The cell biology of cell-in-cell structures

Nature Reviews Molecular Cell Biology

Volumn 9, Issue 10, 2008, Pages 796-809

  Overholtzer, Michael ^a   Brugge, Joan S ^b  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

VINCRISTINE;

APOPTOSIS; CAENORHABDITIS ELEGANS; CANNIBALISM; CAVEOLA; CELL FUNCTION; CELL FUSION; CELL IN CELL STRUCTURE; CELL PROLIFERATION; CELL STRUCTURE; CELL TYPE; CYTOLOGY; CYTOPLASM; DROSOPHILA MELANOGASTER; GENOMIC INSTABILITY; HOST CELL; HUMAN; NONHUMAN; PHAGOCYTOSIS; PRIORITY JOURNAL; REVIEW; TARGET CELL; THYMOCYTE; TUMOR CELL;

ANIMALS; APOPTOSIS; CELL COMMUNICATION; CELL FUSION; CELLULAR STRUCTURES; CYTOPLASMIC VESICLES; GENOMIC INSTABILITY; HUMANS; MODELS, BIOLOGICAL; NEOPLASMS; PHAGOCYTOSIS; VACUOLES;

EID: 52449135089     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm2504     Document Type: Review

References (180)

1. Eberth, J. Über die feineren bau der darmschleithaut. Wurzb. Naturwiss. Zeitschr. 5, 11 (1864) (in German).
2. Eimer, A. D. Zur beckerfrage. Virchow's Arch. 40, 282 (1867) (in German).
3. von Arnstein, C. Über becherzellen und ihre beziehung zur fettresorption und sekretion. Arch. Mikrosk. Anat. 39, 527-547 (1867) (in German).
4. Paneth, J. Über die sezernierenden zellen der dünndarmepithels. Arch. F. Mikrosk. Anat. 31, 113-191 (1888) (in German).
5. Bauchwitz, M. A. The bird's eye cell: cannibalism or abnormal division of tumor cells. Acta Cytol. Abstr. 25, 92 (1981).
6. Lewis, W. H. The engulfment of living blood cells by others of the same type. Anat. Rec. 31, 43-49 (1925). The first report to experimentally examine homotypic cell-in-cell structures to investigate the viability of internalized cells.
7. Robertson, A. & Thomson, N. Morphology of programmed cell death in the ventral nerve cord of Caenorhabditis elegans larvae. J. Embryol. Exp. Morphol. 67, 89-100 (1982).
8. Fujinami, N., Zucker-Franklin, D. & Valentine, F. Interaction of mononuclear leukocytes with malignant melanoma. Lab. Invest. 45, 28-37 (1981). Showed the complete internalization of lymphocytes inside cultured metastatic melanoma cells by exclusion of ruthenium red from the internalized cell membrane.
9. Ioachim, H. L. Emperipolesis of lymphoid cells in mixed cultures. Lab. Invest. 14, 1784-1794 (1965).
10. Shamoto, M. Emperipolesis of hematopoietic cells in myelocytic leukemia. Electron microscopic and phase contrast microscopic studies. Virchow's Arch., B, Cell Pathol. 35, 283-290 (1981).
11. Trowell, O. A. Intracellular lymphocytes in thymus reticular cells and in fibroblasts cultured in vitro. J. Physiol. 110, 5 (1949).
12. Trowell, O. A. The lymphocyte. Int. Rev. Cytol. 7, 236-286 (1958).
13. Sahebekhitiari, H. A. & Tavassoli, M. Marrow cell uptake by megakaryocytes in routine bone marrow smears during blood loss. Scand. J. Haematol. 16, 13-17 (1976). Examined a large panel of human bone marrow smears and correlated a high frequency of haematopoietic cell-megakaryocyte emperipolesis with blood loss.
14. Hughes, D. Invasion of neurones in vitro by non-immune lymphocytes. Br. J. Exp. Pathol. 48, 386-389 (1967).
15. Klein, R. Ilots reticulo-lymphocytaires thymiques at spleniques foetaux humains et genese des mecanismes immunitaires. C. R. Seances. Soc. Biol. Fil. 156, 1623-1626 (1962) (in French).
16. Dreyer, D. A., Shullenberger, C. C. & Dmochowski, L. A study on intracellular lymphocytes ("emperipolesis") in tissue culture of lymph nodes from patients with malignant lymphoma. Tex. Rep. Biol. Med. 22, 61-69 (1964).
17. Humble, J. G., Jayne, W. H. & Pulvertaft, R. J. Biological interaction between lymphocytes and other cells. Br. J. Haematol. 2, 283-294 (1956). Examined live lymphocytes internalized into various host cells in vitro by time-lapse microscopy, and coined the term emperipolesis, for "inside round about wandering", to describe the long-term movements of internalized cells.
