Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Generation of erythroid cells from polyploid giant cancer cells: re-thinking about tumor blood supply

Abstract

Introduction

During development and tumor progression, cells need a sufficient blood supply to maintain development and rapid growth. It is reported that there are three patterns of blood supply for tumor growth: endothelium-dependent vessels, mosaic vessels, and vasculogenic mimicry (VM). VM was first reported in highly aggressive uveal melanomas, with tumor cells mimicking the presence and function of endothelial cells forming the walls of VM vessels. The walls of mosaic vessels are randomly lined with both endothelial cells and tumor cells. We previously proposed a three-stage process, beginning with VM, progressing to mosaic vessels, and eventually leading to endothelium-dependent vessels. However, many phenomena unique to VM channel formation remain to be elucidated, such as the origin of erythrocytes before VM vessels connect with endothelium-dependent vessels.

Results

In adults, erythroid cells are generally believed to be generated from hematopoietic stem cells in the bone marrow. In contrast, embryonic tissue obtains oxygen through formation of blood islands, which are largely composed of embryonic hemoglobin with a higher affinity with oxygen, in the absence of mature erythrocytes. Recent data from our laboratory suggest that embryonic blood-forming mechanisms also exist in cancer tissue, particularly when these tissues are under environmental stress such as hypoxia. We review the evidence from induced pluripotent stem cells in vitro and in vivo to support this previously underappreciated cell functionality in normal and cancer cells, including the ability to generate erythroid cells. We will also summarize the current understanding of tumor angiogenesis, VM, and our recent work on polyploid giant cancer cells, with emphasis on their ability to generate erythroid cells and their association with tumor growth under hypoxia.

Conclusion

An alternative embryonic pathway to obtain oxygen in cancer cells exists, particularly when they are under hypoxic conditions.

This is a preview of subscription content, log in to check access.

Fig. 1

Abbreviations

PGCCs:

Polyploidy giant cancer cells

CoCl2 :

Cobalt chloride

CSCs:

Cancer stem cells

VM:

Vasculogenic mimicry

iPS cells:

Induced pluripotent stem cells

MVs:

Mosaic vessels

EVs:

Endothelium-dependent vessels

MSCs:

Mesenchymal stem cells

HSCs:

Hematopoietic stem cells

EPO:

Erythropoietin

ESCs:

Embryonic stem cells

References

  1. Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, Verma A (2001) Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 61:3561–3565

  2. Acs G, Zhang PJ, Rebbeck TR, Acs P, Verma A (2002) Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer 95:969–981. https://doi.org/10.1002/cncr.10787

  3. Acs G et al (2003) Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. Am J Pathol 162:1789–1806. https://doi.org/10.1016/S0002-9440(10)64314-3

  4. Albitar M, Cash FE, Peschle C, Liebhaber SA (1992) Developmental switch in the relative expression of the alpha 1- and alpha 2-globin genes in humans and in transgenic mice. Blood 79:2471–2474

  5. Bianchi N, Ongaro F, Chiarabelli C, Gualandi L, Mischiati C, Bergamini P, Gambari R (2000) Induction of erythroid differentiation of human K562 cells by cisplatin analogs. Biochem Pharmacol 60:31–40

  6. Bianchi Scarra GL, Romani M, Coviello DA, Garre C, Ravazzolo R, Vidali G, Ajmar F (1986) Terminal erythroid differentiation in the K-562 cell line by 1-beta-D-arabinofuranosylcytosine: accompaniment by c-myc messenger RNA decrease. Cancer Res 46:6327–6332

  7. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

  8. Brodbeck WG, Anderson JM (2009) Giant cell formation and function. Curr Opin Hematol 16:53–57. https://doi.org/10.1097/MOH.0b013e32831ac52e

  9. Chandramohanadas R et al (2009) Apicomplexan parasites co-opt host calpains to facilitate their escape from infected cells. Science 324:794–797. https://doi.org/10.1126/science.1171085

  10. Chang KH, Huang A, Hirata RK, Wang PR, Russell DW, Papayannopoulou T (2010) Globin phenotype of erythroid cells derived from human induced pluripotent stem cells. Blood 115:2553–2554. https://doi.org/10.1182/blood-2009-11-252650

