High Frequency of Cell-in-Cell Formation in Heterogeneous Human Breast Cancer Tissue in a Patient With Poor Prognosis: A Case Report and Literature Review

Banzhan Ruan, Zubiao Niu, Xiaoyi Jiang, Zhuo Li, Yanhong Tai, Hongyan Huang, Qiang Sun, Banzhan Ruan, Zubiao Niu, Xiaoyi Jiang, Zhuo Li, Yanhong Tai, Hongyan Huang, Qiang Sun

Abstract

Cell cannibalism is a unique pathological phenomenon that has been observed at low frequency in a variety of human tumor samples (<0.5%), including breast cancer. Cannibalistic cells typically form cell-in-cell (CIC) structures characterized by enclosure of one cell or more by another, mediating a novel type of cell death "entosis," which was proposed as the type IV cell death. A large number of CIC structures are generally associated with malignant transformation and progression, and they are believed to be primed by and form among heterogeneous cells. However, there is currently no in vivo evidence from human tumor samples. In this case report, covering a 37-year-old female breast cancer patient, we observed considerable heterogeneity and proliferative activity (>70% Ki-67 positivity) in her breast cancer cells, accompanied by high frequency of CIC formation (~6%) and poor prognosis. We consider this a typical example of cell cannibalism, supporting a role of heterogeneity in cell-in-cell formation and malignant progression. It may serve as a pretest basis for further investigations of cell-in-cell biology and breast cancer treatment.

Keywords: breast cancer; cell cannibalism; cell-in-cell formation; entosis; heterogeneity; poor prognosis.

Copyright © 2019 Ruan, Niu, Jiang, Li, Tai, Huang and Sun.

Figures

Figure 1
Figure 1
Extensive CIC formation in heterogeneous cancer tissue. (A) Representative image for HER-2 staining. Inner cells of CIC structures are indicated with red asterisks. Scale bar: 100 μm. (B) Representative image for a typical CIC depicted with E-cadherin staining. Inserted picture of the top merged image is a schematic cartoon for the indicated CIC structure. Scale bar: 20 μm. (C,D) Histogram plots of cell size (C) and cell circularity (D) for (A).
Figure 2
Figure 2
Images of Ki-67 staining indicating active cell division. (A) representative image for breast cancer tissue with Ki-67 staining. (B–F) zoomed in images for boxed regions in (A). The scale bars are 400 and 100 μm, respectively.
Figure 3
Figure 3
Complex morphologies of CIC structures. (A) One cell was internalized. (B) abnormal nucleus of the outer cell. (C) Two cells were internalized, and the nucleus of one of them was missing. (D) The cell enclosing two cells was inside of another cell (yellow arrow) without nucleus. (E) Two cells were internalized, and the nucleus of the outer cell was deformed. (F) Sequential internalization of three cells. Inserted pictures are schematic cartoons for the indicated CIC structures, respectively. Scale bar: 20 μm.