18. Koller, P. C. & Waymouth, C. Observations on intracellular leucocytes in tissue cultures of a rat tumour. J. R. Microsc. Soc. 72, 173-176 (1952).
19. Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966-979 (2007). Characterized a novel mechanism of cell-in-cell formation, termed entosis, whereby viable cells invade into their hosts using contractile force associated with adherens junction formation. Showed that entosis occurs in tumours in vivo and proposed that the process is tumour suppressive.
20. Pulvertaft, R. J. Cellular associations in normal and abnormal lymphocytes. Proc. R. Soc. Med. 52, 315-322 (1959).
21. Tsunoda, R. et al. Emperipolesis of lymphoid cells by human follicular dendritic cells in vitro. Virchow's Arch., B, Cell Pathol. 62, 69-78 (1992).
22. Lee, W. B., Erm, S. K., Kim, K. Y. & Becker, R. P. Emperipolesis of erythroblasts within Kupffer cells during hepatic hemopoiesis in human fetus. Anat. Rec. 256, 158-164 (1999).
23. Takeya, M. & Takahashi, K. Emperipolesis in a case of malignant lymphoma: electron microscopic and immunohistochemical investigation. Ultrastruct. Pathol. 12, 651-658 (1988).
24. Ioachim, H. & Furth, J. Intrareticular cell multiplication of leukemic lymphoblasts in thymic tissue cultures. J. Natl Cancer Inst. 32, 339-359 (1964).
25. Andrew, W. & Andrew, N. V. Mitotic division and degeneration of lymphocytes within the cells of intestinal epithelium in the mouse. Anat. Rec. 9, 251-277 (1945).
26. Andrew, W. & Sosa, J. M. Mitotic division and degeneration of lymphocytes within cells of intestinal epithelium in young and in adult white mice. Anat. Rec. 97, 63 (1947).
27. Wekerle, H., Ketelsen, U. P. & Ernst, M. Thymic nurse cells. Lymphoepithelial cell complexes in murine thymuses: morphological and serological characterization. J. Exp. Med. 151, 925-944 (1980). This report and reference 30 were the first two reports to describe thymic nurse cells with internalized thymocytes, isolated from dissociated mouse and rat thymus tissue. Internalized thymocytes were viable and could be mitotic, and the authors speculated that they could be released from the host. These reports also showed that thymic nurse cells express MHC class I and II, and the authors speculated that these host cells play a role in thymocyte differentiation.
28. Andrew, W. & Collings, C. K. Lymphocytes within the cell of intestinal epithelium in man. Anat. Rec. 96, 445-457 (1946).
29. Benyesh-Melnick, M., Fernbach, D. J. & Lewis, R. T. Studies on human leukemia. I. Spontaneous lymphoblastoid transformation of fibroblastic bone marrow cultures derived from leukemic and nonleukemic children. J. Natl Cancer Inst. 31, 1311-1331 (1963).
30. Wekerle, H. & Ketelsen, U. P. Thymic nurse cells - Ia-bearing epithelium involved in T-lymphocyte differentiation? Nature 283, 402-404 (1980).
31. Boll, I. T., Domeyer, C. & Buhrer, C. Human megakaryoblastic proliferation and differentiation events observed by phase-contrast cinematography. Acta Haematol. 97, 144-152 (1997).
32. Philp, D. et al. The binding, internalization, and release of thymocytes by thymic nurse cells. Cell. Immunol. 148, 301-315 (1993). Showed the dynamic interaction between thymocytes and thymic nurse cells in vitro by time-lapse microscopy, including the ability of internalized thymocytes to be released from the host.
33. Larsen, T. E. Emperipolesis of granular leukocytes within megakaryocytes in human hemopoietic bone marrow. Am. J. Clin. Pathol. 53, 485-489 (1970). First report to document megakaryocytes acting as hosts for viable internalized granular leukocytes, incuding neutrophils. Examined the interaction by time-lapse microscopy and found that an internalized cell could be released.
34. Ling, N. R., Acton, A. B., Roitt, I. M. & Doniach, D. Interaction of lymphocytes from immunized hosts with thyroid and other cells in culture. Br. J. Exp. Pathol. 46, 348-359 (1965).
35. Tavassoli, M. Emperipolesis by megakaryocytes in blood loss. Br. J. Haematol. 49, 660-661 (1981).
36. Chemnitz, J. & Bichel, P. Tumour cell-tumour cell emperipolesis studied by transmission electron microscopy. Exp. Cell Res. 82, 319-324 (1973).
