title: Prevalence of heterotypic tumor/immune cell-in-cell structure in vitro and in vivo leading to formation of aneuploidy.
abstract: Cell-in-cell structures refer to a unique phenomenon that one living cell enters into another living cell intactly, occurring between homotypic tumor cells or tumor (or other tissue cells) and immune cells (named as heterotypic cell-in-cell structure). In the present study, through a large scale of survey we observed that heterotypic cell-in-cell structure formation occurred commonly in vitro with host cells derived from different human carcinomas as well as xenotypic mouse tumor cell lines. Most of the lineages of human immune cells, including T, B, NK cells, monocytes as well as in vitro activated LAK cells, were able to invade tumor cell lines. Poorly differentiated stem cells were capable of internalizing immune cells as well. More significantly, heterotypic tumor/immune cell-in-cell structures were observed in a higher frequency in tumor-derived tissues than those in adjacent tissues. In mouse hepatitis models, heterotypic immune cell/hepatocyte cell-in-cell structures were also formed in a higher frequency than in normal controls. After in vitro culture, different forms of internalized immune cells in heterotypic cell-in-cell structures were observed, with one or multiple immune cells inside host cells undergoing resting, degradation or mitosis. More strikingly, some internalized immune cells penetrated directly into the nucleus of target cells. Multinuclear cells with aneuploid nucleus were formed in target tumor cells after internalizing immune cells as well as in situ tumor regions. Therefore, with the prevalence of heterotypic cell-in-cell structures observed, we suggest that shielding of immune cells inside tumor or inflammatory tissue cells implies the formation of aneuploidy with the increased multinucleation as well as fine-tuning of microenvironment under pathological status, which may define distinct mechanisms to influence the etiology and progress of tumors.
authors.affiliation: The State Key Laboratory of Kidney, Beijing/Provincial Key Laboratory of Biotechnology, Institute of Life Sciences, Chinese PLA General Hospital and SCUT, Guangzhou, China.
authors.forename: Yu-hui
authors.initials: YH
authors.lastname: Chen
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.forename: Mei-fang
authors.initials: MF
authors.lastname: He
authors.forename: Yanyi
authors.initials: Y
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhao
authors.forename: Han-yu
authors.initials: HY
authors.lastname: Zhu
authors.forename: Xiao-min
authors.initials: XM
authors.lastname: Yu
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Xiao-juan
authors.initials: XJ
authors.lastname: Che
authors.forename: Ju-fang
authors.initials: JF
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiao-ning
authors.initials: XN
authors.lastname: Wang
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002277:Carcinoma / Q000276:immunology / Q000473:pathology*; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology*; D015726:Giant Cells / Q000276:immunology / Q000473:pathology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D051379:Mice; D008938:Mitosis; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured
references.citation: Cancer Res. 2004 Sep 15;64(18):6775-82
references.pmid: 15374996
references.citation: Microbiol Mol Biol Rev. 2001 Sep;65(3):390-403, table of contents
references.pmid: 11528002
references.citation: Annu Rev Immunol. 2003;21:807-39
references.pmid: 12615893
references.citation: Scand J Haematol. 1981 Feb;26(2):91-6
references.pmid: 6942488
references.citation: Acta Cytol. 2002 Sep-Oct;46(5):883-6
references.pmid: 12365224
references.citation: Trends Immunol. 2002 Nov;23(11):549-55
references.pmid: 12401408
references.citation: J Cell Physiol. 2003 Jun;195(3):346-55
references.pmid: 12704644
references.citation: Cell. 2007 Nov 30;131(5):966-79
references.pmid: 18045538
references.citation: Nature. 2005 Jun 9;435(7043):752-3
references.pmid: 15944689
references.citation: Cell Res. 2009 Dec;19(12):1320-1
references.pmid: 19956185
references.citation: Cell Res. 2009 Dec;19(12):1350-62
references.pmid: 19786985
references.citation: Arch Pathol Lab Med. 2004 Dec;128(12):1435-8
references.pmid: 15578891
references.citation: Expert Opin Biol Ther. 2011 Jul;11(7):893-909
references.pmid: 21449634
references.citation: Melanoma Res. 2001 Jun;11(3):275-81
references.pmid: 11468516
references.citation: Curr Opin Immunol. 2006 Apr;18(2):220-5
references.pmid: 16460921
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16735-40
references.pmid: 21933957
references.citation: Nat Rev Mol Cell Biol. 2008 Oct;9(10):796-809
references.pmid: 18784728
references.citation: Nature. 1980 Jan 24;283(5745):402-4
references.pmid: 6965423
references.citation: Hepatology. 2009 Mar;49(3):940-9
references.pmid: 19177594
references.citation: J Biol Chem. 2006 Jul 7;281(27):18763-73
references.pmid: 16648140
references.citation: Anat Rec (Hoboken). 2012 Mar;295(3):372-7
references.pmid: 22271432
references.citation: J Clin Invest. 1992 Jul;90(1):196-203
references.pmid: 1634608
references.citation: Nature. 2002 Dec 19-26;420(6917):860-7
references.pmid: 12490959
references.citation: Diagn Cytopathol. 2000 Mar;22(3):181-5
references.pmid: 10680000
references.citation: Br J Haematol. 1956 Jul;2(3):283-94
references.pmid: 13342362
references.citation: Trends Immunol. 2012 Mar;33(3):136-43
references.pmid: 22227317
references.citation: J Mol Cell Biol. 2010 Jun;2(3):139-51
references.pmid: 20348186
references.citation: Nat Cell Biol. 2011 Mar;13(3):324-30
references.pmid: 21336303