Die Rolle der Zellfusion im Tumorkontext. Fakt oder Fiktion?

Zusammenfassung

Das biologische Phänomen der Zellfusion spielt bei verschiedenen physiologischen Prozessen, wie bei der Fertilisation, der Plazentabildung oder der Wundheilung/ Geweberegeneration, aber auch pathophysiologischen Prozessen, wie Krebs, eine bedeutende Rolle. Insbesondere bei Krebs wird vermutet, dass aus der Fusion zwischen Tumorzellen und normalen Zellen, wie Makrophagen, Fibroblasten oder Stammzellen, Tumor-Hybridzellen hervorgehen können, die neue Eigenschaften besitzen können, wie z. B. ein erhöhtes metastatogenes Potenzial oder eine erhöhte Unempfindlichkeit gegenüber Zytostatika. Doch obwohl in zahlreichen In-vitro- und In-vivo-Studien gezeigt werden konnte, dass durch Fusion stabile Tumor-Hybridzellen hervorgehen können, wird diese Hypothese nach wie vor kritisch diskutiert. Andererseits mehren sich die Studien, in denen eindeutig Tumor-Hybridzellen in humanen Tumoren und im peripheren Blut nachgewiesen wurden, was zudem mit einer schlechten Prognose für die Patienten korrelierte. Daher soll in diesem Übersichtsartikel das Phänomen der Zellfusion im Tumorkontext näher betrachtet werden und zusammengefasst werden, was für diese Hypothese spricht und warum Zellfusionsereignisse im humanen Tumorkontext durchaus etwas Reales sind.

Abstract

The biological phenomenon of cell fusion plays a crucial role in several physiological processes, like fertilization, placentation and wound healing/ tissue regeneration, as well as in pathophysiological conditions, like cancer. Particularly in cancer it is assumed that tumor cells could fuse with normal cells, like macrophages, fibroblasts and stem cells, thereby giving rise to tumor-hybrid cells that exhibit novel properties, such as an enhanced metastatogenic capacity and/or an enhanced drug resistance. However, even though a plethora of in vitro and in vivo studies demonstrated that tumor-hybrid cells will originate from hybridization events, the hypothesis of cell fusion in cancer is still a matter of controversial debates. In contrast, more and more published data provide evidence that tumor-hybrid cells are truly detectable both in human tumors and in the circulation of cancer patients, which was further associated with a poor prognosis. Here, we will review the hypothesis of cell fusion in cancer and will sum up the arguments why cell fusion in human cancers could be a real phenomenon.