37. Shelton, E. & Dalton, A. J. Electron microscopy of emperipolesis. J. Biophys. Biochem. Cytol. 6, 513-514 (1959).
38. Klug, H. Über das vorkommen von lymphocyten in reticulumzellen. Experientia 18, 317-318 (1962) (in German).
39. Lee, K. P. Emperipolesis of hematopoietic cells within megakaryocytes in bone marrow of the rat. Vet. Pathol. 26, 473-478 (1989).
40. Lussier, C. et al. Cytology of Rosai-Dorfman disease. Diagn. Cytopathol. 24, 298-300 (2001).
41. McClain, K. L., Natkunam, Y. & Swerdlow, S. H. Atypical cellular disorders. Hematology Am. Soc. Hematol. Educ. Program 2004, 283-296 (2004).
42. von Andrian, U. H. & Mackay, C. R. T-cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020-1034 (2000).
43. Marchesi, V. T. & Gowans, J. L. The migration of lymphocytes through the endothelium of venules in lymph nodes: an electron microscope study. Proc. R. Soc. Lond. B 159, 283-290 (1964). Documented, using serial electron microscopy, that lymphocytes can exit post capillary venules in vivo by traversing endothelial cell cytoplasm (transcellular migration), rather than by crossing between endothelial cell-cell junctions.
44. De Bruyn, P. P., Michelson, S. & Thomas, T. B. The migration of blood cells of the bone marrow through the sinusoidal wall. J. Morphol. 133, 417-437 (1971).
45. Farr, A. G. & De Bruyn, P. P. The mode of lymphocyte migration through postcapillary venule endothelium in lymph node. Am. J. Anat. 143, 59-92 (1975).
46. Becker, R. P. & De Bruyn, P. P. The transmural passage of blood cells into myeloid sinusoids and the entry of platelets into the sinusoidal circulation; a scanning electron microscopic investigation. Am. J. Anat. 145, 183-205 (1976).
47. Carman, C. V. & Springer, T. A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377-388 (2004).
48. Engelhardt, B. & Wolburg, H. Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur. J. Immunol. 34, 2955-2963 (2004).
49. Cernuda-Morollon, E. & Ridley, A. J. Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ. Res. 98, 757-767 (2006).
50. Azzali, G., Arcari, M. L. & Caldara, G. F. The "mode" of lymphocyte extravasation through HEV of Peyer's patches and its role in normal homing and inflammation. Microvasc. Res. 75, 227-237 (2008).
51. Carman, C. V. & Springer, T. A. Trans-cellular migration: cell-cell contacts get intimate. Curr. Opin. Cell Biol. 30 Jun 2008 (doi:10.1016/j.ceb.2008.05.007).
52. Williamson, J. R. & Grisham, J. W. Leucocytic emigration from inflamed capillaries. Nature 188, 1203 (1960).
53. Williamson, J. R. & Grisham, J. W. Electron microscopy of leukocytic margination and emigration in acute inflammation in dog pancreas. Am. J. Pathol. 39, 239-256 (1961).
54. Bobik, R. & Dabrowski, Z. Emperipolesis of marrow cells within megakaryocytes in the bone marrow of sublethally irradiated mice. Ann. Hematol. 70, 91-95 (1995).
55. Tavassoli, M. Modulation of megakaryocyte emperipolesis by phlebotomy: megakaryocytes as a component of marrow-blood barrier. Blood Cells 12, 205-216 (1986).
56. Dzieciol, J. et al. Megakaryocytes in the acute stage of experimental hemorrhagic shock. Part II. Megakaryocytic regulation of cell release from the bone marrow. Rocz. Akad. Med. Bialymst. 40, 94-98 (1995).
57. Weiss, L. The structure of bone marrow. Functional interrelationships of vascular and hematopoietic compartments in experimental hemolytic anemia: an electron microscopic study. J. Morphol. 117, 467-537 (1965).
58. Weiss, L. Transmural cellular passage in vascular sinuses of rat bone marrow. Blood 36, 189-208 (1970).
59. Thiele, J., Krech, R., Choritz, H. & Georgii, A. Emperipolesis - a peculiar feature of megakaryocytes as evaluated in chronic myeloproliferative diseases by morphometry and ultrastructure. Virchow's Arch., B, Cell Pathol. 46, 253-263 (1984).
60. Behnke, O. An electron microscope study of the megacaryocyte of the rat bone marrow. I. The development of the demarcation membrane system and the platelet surface coat. J. Ultrastruct. Res. 24, 412-433 (1968).