  11. Chang CJ, Mitra K, Koya M, Velho M, Desprat R, Lenz J, Bouhassira EE (2011) Production of embryonic and fetal-like red blood cells from human induced pluripotent stem cells. PLoS One 6:e25761. https://doi.org/10.1371/journal.pone.0025761

  12. Chen L, Zhang S, Li X, Sun B, Zhao X, Zhang D, Zhao S (2009) A pilot study of vasculogenic mimicry immunohistochemical expression in intraocular melanoma model. Oncol Rep 21:989–994

  13. Chen WL, Chen YM, Chu HS, Lin CT, Chow LP, Chen CT, Hu FR (2014) Mechanisms controlling the effects of bevacizumab (avastin) on the inhibition of early but not late formed corneal neovascularization. PLoS One 9:e94205. https://doi.org/10.1371/journal.pone.0094205

  14. Choi KD, Vodyanik MA, Slukvin II (2009a) Generation of mature human myelomonocytic cells through expansion and differentiation of pluripotent stem cell-derived lin-CD34 + CD43 + CD45 + progenitors. J Clin Invest 119:2818–2829. https://doi.org/10.1172/JCI38591

  15. Choi KD et al (2009b) Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 27:559–567. https://doi.org/10.1634/stemcells.2008-0922

  16. Cioe L, McNab A, Hubbell HR, Meo P, Curtis P, Rovera G (1981) Differential expression of the globin genes in human leukemia K562(S) cells induced to differentiate by hemin or butyric acid. Cancer Res 41:237–243

  17. Clevers H (2011) The cancer stem cell: premises, promises challenges. Nat Med 17:313–319. https://doi.org/10.1038/nm.2304

  18. Ebihara Y, Ma F, Tsuji K (2012) Generation of red blood cells from human embryonic/induced pluripotent stem cells for blood transfusion. Int J Hematol 95:610–616. https://doi.org/10.1007/s12185-012-1107-9

  19. Folkman J (1971a) Transplacental carcinogenesis by stilbestrol. N Engl J Med 285:404–405. https://doi.org/10.1056/NEJM197108122850711

  20. Folkman J (1971b) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. https://doi.org/10.1056/NEJM197111182852108

  21. Folkman J, Merler E, Abernathy C, Williams G (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275–288

  22. Fried W (2009) Erythropoietin and erythropoiesis. Exp Hematol 37:1007–1015 https://doi.org/10.1016/j.exphem.2009.05.010

  23. Fu OY, Hou MF, Yang SF, Huang SC, Lee WY (2009) Cobalt chloride-induced hypoxia modulates the invasive potential and matrix metalloproteinases of primary and metastatic breast cancer cells. Anticancer Res 29:3131–3138

  24. Gambari R, Amelotti F, Piva R (1985) Efficient cell proliferation and predominant accumulation of epsilon-globin mRNA in human leukemic K562 cells which produce mostly Hb Gower 1. Experientia 41:673–675

  25. Gambari R et al (1986) Human leukemic K562 cells: suppression of hemoglobin accumulation by a monoclonal antibody to human transferrin receptor. Biochim Biophys Acta 886:203–213

  26. Guo Y et al (2009) c-Myc-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Blood 114:2097–2106. https://doi.org/10.1182/blood-2009-01-197947

  27. Gupta PB, Chaffer CL, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–1012. https://doi.org/10.1038/nm0909-1010

  28. Gurdon JB, Melton DA (2008) Nuclear reprogramming in cells. Science 322:1811–1815. https://doi.org/10.1126/science.1160810

  29. Hafid-Medheb K, Augery-Bourget Y, Minatchy MN, Hanania N, Robert-Lezenes J (2003) Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function. Blood 101:2575–2583. https://doi.org/10.1182/blood-2002-02-0478 pii]

  30. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580. https://doi.org/10.1124/pr.56.4.3

