, Rajaraman MM, Rajaraman SR, Guernsey DL . Neosis—a paradigm of self-renewal in cancer. Cell Biol Int 2005; 29: 1084–1097.
Erenpreisa J, Kalejs M, Cragg MS . Mitotic catastrophe and endomitosis in tumour cells: an evolutionary key to a molecular solution. Cell Biol Int 2005; 29: 1012–1018.
Carlton JG, Martin-Serrano J . Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 2007; 316: 1908–1912.
Comai L . The advantages and disadvantages of being polyploid. Nat Rev Genet 2005; 6: 836–846.
Trail F . ‘Fungal cannons: explosive spore discharge in the Ascomycota’. FEMS Microbiol Lett 2011; 276: 12–18.
Knop M . Yeast cell morphology and sexual reproduction—a short overview and some considerations. C R Biol 2011; 334: 599–606.
Liu G, Yang G, Chang B, Mercado-Uribe I, Huang M, Zheng J et al. Stanniocalcin 1 and ovarian tumorigenesis. J Natl Cancer Inst 2010; 102: 812–827.
Yang G, Cai KQ, Thompson-Lanza JA, Bast RC, Liu J . Inhibition of breast and ovarian tumor growth through multiple signaling pathways by using retrovirus-mediated small interfering RNA against Her-2/neu gene expression. J Biol Chem 2004; 279: 4339–4345.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92: 9363–9367.
Liu J, Yang G, Thompson-Lanza JA, Glassman A, Hayes K, Patterson A et al. A genetically defined model for human ovarian cancer. Cancer Res 2004; 64: 1655–1663.
Acknowledgements
We thank the Department of Scientific Publications and Ms Christine Wogan for their excellent editorial assistance on the manuscript and Ms Kim Vu for help in figure preparation. Jinsong Liu was supported by an R01 Grant (R01CA131183-01A2) and an ovarian cancer Specialized Programs of Research Excellence (SPORE) grant (P50CA83638) from the National Institutes of Health and a multi-investigator grant from Cancer Prevention and Research Institute of Texas (CPRIT) (RP1105995). Short tandem repeat DNA fingerprinting was carried out by the Cancer Center Support Grant-funded Characterized Cell Line core, NCI No. CA016672.
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Zhang, S., Mercado-Uribe, I., Xing, Z. et al. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33, 116–128 (2014). https://doi.org/10.1038/onc.2013.96
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DOI: https://doi.org/10.1038/onc.2013.96
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