61. Breton-Gorius, J. On the alleged phagocytosis by megakaryocytes. Br. J. Haematol. 47, 635-636 (1981).
62. Tefferi, A. Pathogenesis of myelofibrosis with myeloid metaplasia. J. Clin. Oncol. 23, 8520-8530 (2005).
63. Schmitt, A. et al. Polymorphonuclear neutrophil and megakaryocyte mutual involvement in myelofibrosis pathogenesis. Leuk. Lymphoma 43, 719-724 (2002).
64. Schmitt, A. et al. Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis. Blood 96, 1342-1347 (2000).
65. Falik-Zaccai, T. C. et al. A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics. Mol. Genet. Metab. 74, 303-313 (2001).
66. Centurione, L. et al. Increased and pathologic emperipolesis of neutrophils within megakaryocytes associated with marrow fibrosis in GATA-1(low) mice. Blood 104, 3573-3580 (2004).
67. Novak, E. K. et al. Inherited thrombocytopenia caused by reduced platelet production in mice with the gunmetal pigment gene mutation. Blood 85, 1781-1789 (1995).
68. McGarry, M. P. et al. Increased incidence and analysis of emperipolesis in megakaryocytes of the mouse mutant gunmetal. Exp. Mol. Pathol. 66, 191-200 (1999).
69. Stenberg, P. E., McDonald, T. P. & Jackson, C. W. Disruption of microtubules in vivo by vincristine induces large membrane complexes and other cytoplasmic abnormalities in megakaryocytes and platelets of normal rats like those in human and Wistar Furth rat hereditary macrothrombocytopenias. J. Cell Physiol. 162, 86-102 (1995).
70. Jackson, C. W. et al. The Wistar Furth rat: an animal model of hereditary macrothrombocytopenia. Blood 71, 1676-1686 (1988).
71. Leven, R. M. & Tablin, F. Megakaryocyte and platelet ultrastructure in the Wistar Furth rat. Am. J. Pathol. 132, 417-426 (1988).
72. Dipasquale, B. & Tridente, G. Immunohistochemical characterization of nurse cells in normal human thymus. Histochemistry 96, 499-503 (1991).
73. Ritter, M. A., Sauvage, C. A. & Cotmore, S. F. The human thymus microenvironment: in vivo identification of thymic nurse cells and other antigenically-distinct subpopulations of epithelial cells. Immunology 44, 439-446 (1981).
74. Penit, C. In vivo thymocyte maturation. BUdR labeling of cycling thymocytes and phenotypic analysis of their progeny support the single lineage model. J. Immunol. 137, 2115-2121 (1986).
75. Webb, O. et al. The identification of thymic nurse cells in vivo and the role of cytoskeletal proteins in thymocyte internalization. Cell. Immunol. 228, 119-129 (2004).
76. Pezzano, M., Samms, M., Martinez, M. & Guyden, J. Questionable thymic nurse cell. Microbiol. Mol. Biol. Rev. 65, 390-403 (2001).
77. Sandilands, G. P., Reid, F. M., Gray, K. G. & Anderson, J. R. Lymphocyte emperipolesis revisited. I. Development of in vitro assay and preliminary characterisation of the lymphocyte subpopulation involved. Immunology 35, 381-389 (1978).
78. Reid, F. M., Sandilands, G. P., Gray, K. G. & Anderson, J. R. Lymphocyte emperipolesis revisited. II. Further characterization of the lymphocyte subpopulation involved. Immunology 36, 367-372 (1979).
79. Tanaka, M., Aze, Y. & Fujita, T. Adhesion molecule LFA-1/ICAM-1 influences on LPS-induced megakaryocytic emperipolesis in the rat bone marrow. Vet. Pathol. 34, 463-466 (1997).
80. Lindhout, E., Lakeman, A., Mevissen, M. L. & de Groot, C. Functionally active Epstein-Barr virus-transformed follicular dendritic cell-like cell lines. J. Exp. Med. 179, 1173-1184 (1994).
81. Yang, L. et al. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-α-activated vascular endothelium under flow. Blood 106, 584-592 (2005).
82. Lugini, L. et al. Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res. 66, 3629-3638 (2006). Showed that internalization of live T cells can increase the survival of metastatic melanoma host cells under starvation conditions.
83. Fais, S. Cannibalism: a way to feed on metastatic tumors. Cancer Lett. 258, 155-164 (2007).
84. Millan, J. et al. Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains. Nature Cell Biol. 8, 113-123 (2006).
85. Heiska, L. et al. Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. J. Biol. Chem. 273, 21893-21900 (1998).
86. Schnitzer, J. E., Oh, P., Pinney, E. & Allard, J. Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J. Cell Biol. 127, 1217-1232 (1994).