  31. Huehns ER, Faroqui AM (1975) Oxygen dissociation properties of human embryonic red cells. Nature 254:335–337

  32. Hurwitz HI et al (2014) Safety and effectiveness of bevacizumab treatment for metastatic colorectal cancer: final results from the Avastin((R)) Registry - Investigation of Effectiveness and Safety (ARIES) observational cohort study. Clin Oncol (R Coll Radiol) 26:323–332. https://doi.org/10.1016/j.clon.2014.03.001

  33. Jelkmann W (1992) Erythropoietin: structure, control of production and function. Physiol Rev 72:449–489

  34. Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458:771–775. https://doi.org/10.1038/nature07864

  35. Kazazian HH Jr, Woodhead AP (1973) Hemoglobin A synthesis in the developing fetus. N Engl J Med 289:58–62. https://doi.org/10.1056/NEJM197307122890202

  36. Kim D et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476. https://doi.org/10.1016/j.stem.2009.05.005

  37. Konopleva M, Andreeff M (2007) Targeting the leukemia microenvironment. Curr Drug Targets 8:685–701

  38. Konopleva MY, Jordan CT (2011) Leukemia stem cells and microenvironment: biology and therapeutic targeting. J Clin Oncol 29:591–599. https://doi.org/10.1200/jco.2010.31.0904

  39. Korkaya H, Wicha MS (2010) Cancer stem cells: nature versus nurture. Nat Cell Biol 12:419–421. https://doi.org/10.1038/ncb0510-419

  40. Kupersmith J et al (2005) Creating a new structure for research on health care effectiveness. J Investig Med 53:67–72

  41. Lam BS, Adams GB (2011) Blocking HIF1alpha activity eliminates hematological cancer stem cells. Cell Stem Cell 8:354–356. https://doi.org/10.1016/j.stem.2011.03.006

  42. Lapillonne H et al (2010) Red blood cell generation from human induced pluripotent stem cells: perspectives for transfusion medicine. Haematologica 95:1651–1659. https://doi.org/10.3324/haematol.2010.023556

  43. Lengerke C, Grauer M, Niebuhr NI, Riedt T, Kanz L, Park IH, Daley GQ (2009) Hematopoietic development from human induced pluripotent stem cells. Ann N Y Acad Sci 1176:219–227. https://doi.org/10.1111/j.1749-6632.2009.04606.x

  44. Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26:281–290. https://doi.org/10.1007/s10555-007-9066-y

  45. Lu X, Kang Y (2009) Cell fusion as a hidden force tumor progression. Cancer Res 69:8536–8539. https://doi.org/10.1158/0008-5472.CAN-09-2159

  46. Lv H et al (2014) 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 14:576. https://doi.org/10.1186/1471-2407-14-576

  47. Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715. https://doi.org/10.1016/j.cell.2008.03.027 pii] (: do

  48. Marotta LL, Polyak K (2009) Cancer stem cells: a model in the making. Curr Opin Genet Dev 19:44–50. https://doi.org/10.1016/j.gde.2008.12.003

  49. Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12:323–334. https://doi.org/10.1038/nrc3261

  50. Medvinsky A, Rybtsov S, Taoudi S (2011) Embryonic origin of the adult hematopoietic system: advances and questions. Development 138:1017–1031. https://doi.org/10.1242/dev.040998

  51. Migliaccio G et al (1986) Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac—liver transition. J Clin Invest 78:51–60. https://doi.org/10.1172/JCI112572

  52. Muller-Sieburg CE, Cho RH, Karlsson L, Huang JF, Sieburg HB (2004) Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood 103:4111–4118. https://doi.org/10.1182/blood-2003-10-3448

  53. Ogle BM, Cascalho M, Platt JL (2005) Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567–575. https://doi.org/10.1038/nrm1678

  54. Olenyuk BZ, Zhang GJ, Klco JM, Nickols NG, Kaelin WG Jr, Dervan PB (2004) Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci U S A 101:16768–16773. https://doi.org/10.1073/pnas.0407617101

  55. Ordway GA, Garry DJ (2004) Myoglobin: an essential hemoprotein in striated muscle. J Exp Biol 207:3441–3446. https://doi.org/10.1242/jeb.01172

  56. Palis J, Segel GB (1998) Developmental biology of erythropoiesis. Blood Rev 12:106–114

  57. Park IH et al (2008a) Disease-specific induced pluripotent stem cells. Cell 134:877–886. https://doi.org/10.1016/j.cell.2008.07.041