Schlüsselwörter

Zellfusion - Krebs - Tumorprogression - Metastasierung - genomische Instabilität

Key words

Cell fusion - cancer - tumor progression - metastasis - genomic instability

• Literatur

• 1 Abmayr SM, Pavlath GK. Myoblast fusion: lessons from flies and mice. Development 2012; 139: 641-656
• 2 Aguilar PS, Baylies MK, Fleissner A. et al. Genetic basis of cell-cell fusion mechanisms. Trends Genet 2013; 29: 427-437
• 3 Aichel O. Über Zellverschmelzung mit quantitativ abnormer Chromosomenverteilung als Ursache der Geschwulstbildung. In Roux W. (ed) Vorträge und Aufsätze über Entwicklungsmechanik der Organismen. Leipzig: Wilhelm Engelmann; 1911: 1-115
• 4 Alison MR, Poulsom R, Otto WR. et al. Recipes for adult stem cell plasticity: fusion cuisine or readymade?. J Clin Pathol 2004; 57: 113-120
• 5 Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968-973
• 6 Andersen TL, Boissy P, Sondergaard TE. et al. Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership?. J Pathol 2007; 211: 10-17
• 7 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?. Lancet 2001; 357: 539-545
• 8 Berndt B, Haverkampf S, Reith G. et al. Fusion of CCL21 non-migratory active breast epithelial and breast cancer cells give rise to CCL21 migratory active tumor hybrid cell lines. PLoS ONE 2013; 8: e63711
• 9 Bhatia B, Multani AS, Patrawala L. et al. Evidence that senescent human prostate epithelial cells enhance tumorigenicity: cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT. Int J Cancer 2008; 122: 1483-1495
• 10 Bjerkvig R, Tysnes BB, Aboody KS. et al. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 2005; 5: 899-904
• 11 Bjerregaard B, Holck S, Christensen IJ, Larsson LI. Syncytin is involved in breast cancer-endothelial cell fusions. Cell Mol Life Sci 2006; 63: 1906-1911
• 12 Bondke Persson A, Buschmann IR. Vascular growth in health and disease. Front Mol Neurosci 2011; 4: 14
• 13 Boveri T. On multipolar mitosis as a means of analysis of the cell nucleus. In: Willier BH, Oppenheimer JM. ed. Foundations of Experimental Embryology. Prentice Hall; 1902/1964 74-97
• 14 Chakraborty A, Lazova R, Davies S. et al. Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant recipient. Bone Marrow Transplant 2004; 34: 183-186
• 15 Chakraborty AK, Sodi S, Rachkovsky M. et al. A spontaneous murine melanoma lung metastasis comprised of host x tumor hybrids. Cancer Res 2000; 60: 2512-2519
• 16 Clawson GA, Matters GL, Xin P. et al. Macrophage-tumor cell fusions from peripheral blood of melanoma patients. PLoS ONE 2015; 10: e0134320
• 17 Clawson GA, Matters GL, Xin P. et al. “Stealth dissemination” of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma. PLoS ONE 2017; 12: e0184451
• 18 Daley GQ. Alchemy in the liver: fact or fusion?. Nat Med 2004; 10: 671-672
• 19 Davies PS, Powell AE, Swain JR, Wong MH. Inflammation and proliferation act together to mediate intestinal cell fusion. PLoS ONE 2009; 4: e6530
• 20 Dittmar T, Nagler C, Schwitalla S. et al. Recurrence cancer stem cells – made by cell fusion?. Med Hypotheses 2009; 73: 542-547
• 21 Dittmar T, Schwitalla S, Seidel J. et al. Characterization of hybrid cells derived from spontaneous fusion events between breast epithelial cells exhibiting stem-like characteristics and breast cancer cells. Clin Exp Metastasis 2011; 28: 75-90
• 22 Dittmar T, Zänker KS. Cell Fusion in Health and Disease. Volume II Dordrecht, The Netherlands: Springer; 2011
• 23 Dittmar T, Zänker KS. Tissue regeneration in the chronically inflamed tumor environment: implications for cell fusion driven tumor progression and therapy resistant tumor hybrid cells. Int J Mol Sci 2015; 16: 30362-30381
• 24 Dittmar T, Zänker KS. Cell Fusion in Health and Disease. Volume I Dordrecht, The Netherlands: Springer; 2011
• 25 Duelli D, Lazebnik Y. Cell fusion: a hidden enemy?. Cancer Cell 2003; 3: 445-448
• 26 Duelli D, Lazebnik Y. Cell-to-cell fusion as a link between viruses and cancer. Nat Rev Cancer 2007; 7: 968-976
• 27 Duelli DM, Hearn S, Myers MP, Lazebnik Y. A primate virus generates transformed human cells by fusion. J Cell Biol 2005; 171: 493-503
• 28 Duelli DM, Padilla-Nash HM, Berman D. et al. A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr Biol 2007; 17: 431-437
• 29 Duesberg P. Chromosomal chaos and cancer. Sci Am 2007; 296: 52-59
• 30 Duesberg P, Rausch C, Rasnick D, Hehlmann R. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci USA 1998; 95: 13692-13697
• 31 Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315: 1650-1659
• 32 Eisenberg LM, Eisenberg CA. Stem cell plasticity, cell fusion, and transdifferentiation. Birth Defects Res Part C Embryo Today 2003; 69: 209-218