87. Yamada, S. & Nelson, W. J. Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell-cell adhesion. J. Cell Biol. 178, 517-527 (2007).
88. Liebman, E. The function of leucocytes in the growth and regression of the egg of Triturus viridescens. Am. J. Anat. 77, 273 (1945).
89. Ioachim, H. L. Emperipolesis of lymphoid cells in mixed cultures. Proc. Am. Assoc. Cancer Res. 6, 32 (1965).
90. Tinari, A., Matarrese, P., Minetti, M. & Malorni, W. Hyperphagia by self- and xeno-cannibalism: cell death by indigestion?: a reminiscence of the Phedrus Fabula "Rana Rupta et Bos"? Autophagy 4, 128-130 (2008).
91. Nishie, M. et al. Oligodendrocytes within astrocytes ("emperipolesis") in the cerebral white matter in hepatic and hypoglycemic encephalopathy. Neuropathology 26, 62-65 (2006).
92. Wu, E. & Raine, C. S. Multiple sclerosis. Interactions between oligodendrocytes and hypertrophic astrocytes and their occurrence in other, nondemyelinating conditions. Lab. Invest. 67, 88-99 (1992).
93. Shintaku, M. & Yutani, C. Oligodendrocytes within astrocytes ("emperipolesis") in the white matter in Creutzfeldt-Jakob disease. Acta Neuropathol. 108, 201-206 (2004).
94. de Pasquale, A., Paterlini, P., Quaglino, D. & Quaglino, D. Emperipolesis of granulocytes within megakaryocytes. Br. J. Haematol. 60, 384-386 (1985).
95. + thymocytes from apoptosis. Cell. Mol. Biol. (Noisy-le-grand) 41, 1099-1111 (1995).
96. Martinez, M. et al. Thymic nurse cell multicellular complexes in HY-TCR transgenic mice demonstrate their association with MHC restriction. Exp. Biol. Med. (Maywood) 232, 780-788 (2007).
97. van de Wijngaert, F. P., Rademakers, L. H., Schuurman, H. J., de Weger, R. A. & Kater, L. Identification and in situ localization of the "thymic nurse cell" in man. J. Immunol. 130, 2348-2351 (1983).
98. Hiramine, C., Nakagawa, T., Miyauchi, A. & Hojo, K. Thymic nurse cells as the site of thymocyte apoptosis and apoptotic cell clearance in the thymus of cyclophosphamide-treated mice. Lab. Invest. 75, 185-201 (1996).
99. Schwartz, R. H. Acquisition of immunologic self-tolerance. Cell 57, 1073-1081 (1989).
100. Tsunoda, R. et al. Human follicular dendritic cells in vitro and follicular dendritic-cell-like cells. Cell Tissue Res. 288, 381-389 (1997).
101. Tsunoda, R., Heinen, E. & Sugai, N. Follicular dendritic cells in vitro modulate the expression of Fas and Bcl-2 on germinal center B cells. Cell Tissue Res. 299, 395-402 (2000).
102. Moore, A. E. & Hlinka, J. Activities of lymphocytes inside fibroblasts. Proc. Am. Assoc. Cancer Res. 5, 46 (1964).
103. Sinkovics, J. G. Intracellular lymphocytes in leukaemia. Nature 196, 80-81 (1962).
104. Sinkovics, J. G., Shullenberger, C. C. & Howe, C. D. Cell destruction by lymphocytes. Lancet 287, 1215-1216 (1966).
105. Hughes, D., Raine, C. S. & Field, E. J. Invasion of neurones in vitro by non immune lymphocytes. An electron microscopic study. Br. J. Exp. Pathol. 49, 356-359 (1968).
106. Xia, P., Wang, S., Guo, Z. & Yao, X. Emperipolesis, entosis and beyond: dance with fate. Cell Res. 18, 705-707 (2008).
107. Radosevic, K. et al. Occurrence and a possible mechanism of penetration of natural killer cells into K562 target cells during the cytotoxic interaction. Cytometry 20, 273-280 (1995).
108. Burns, E. R., Zucker-Franklin, D. & Valentine, F. Characterization of the cell population mediating cytotoxicity and emperipolesis in human malignant melanomas. Trans. Assoc. Am. Physicians 94, 366-371 (1981).
109. Pihl, E., Nind, A. P. & Nairn, R. C. Electron microscope observations of the in vitro interaction between human leucocytes and cancer cells. Aust. J. Exp. Biol. Med. Sci. 52, 737-743 (1974).
110. Wang, X. & Li, W. Mechanisms of natural killer cell-mediated tumor cell cytolysis at a single cell level. J. Med. Coll. PLA 2, 107-117 (1987).