  58. Park IH et al (2008b) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146. https://doi.org/10.1038/nature06534

  59. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104:5431–5436. https://doi.org/10.1073/pnas.0701152104

  60. Peschle C et al (1985) Haemoglobin switching in human embryos: asynchrony of zeta–alpha and epsilon–gamma-globin switches in primitive and definite erythropoietic lineage. Nature 313:235–238

  61. Qu Y, Zhang L, Rong Z, He T, Zhang S (2013) Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma. J Exp Clin Cancer Res 32:75. https://doi.org/10.1186/1756-9966-32-75

  62. Ren JG, Seth P, Everett P, Clish CB, Sukhatme VP (2010) Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2. PLoS One. https://doi.org/10.1371/journal.pone.0012520

  63. Ricci-Vitiani L et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828. https://doi.org/10.1038/nature09557

  64. Risau W, Flamme I (1995) Vasculogenesis Ann Rev Cell Dev Biol 11:73–91 https://doi.org/10.1146/annurev.cb.11.110195.000445

  65. Roitbak T, Surviladze Z, Cunningham LA (2011) Continuous expression of HIF-1alpha in neural stem/progenitor cells. Cell Mol Neurobiol 31:119–133. https://doi.org/10.1007/s10571-010-9561-5

  66. Rubin R, Strayer DS, Rubin E (2012) Rubin’s pathology: clinicopathologic foundations of medicine. 6 edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia

  67. Rutherford TR, Clegg JB, Weatherall DJ (1979) K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin. Nature 280:164–165

  68. Seftor EA et al (2002a) Molecular determinants of human uveal melanoma invasion and metastasis. Clin Exp Metastasis 19:233–246

  69. Seftor EA et al (2002b) Expression of multiple molecular phenotypes by aggressive melanoma tumor cells: role in vasculogenic mimicry. Crit Rev Oncol Hematol 44:17–27

  70. Seftor EA, Meltzer PS, Kirschmann DA, Margaryan NV, Seftor RE, Hendrix MJ (2006) The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment. J Cell Mol Med 10:174–196

  71. Shams I, Avivi A, Nevo E (2004) Hypoxic stress tolerance of the blind subterranean mole rat: expression of erythropoietin and hypoxia-inducible factor 1 alpha. Proc Nat Acad Sci USA 101:9698–9703. https://doi.org/10.1073/pnas.0403540101

  72. Silvan U, Diez-Torre A, Arluzea J, Andrade R, Silio M, Arechaga J (2009) Hypoxia and pluripotency in embryonic and embryonal carcinoma stem cell biology. Differentiation 78:159–168. https://doi.org/10.1016/j.diff.2009.06.002

  73. Simon MC, Keith B (2008) The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9:285–296. https://doi.org/10.1038/nrm2354

  74. Squatrito M, Brennan CW, Helmy K, Huse JT, Petrini JH, Holland EC (2010) Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell 18:619–629. https://doi.org/10.1016/j.ccr.2010.10.034

  75. Sun B et al (2006) Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma. Oncol Rep 16:693–698

  76. Sun B, Zhang D, Zhang S, Zhang W, Guo H, Zhao X (2007) Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett 249:188–197. https://doi.org/10.1016/j.canlet.2006.08.016

  77. Sun B et al (2008) Role and mechanism of vasculogenic mimicry in gastrointestinal stromal tumors. Human Pathol 39:444–451. https://doi.org/10.1016/j.humpath.2007.07.018

  78. Sun T et al (2010) Expression and functional significance of twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology 51:545–556. https://doi.org/10.1002/hep.23311

  79. Szabo E et al (2010) Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468:521–526. https://doi.org/10.1038/nature09591

  80. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. https://doi.org/10.1016/j.cell.2006.07.024

  81. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019

  82. Tolar J et al (2011) Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome). Blood 117:839–847. https://doi.org/10.1182/blood-2010-05-287607