• 33 Fabarius A, Hehlmann R, Duesberg PH. Instability of chromosome structure in cancer cells increases exponentially with degrees of aneuploidy. Cancer Genet Cytogenet 2003; 143: 59-72
• 34 Gadella BM, Evans JP. Membrane fusions during Mammalian fertilization. Adv Exp Med Biol 2011; 713: 65-80
• 35 Garvin S, Oda H, Arnesson LG. et al. Tumor cell expression of CD163 is associated to postoperative radiotherapy and poor prognosis in patients with breast cancer treated with breast-conserving surgery. J Cancer Res Clin Oncol 2018; 144: 1253-1263
• 36 Gast CE, Silk AD, Zarour L. et al. Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival. Sci Adv 2018; 4: eaat7828
• 37 Grigsby RV, Fairbairn D, O'Neill KL. Differential DNA damage detected in hybridomas. Hybridoma 1993; 12: 755-761
• 38 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674
• 39 Hansemann D. Ueber asymmetrische Zelltheilung in Epithelkrebsen und deren biologische Bedeutung. Virchows Arch Pathol Anat 1890; 119: 299-326
• 40 Hatch EM, Hetzer MW. Chromothripsis. Curr Biol 2015; 25: R397-R399
• 41 He X, Li B, Shao Y. et al. Cell fusion between gastric epithelial cells and mesenchymal stem cells results in epithelial-to-mesenchymal transition and malignant transformation. BMC Cancer 2015; 15: 24
• 42 Helming L, Gordon S. Molecular mediators of macrophage fusion. Trends Cell Biol 2009; 19: 514-522
• 43 Hernandez JM, Podbilewicz B. The hallmarks of cell-cell fusion. Development 2017; 144: 4481-4495
• 44 Hu L, Plafker K, Vorozhko V. et al. Human papillomavirus 16 E5 induces bi-nucleated cell formation by cell-cell fusion. Virology 2009; 384: 125-134
• 45 Huppertz B, Gauster M. Trophoblast fusion. Adv Exp Med Biol 2011; 713: 81-95
• 46 Jacobsen BM, Harrell JC, Jedlicka P. et al. Spontaneous fusion with, and transformation of mouse stroma by, malignant human breast cancer epithelium. Cancer Res 2006; 66: 8274-8279
• 47 Johansson CB, Youssef S, Koleckar K. et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol 2008; 10: 575-583
• 48 Kemeny LV, Kurgyis Z, Buknicz T. et al. Melanoma cells can adopt the phenotype of stromal fibroblasts and macrophages by spontaneous cell fusion in vitro. Int J Mol Sci 2016; 17 pii E826
• 49 Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495-497
• 50 Kurgyis Z, Kemeny LV, Buknicz T. et al. Melanoma-derived BRAF(V600E) mutation in peritumoral stromal cells: implications for in vivo cell fusion. Int J Mol Sci 2016; 17 pii E980
• 51 LaBerge GS, Duvall E, Grasmick Z. et al. A melanoma lymph node metastasis with a donor-patient hybrid genome following bone marrow transplantation: a second case of leucocyte-tumor cell hybridization in cancer metastasis. PLoS ONE 2017; 12: e0168581
• 52 Lazova R, Laberge GS, Duvall E. et al. A melanoma brain metastasis with a donor-patient hybrid genome following bone marrow transplantation: first evidence for fusion in human cancer. PLoS ONE 2013; 8: e66731
• 53 Lindstrom A, Midtbo K, Arnesson LG. et al. Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity. Oncotarget 2017; 8: 51370-51386
• 54 Loeb LA. Mutator phenotype in cancer: origin and consequences. Semin Cancer Biol 2010; 20: 279-280
• 55 Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Cancer Res 2009; 69: 8536-8539
• 56 Luo F, Liu T, Wang J. et al. Bone marrow mesenchymal stem cells participate in prostate carcinogenesis and promote growth of prostate cancer by cell fusion in vivo. Oncotarget 2016; 7: 30924-30934
• 57 Ly P, Cleveland DW. Rebuilding chromosomes after catastrophe: emerging mechanisms of chromothripsis. Trends Cell Biol 2017; 27: 917-930
• 58 Martin-Padura I, Marighetti P, Gregato G. et al. Spontaneous cell fusion of acute leukemia cells and macrophages observed in cells with leukemic potential. Neoplasia 2012; 14: 1057-1066
• 59 McNally AK, Anderson JM. Macrophage fusion and multinucleated giant cells of inflammation. Adv Exp Med Biol 2011; 713: 97-111
• 60 Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501: 328-337
• 61 Melzer C, von der Ohe J, Hass R. In vitro fusion of normal and neoplastic breast epithelial cells with human mesenchymal stroma/stem cells partially involves tumor necrosis factor receptor signaling. Stem Cells 2018; 36: 977-989
• 62 Mi R, Pan C, Bian X. et al. Fusion between tumor cells enhances melanoma metastatic potential. J Cancer Res Clin Oncol 2012; 138: 1651-1658
• 63 Mi S, Lee X, Li X. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000; 403: 785-789
• 64 Miller FR, McInerney D, Rogers C, Miller BE. Spontaneous fusion between metastatic mammary tumor subpopulations. J Cell Biochem 1988; 36: 129-136