111. Burns, E. R., Zucker-Franklin, D. & Valentine, F. Cytotoxicity of natural killer cells: correlation with emperipolesis and surface enzymes. Lab. Invest. 47, 99-107 (1982).
112. Saxena, S., Beena, K. R., Bansal, A. & Bhatnagar, A. Emperipolesis in a common breast malignancy. A case report. Acta Cytol. 46, 883-886 (2002).
113. Ng, Y. K. & Ling, E. A. Emperipolesis of lymphoid cells in vagal efferent neurons following an intraneural injection of ricin into the vagus nerve in rats. Neurosci. Lett. 270, 153-156 (1999).
114. Brouwer, M., de Ley, L., Feltkamp, C. A., Elema, J. & Jongsma, A. P. Serum-dependent "cannibalism" and autodestruction in cultures of human small cell carcinoma of the lung. Cancer Res. 44, 2947-2951 (1984). Showed an engulfment process termed cannibalism that limited the survival of lung tumour explants in vitro, and also occurred in tumours in vivo. It also proposed that engulfment was a tumour-suppressive process.
115. Shelton, E. & Rice, M. Studies on mouse lymphomas. III. Behavior of tumor- and non-tumor-cell populations during growth of three ascites lymphomas. J. Natl Cancer Inst. 21, 163-191 (1958).
116. Domingo-Claros, A. et al. Oligoblastic leukaemia with (8;21) translocation and haemophagocytic syndrome and granulocytic cannibalism. Leuk. Res. 20, 517-521 (1996).
117. Jin, J. & Woodgett, J. R. Chronic activation of protein kinase Bβ/Akt2 leads to multinucleation and cell fusion in human epithelial kidney cells: events associated with tumorigenesis. Oncogene 24, 5459-5470 (2005).
118. Terui, T. et al. The production of transforming growth factor-β in acute megakaryoblastic leukemia and its possible implications in myelofibrosis. Blood 75, 1540-1548 (1990).
119. Bratton, D. L. & Henson, P. M. Apoptotic cell recognition: will the real phosphatidylserine receptor(s) please stand up? Curr. Biol. 18, R76-R79 (2008).
120. Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430-434 (2007).
121. Park, S. Y. et al. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 15, 192-201 (2008).
122. Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435-439 (2007).
123. Ravichandran, K. S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nature Rev. Immunol. 7, 964-974 (2007).
124. Shelton, E. & Rice, M. Studies on mouse lymphomas. II. Behavior of three lymphomas in diffusion chambers in relation to their invasive capacity in the host. J. Natl Cancer Inst. 21, 137-161 (1958).
125. Dey, P., Amir, T., Jogai, S. & Al Jussar, A. Fine-needle aspiration cytology of metastatic transitional cell carcinoma. Diagn. Cytopathol. 32, 226-228 (2005).
126. Fischer, A. & Dolschansky, L. Uber das wachstum von milzstromazellen in vitro. Arch. Entwmech.Org. 116, 123 (1929).
127. Loreti, F. Z. Nuove ricerche ed osservazioni sulla migrazione di cellule linfoidi attraverso il tessuto epiteliale. (Nota II - La migrazione linfoide nell'epitelio del canalicolo renale nei pesci teleostei, ed il fenomeno della cario-anabiosi del Guieysse-Pellissier). Anat. Embryol. 103, 679-693 (1934).
128. Rosin, A. & Doljanski, L. Erythrocytes in the cytoplsm and nuclei of liver cells. Br. J. Exp. Pathol. 25, 111-115 (1944).
129. Pulvertaft, R. J. & Humble, J. G. Intracellular phase of existence of lymphycotes during remission of acute lymphatic leukaemia. Nature 194, 194-195 (1962).
130. Wheatley, D. N. Cellular engulfment of erythrocytes. Br. J. Exp. Pathol. 49, 541-543 (1968).
131. Halil, O. & Barrett, A. J. Phagocytosis by megakaryocytes in malignant disorders. Br. J. Haematol. 46, 161 (1980).
132. Djaldetti, M. & Strauss, Z. Emperipolesis by megakaryocytes in patients with non-Hodgkin's lymphoma and megaloblastic anemia. J. Submicrosc. Cytol. 14, 407-413 (1982).
133. de Waal Malefijt, R., Leene, W., Roholl, P. J., Wormmeester, J. & Hoeben, K. A. T cell differentiation within thymic nurse cells. Lab. Invest. 55, 25-34 (1986).
134. Tsunoda, R. et al. Immunohistochemical study on cultured FDC-C enriched lymphoid cell populations. Adv. Exp. Med. Biol. 237, 177-180 (1988).