  83. Tsuchida E et al (2000) Exchange transfusion with albumin-heme as an artificial O2-infusion into anesthetized rats: physiological responses, O2-delivery, and reduction of the oxidized hemin sites by red blood cells. Bioconjug Chem 11:46–50 pii]

  84. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768. https://doi.org/10.1038/nrc2499

  85. Vunjak-Novakovic G, Tandon N, Godier A, Maidhof R, Marsano A, Martens TP, Radisic M (2010) Challenges in cardiac tissue engineering Tissue engineering Part B. Reviews 16:169–187. https://doi.org/10.1089/ten.TEB.2009.0352

  86. Walen KH (2006) Human diploid fibroblast cells in senescence; cycling through polyploidy to mitotic cells. Vitro Cell Dev Biol Anim 42:216–224. https://doi.org/10.1290/0603019.1

  87. Wang X et al (2003) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422:897–901. https://doi.org/10.1038/nature01531

  88. Wang R et al (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–833. https://doi.org/10.1038/nature09624

  89. Wang Y, Liu Y, Malek SN, Zheng P (2011) Targeting HIF1alpha eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8:399–411. https://doi.org/10.1016/j.stem.2011.02.006

  90. Witt O, Sand K, Pekrun A (2000) Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. Blood 95:2391–2396

  91. Wolk M (2014) Considerations on the possible origins of fetal hemoglobin cells produced in developing tumors. Stem Cells Dev 23:791–795. https://doi.org/10.1089/scd.2013.0450

  92. Woltjen K et al (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766–770. https://doi.org/10.1038/nature07863

  93. Yasuda Y et al (2002) Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs. Carcinogenesis 23:1797–1805

  94. Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920. https://doi.org/10.1126/science.1151526

  95. Zhang S, Zhang D, Sun B (2007) Vasculogenic mimicry: current status and future prospects. Cancer Lett 254:157–164. https://doi.org/10.1016/j.canlet.2006.12.036

  96. Zhang S, Mercado-Uribe I, Liu J (2013) Generation of erythroid cells from fibroblasts and cancer cells in vitro and in vivo. Cancer Lett 333:205–212. https://doi.org/10.1016/j.canlet.2013.01.037

  97. Zhang L et al. (2014a) Number of polyploid giant cancer cells and expression of EZH2 are associated with VM formation and tumor grade in human ovarian tumor. BioMed Res Int 2014:903542 https://doi.org/10.1155/2014/903542

  98. Zhang S, Mercado-Uribe I, Liu J (2014b) Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel. Int J Cancer 134:508–518. https://doi.org/10.1002/ijc.28319

  99. Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J (2014c) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33:116–128. https://doi.org/10.1038/onc.2013.96

  100. Zhang S, Mercado-Uribe I, Sood A, Bast RC, Liu J (2016a) Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells. Genes Cancer 7:60–72. https://doi.org/10.18632/genesandcancer.102

  101. Zhang S, Zhang D, Yang Z, Zhang X (2016b) Tumor Budding, micropapillary pattern, and polyploidy giant cancer cells in colorectal cancer: current status and future prospects. Stem Cells Int 2016:4810734 https://doi.org/10.1155/2016/4810734

  102. Zhang D et al (2017) Daughter cells and erythroid cells budding from pgccs and their clinicopathological significances in colorectal cancer. J Cancer 8:469–478. https://doi.org/10.7150/jca.17012

  103. Zhou H et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384. https://doi.org/10.1016/j.stem.2009.04.005

Download references

Acknowledgements

This work was supported in part by Grants from the National Science Foundation of China (#81472729 and #81672426), the foundation of Tianjin Health Bureau (15KG112) and the foundation of committee on science and technology of Tianjin (17YFZCSY00700).

Author information

Correspondence to Shiwu Zhang.

Ethics declarations

Human participants or animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that there is no conflict of interest in this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, Z., Yao, H., Fei, F. et al. Generation of erythroid cells from polyploid giant cancer cells: re-thinking about tumor blood supply. J Cancer Res Clin Oncol 144, 617–627 (2018). https://doi.org/10.1007/s00432-018-2598-4

Download citation

Keywords

  • Erythropoiesis
  • Polyploidy giant cancer cells
  • Vasculogenic mimicry
  • Cancer stem cells