• 65 Mohr M, Tosun S, Arnold WH. et al. Quantification of cell fusion events human breast cancer cells and breast epithelial cells using a Cre-LoxP-based double fluorescence reporter system. Cell Mol Life Sci 2015; 72: 3769-3782
• 66 Mohr M, Zaenker KS, Dittmar T. Fusion in cancer: an explanatory model for aneuploidy, metastasis formation, and drug resistance. Methods Mol Biol 2015; 1313: 21-40
• 67 Muir A, Lever AM, Moffett A. Human endogenous retrovirus-W envelope (syncytin) is expressed in both villous and extravillous trophoblast populations. J Gen Virol 2006; 87: 2067-2071
• 68 Noubissi FK, Harkness T, Alexander CM, Ogle BM. Apoptosis-induced cancer cell fusion: a mechanism of breast cancer metastasis. FASEB J 2015; 29: 4036-4045
• 69 Nygren JM, Liuba K, Breitbach M. et al. Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat Cell Biol 2008; 10: 584-592
• 70 Okada Y. Sendai virus-induced cell fusion. Methods Enzymol 1993; 221: 18-41
• 71 Podbilewicz B. Virus and cell fusion mechanisms. Annu Rev Cell Dev Biol 2014; 30: 111-139
• 72 Powell AE, Anderson EC, Davies PS. et al. Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res 2011; 71: 1497-1505
• 73 Rachkovsky M, Sodi S, Chakraborty A. et al. Melanoma x macrophage hybrids with enhanced metastatic potential. Clin Exp Metastasis 1998; 16: 299-312
• 74 Ramakrishnan M, Mathur SR, Mukhopadhyay A. Fusion derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma. Cancer Res 2013; 73: 5360-5370
• 75 Shabo I, Midtbo K, Andersson H. et al. Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction. BMC Cancer 2015; 15: 922
• 76 Shabo I, Olsson H, Stal O, Svanvik J. Breast cancer expression of DAP12 is associated with skeletal and liver metastases and poor survival. Clin Breast Cancer 2013; 13: 371-377
• 77 Shabo I, Olsson H, Sun XF, Svanvik J. Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer 2009; 125: 1826-1831
• 78 Shabo I, Stal O, Olsson H. et al. Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer 2008; 123: 780-786
• 79 Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 2009; 138: 822-829
• 80 Sheltzer JM, Blank HM, Pfau SJ. et al. Aneuploidy drives genomic instability in yeast. Science 2011; 333: 1026-1030
• 81 Skokos EA, Charokopos A, Khan K. et al. Lack of TNF-alpha-induced MMP-9 production and abnormal E-cadherin redistribution associated with compromised fusion in MCP-1-null macrophages. Am J Pathol 2011; 178: 2311-2321
• 82 Soe K, Andersen TL, Hobolt-Pedersen AS. et al. Involvement of human endogenous retroviral syncytin-1 in human osteoclast fusion. Bone 2011; 48: 837-846
• 83 Sotillo R, Hernando E, Diaz-Rodriguez E. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 2007; 11: 9-23
• 84 Sottile F, Aulicino F, Theka I, Cosma MP. Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis. Sci Rep 2016; 6: 36863
• 85 Stratton MR. Journeys into the genome of cancer cells. EMBO Mol Med 2013; 5: 169-172
• 86 Strick R, Ackermann S, Langbein M. et al. Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta. J Mol Med 2007; 85: 23-38
• 87 Su Y, Subedee A, Bloushtain-Qimron N. et al. Somatic cell fusions reveal extensive heterogeneity in basal-like breast cancer. Cell Rep 2015; 11: 1549-1563
• 88 Wang R, Chen S, Li C. et al. Fusion with stem cell makes the hepatocellular carcinoma cells similar to liver tumor-initiating cells. BMC Cancer 2016; 16: 56
• 89 Wang R, Sun X, Wang CY. et al. Spontaneous cancer-stromal cell fusion as a mechanism of prostate cancer androgen-independent progression. PLoS ONE 2012; 7: e42653
• 90 Weiler J, Mohr M, Zanker KS, Dittmar T. Matrix metalloproteinase-9 (MMP9) is involved in the TNF-alpha-induced fusion of human M13SV1-Cre breast epithelial cells and human MDA-MB-435-pFDR1 cancer cells. Cell Commun Signal 2018; 16: 14
• 91 Wilkens L, Flemming P, Gebel M. et al. Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma. Proc Natl Acad Sci USA 2004; 101: 1309-1314
• 92 Wurmser AE, Gage FH. Stem cells: cell fusion causes confusion. Nature 2002; 416: 485-487
• 93 Yan TL, Wang M, Xu Z. et al. Up-regulation of syncytin-1 contributes to TNF-alpha-enhanced fusion between OSCC and HUVECs partly via Wnt/beta-catenin-dependent pathway. Sci Rep 2017; 7: 40983
• 94 Yao J, Zhang L, Hu L. et al. Tumorigenic potential is restored during differentiation in fusion-reprogrammed cancer cells. Cell Death Dis 2016; 7: e2314
• 95 Yilmaz Y, Lazova R, Qumsiyeh M. et al. Donor Y chromosome in renal carcinoma cells of a female BMT recipient: visualization of putative BMT-tumor hybrids by FISH. Bone Marrow Transplant 2005; 35: 1021-1024
• 96 Zhou X, Merchak K, Lee W. et al. Cell fusion connects oncogenesis with tumor evolution. Am J Pathol 2015; 185: 2049-2060