References

    1. Huang H, Chen A, Wang T, Wang M, Ning X, He M, et al. . Detecting cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 triple staining. Oncotarget. (2015) 6:20278–87. 10.18632/oncotarget.4275
    1. Gupta K, Dey P. Cell cannibalism: diagnostic marker of malignancy. Diag Cytopathol. (2003) 28:86–7. 10.1002/dc.10234
    1. Zhang X, Niu Z, Qin H, Fan J, Wang M, Zhang B, et al. . Subtype-based prognostic analysis of cell-in-cell structures in early breast cancer. Front Oncol. (2019) 9:895. 10.3389/fonc.2019.00895
    1. Ferreira FC, Soares MJ, Carvalho S, Borralho L, Vicente G, Branco S, et al. . Four cases of cell cannibalism in highly malignant feline and canine tumors. Diag Pathol. (2015) 10:199. 10.1186/s13000-015-0429-3
    1. Fais S, Overholtzer M. Cell-in-cell phenomena in cancer. Nat Rev Cancer. (2018) 18:758–66. 10.1038/s41568-018-0073-9
    1. Huang H, Chen Z, Sun Q. Mammalian cell competitions, cell-in-cell phenomena and their biomedical implications. Curr Mol Med. (2015) 15:852–60. 10.2174/1566524015666151026101101
    1. Martins I, Raza SQ, Voisin L, Dakhli H, Law F, De Jong D, et al. . Entosis: The emerging face of non-cell-autonomous type IV programmed death. Biomed J. (2017) 40:133–40. 10.1016/j.bj.2017.05.001
    1. Sun Q, Cibas ES, Huang H, Hodgson L, Overholtzer M. Induction of entosis by epithelial cadherin expression. Cell Res. (2014) 24:1288–98. 10.1038/cr.2014.137
    1. Wang M, Ning X, Chen A, Huang H, Ni C, Zhou C, et al. . Impaired formation of homotypic cell-in-cell structures in human tumor cells lacking alpha-catenin expression. Sci Rep. (2015) 5:12223. 10.1038/srep12223
    1. Liang J, Fan J, Wang M, Niu Z, Zhang Z, Yuan L, et al. . CDKN2A inhibits formation of homotypic cell-in-cell structures. Oncogenesis. (2018) 7:1–8. 10.1038/s41389-018-0056-4
    1. Mackay HL, Muller PAJ. Biological relevance of cell-in-cell in cancers. Biochem Soc Trans. (2019) 47:725–32. 10.1042/BST20180618
    1. Sun Q, Luo T, Ren Y, Florey O, Shirasawa S, Sasazuki T, et al. . Competition between human cells by entosis. Cell Res. (2014) 24:1299–310. 10.1038/cr.2014.138
    1. Mackay HL, Moore D, Hall C, Birkbak NJ, Jamal-Hanjani M, Karim SA, et al. Genomic instability in mutant p53 cancer cells upon entotic engulfment. Nat Commun. (2018) 9:3070 10.1038/s41467-018-05368-1
    1. Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, et al. . A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell. (2007) 131:966–79. 10.1016/j.cell.2007.10.040
    1. Abodief WT, Dey P, Al-Hattab O. Cell cannibalism in ductal carcinoma of breast. Cytopathology. (2006) 17:304–5. 10.1111/j.1365-2303.2006.00326.x
    1. Krajcovic M, Johnson NB, Sun Q, Normand G, Hoover N, Yao E, et al. . A non-genetic route to aneuploidy in human cancers. Nat Cell Biol. (2011) 13:324–30. 10.1038/ncb2174
    1. Kroemer G, Perfettini JL. Entosis, a key player in cancer cell competition. Cell Res. (2014) 24:1280–1. 10.1038/cr.2014.133
    1. Sun Q, Huang H, Overholtzer M. Cell-in-cell structures are involved in the competition between cells in human tumors. Mol Cell Oncol. (2015) 2:e1002707. 10.1080/23723556.2014.1002707
    1. Ning X, Luo T, Chen Z, Sun Q. The physics for the formation of cell-in-cell structures. Curr Mol Med. (2015) 15:867–72. 10.2174/1566524015666151026105123
    1. Ruan B, Zhang B, Chen A, Yuan L, Liang J, Wang M, et al. . Cholesterol inhibits entotic cell-in-cell formation and actomyosin contraction. Biochem Biophys Res Commun. (2018) 495:1440–6. 10.1016/j.bbrc.2017.11.197
    1. Ruan B, Wang C, Chen A, Liang J, Niu Z, Zheng Y, et al. . Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation. BMB Rep. (2018) 51:412–7. 10.5483/BMBRep.2018.51.8.089
    1. Durgan J, Tseng YY, Hamann JC, Domart MC, Collinson L, Hall A, et al. . Mitosis can drive cell cannibalism through entosis. eLife. (2017) 6:1–26. 10.7554/eLife.27134.031
    1. Fujii M, Ishii Y, Wakabayashi T, Itoyanagi N, Hagiwara K, Saito M, et al. . Cytologic diagnosis of male breast cancer with nipple discharge. A case report. Acta Cytol. (1986) 30:21–4.
    1. Almeida SM, Rotta I. Cerebrospinal fluid cell cannibalism in metastatic breast adenocarcinoma. Arquivos Neuro-psiquiatr. (2015) 73:469. 10.1590/0004-282X20150028
    1. Kinoshita M, Matsuda Y, Arai T, Soejima Y, Sawabe M, Honma N. Cytological diagnostic clues in poorly differentiated squamous cell carcinomas of the breast: Streaming arrangement, necrotic background, nucleolar enlargement and cannibalism of cancer cells. Cytopathology. (2018) 29:22–7. 10.1111/cyt.12461
    1. Ruan B, Niu Z, Jiang X, Li Z, Tai Y, Huang H, et al. High frequency of cell-in-cell formation in heterogeneous human breast cancer tissue in a patient with poor prognosis: a case report and literature review. Front Oncol. (2019) 9:1444 10.3389/fonc.2019.01444
    1. 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. (1980) 24:522–8.

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