135. Lindhout, E., Mevissen, M. L., Kwekkeboom, J., Tager, J. M. & de Groot, C. Direct evidence that human follicular dendritic cells (FDC) rescue germinal centre B cells from death by apoptosis. Clin. Exp. Immunol. 91, 330-336 (1993).
136. Dzieciol, J. et al. [Phenomenon of emperipolesis of bone marrow megakaryocytes in experimental hemorrhage shock in rats]. Acta Haematol. Pol. 25, 165-169 (1994) (in Polish).
137. Samms, M. et al. Lysosomal-mediated degradation of apoptotic thymocytes within thymic nurse cells. Cell. Immunol. 197, 108-115 (1999).
138. Avci, Z. et al. Thrombocytopenia and emperipolesis in a patient with hepatitis A infection. Pediatr. Hematol. Oncol. 19, 67-70 (2002).
139. Woulfe, D. S. et al. Serglycin proteoglycan deletion induces defects in platelet aggregation and thrombus formation in mice. Blood 111, 3458-3467 (2008).
140. Richters, A., Sherwin, R. P. & Richters, V. The lymphocyte and human lung cancers. Cancer Res. 31, 214-222 (1971).
141. DeSimone, P. A., East, R. & Powell, R. D. Jr. Phagocytic tumor cell activity in oat cell carcinoma of the lung. Hum. Pathol. 11, 535-539 (1980).
142. Ino, T., Hirano, M. & Shamoto, M. Emperipolesis observed in immature cells in blast crisis of chronic myelogenous leukaemia. Scand. J. Haematol. 26, 91-96 (1981).
143. Kamiyama, R., Onozawa, Y., Yamaguchi, H. & Tsukada, T. Emperipolesis and annulate lamellae in erythroleukaemia. Scand. J. Haematol. 30, 331-336 (1983).
144. Bacchi, C. E., Dorfman, R. F., Hoppe, R. T., Chan, J. K. & Warnke, R. A. Metastatic carcinoma in lymph nodes simulating "syncytial variant" of nodular sclerosing Hodgkin's disease. Am. J. Clin. Pathol. 96, 589-593 (1991).
145. Caruso, R. A., Famulari, C., Giuffre, G. & Mazzeo, G. Pleomorphic carcinoma of the gallbladder: report of a case. Tumori 77, 523-526 (1991).
146. Chetty, R. & Cvijan, D. Giant (bizarre) cell variant of renal carcinoma. Histopathology 30, 585-587 (1997).
147. Skinnider, L. F., Pabello, P. & Zheng, C. Y. Characteristics of a cell line established from a case of acute megakaryoblastic leukemia. Acta Haematol. 98, 26-31 (1997).
148. Kinkor, Z., Mukensnabl, P. & Michal, M. Inflammatory myxohyaline tumor with massive emperipolesis. Pathol. Res. Pract 198, 639-642 (2002).
149. Shen, R. & Wen, P. Clear cell renal cell carcinoma with syncytial giant cells: a case report and review of the literature. Arch. Pathol. Lab. Med. 128, 1435-1438 (2004).
150. Khayyata, S., Basturk, O. & Adsay, N. V. Invasive micropapillary carcinomas of the ampullopancreatobiliary region and their association with tumor-infiltrating neutrophils. Mod. Pathol. 18, 1504-1511 (2005).
151. Yasunaga, M. et al. Ovarian undifferentiated carcinoma resembling giant cell carcinoma of the lung. Pathol. Int. 58, 244-248 (2008).
152. Burns, E. R. Tumor cell-tumor cell emperipolesis. Exp. Cell Res. 48, 229-231 (1967).
153. Chemnitz, J., Skaaring, P. & Bichel, P. Light and electron microscopy of the JB-1 ascites tumor at different stages of growth. Z. Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 82, 111-131 (1974).
154. Chemnitz, J. & Skaaring, P. Increasing occurence of tumour cell - tumour cell emperipolesis in the regenerating JB-1 ascites tumour. Z. Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 84, 89-96 (1975).
155. Chemnitz, J. & Skaaring, P. Tumor cell interactions in vitro microtubules, 100 Å filaments, and contractile microfilaments of tumor cells involved in "emperipolesis". Z. Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 92, 287-293 (1978).
156. Chemnitz, J. & Skaaring, P. Tumour cell interactions in vitro. Evidence for the occurrence of tumour cells within other tumour cells. Virchow's Arch., B, Cell Pathol. 28, 87-91 (1978).
157. Masukawa, T. & Friedrich, E. G. Jr. Cytopathology of Paget's disease of the vulva. Diagnostic abrasive cytology. Acta Cytol. 22, 476-478 (1978).
158. Towers, K. J. & Melamed, M. R. Absence of prognostic features in the cytology of effusions due to mammary cancer. Acta Cytol. 23, 30-34 (1979).
159. Uei, Y., Watanabe, Y., Hirota, T., Yamamoto, H. & Watanabe, H. Cytologic diagnosis of breast carcinoma with nipple discharge: special significance of the spherical cell cluster. Acta Cytol. 24, 522-528 (1980).
160. Frable, W. J., Bonfiglio, T. A., Kaminsky, D. B. & Murphy, W. M. Diagnostic cytology seminar. Acta Cytol. 24, 90-136 (1980).
161. Hong, J. S. The exfoliative cytology of endometrial stromal sarcoma in peritoneal fluid. Acta Cytol. 25, 277-281 (1981).
162. Craig, I. D., Desrosiers, P. & Lefcoe, M. S. Giant-cell carcinoma of the lung. A cytologic study. Acta Cytol. 27, 293-298 (1983).
163. Ehya, H. The cytologic diagnosis of mesothelioma. Semin. Diagn. Pathol. 3, 196-203 (1986).
164. Silverman, J. F., Dabbs, D. J., Finley, J. L. & Geisinger, K. R. Fine-needle aspiration biopsy of pleomorphic (giant cell) carcinoma of the pancreas. Cytologic, immunocytochemical, and ultrastructural findings. Am. J. Clin. Pathol. 89, 714-720 (1988).
165. Silverman, J. F., Finley, J. L., Berns, L. & Unverferth, M. Significance of giant cells in fine-needle aspiration biopsies of benign and malignant lesions of the pancreas. Diagn. Cytopathol. 5, 388-391 (1989).
166. Gupta, R. K. & Wakefield, S. J. Needle aspiration cytology, immunocytochemistry, and electron microscopic study of unusual pancreatic carcinoma with pleomorphic giant cells. Diagn. Cytopathol. 8, 522-527 (1992).
167. Stevens, M. W., Leong, A. S., Fazzalari, N. L., Dowling, K. D. & Henderson, D. W. Cytopathology of malignant mesothelioma: a stepwise logistic regression analysis. Diagn. Cytopathol. 8, 333-341 (1992).
168. Abati, A., Cajigas, A. & Hijazi, Y. M. Metastatic epithelioid hemangioendothelioma in a pleural effusion: diagnosis by cytology. Diagn. Cytopathol. 11, 64-67 (1994).
169. Nakajima, T. et al. Multivariate statistical analysis of bile cytology. Acta Cytol. 38, 51-55 (1994).
170. Kojima, S., Sekine, H., Fukui, I. & Ohshima, H. Clinical significance of "cannibalism" in urinary cytology of bladder cancer. Acta Cytol. 42, 1365-1369 (1998).
171. Yokoo, H. et al. Retroperitoneal epithelioid angiomyolipoma leading to fatal outcome. Pathol. Int. 50, 649-654 (2000).
172. Kumar, P. V., Hosseinzadeh, M. & Bedayat, G. R. Cytologic findings of medulloblastoma in crush smears. Acta Cytol. 45, 542-546 (2001).
173. Demir, M. A., Ryd, W., Aldenborg, F. & Holmang, S. Cytopathological expression of different types of urothelial carcinoma in situ in urinary bladder washings. BJU Int. 92, 906-910 (2003).
174. Gupta, K. & Dey, P. Cell cannibalism: diagnostic marker of malignancy. Diagn. Cytopathol. 28, 86-87 (2003).
175. Lugini, L. et al. Potent phagocytic activity discriminates metastatic and primary human malignant melanomas: a key role of ezrin. Lab. Invest. 83, 1555-1567 (2003).
176. Ng, W. K. et al. Thin-layer cytology findings of small cell carcinoma of the lower female genital tract. Review of three cases with molecular analysis. Acta Cytol. 47, 56-64 (2003).
177. Gu, M., Ghafari, S. & Lin, F. Pap smears of patients with extramammary Paget's disease of the vulva. Diagn. Cytopathol. 32, 353-357 (2005).
178. Ylagan, L. R. & Zhai, J. The value of ThinPrep and cytospin preparation in pleural effusion cytological diagnosis of mesothelioma and adenocarcinoma. Diagn. Cytopathol. 32, 137-144 (2005).
179. Abodief, W. T., Dey, P. & Al-Hattab, O. Cell cannibalism in ductal carcinoma of breast. Cytopathology 17, 304-305 (2006).
180. Hattori, M. et al. Cell cannibalism and nucleus-fragmented cells in voided urine: useful parameters for cytologic diagnosis of low-grade urothelial carcinoma. Acta Cytol. 51, 547-551 (2007).