Abstract
Cell-in-cell structures are reported in numerous cancers, and their presence is an indicator for poor prognosis. Mechanistic studies have identified how cancer cells manage to ingest whole neighbouring cells to form such structures, and the consequences of cell-in-cell formation on cancer progression have been elucidated. In this Opinion article, we discuss how two related cell-in-cell processes, cell cannibalism and entosis, are regulated and how these mechanisms promote cancer progression. We propose that cannibalistic activity is a hallmark of cancer that results in part from selection by metabolic stress and serves to feed aggressive cancer cells.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Steinhaus, J. Ueber carcinoma-einschlusse. Virchows Arch. 126, 533–535 (1891).
Stroebe, H. Zur Kenntniss verschiedener cellularer Vorgange und Erscheinungen in Geschwulsten. Beitrage Pathol. 11, 1 (1892).
Bauchwitz, M. The bird’s eye cell: cannibalism or abnormal division of tumor cells. Acta Cytol. 25, 92 (1981).
Overholtzer, M. & Brugge, J. S. The cell biology of cell-in-cell structures. Nat. Rev. Mol. Cell Biol. 9, 796–809 (2008).
Fais, S. Cannibalism: a way to feed on metastatic tumors. Cancer Lett. 258, 155–164 (2007).
Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).
Lugini, L. et al. Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res. 66, 3629–3638 (2006).
Cano, C. E. et al. Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer. EMBO Mol. Med. 4, 964–979 (2012).
Brown, G. C. & Neher, J. J. Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’. Trends Biochem. Sci. 37, 325–332 (2012).
Benseler, V. et al. Hepatocyte entry leads to degradation of autoreactive CD8 T cells. Proc. Natl Acad. Sci. USA 108, 16735–16740 (2011).
Wang, S. et al. Rapid reuptake of granzyme B leads to emperitosis: an apoptotic cell-in-cell death of immune killer cells inside tumor cells. Cell Death Dis. 4, e856 (2013).
Underhill, D. M., Gordon, S., Imhof, B. A., Nunez, G. & Bousso, P. Elie Metchnikoff (1845–1916): celebrating 100 years of cellular immunology and beyond. Nat. Rev. Immunol. 16, 651–656 (2016).
Finicle, B. T., Jayashankar, V. & Edinger, A. L. Nutrient scavenging in cancer. Nat. Rev. Cancer https://doi.org/10.1038/s41568-018-0048-x (2018).
Palm, W. & Thompson, C. B. Nutrient acquisition strategies of mammalian cells. Nature 546, 234–242 (2017).
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).
Bartosh, T. J., Ullah, M., Zeitouni, S., Beaver, J. & Prockop, D. J. Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). Proc. Natl Acad. Sci. USA 113, E6447–E6456 (2016).
Cornillon, S. et al. Phg1p is a nine-transmembrane protein superfamily member involved in dictyostelium adhesion and phagocytosis. J. Biol. Chem. 275, 34287–34292 (2000).
Fais, S. & Fauvarque, M. O. TM9 and cannibalism: how to learn more about cancer by studying amoebae and invertebrates. Trends Mol. Med. 18, 4–5 (2012).
Bergeret, E. et al. TM9SF4 is required for Drosophila cellular immunity via cell adhesion and phagocytosis. J. Cell Sci. 121, 3325–3334 (2008).
Chang, H. et al. Identification of genes associated with chemosensitivity to SAHA/taxane combination treatment in taxane-resistant breast cancer cells. Breast Cancer Res. Treat. 125, 55–63 (2011).
Oo, H. Z. et al. Identification of novel transmembrane proteins in scirrhous-type gastric cancer by the Escherichia coli ampicillin secretion trap (CAST) method: TM9SF3 participates in tumor invasion and serves as a prognostic factor. Pathobiology 81, 138–148 (2014).
Mackinnon, R. N. et al. The paradox of 20q11.21 amplification in a subset of cases of myeloid malignancy with chromosome 20 deletion. Genes Chromosomes Cancer 49, 998–1013 (2010).
Lozupone, F. et al. The human homologue of Dictyostelium discoideum phg1A is expressed by human metastatic melanoma cells. EMBO Rep. 10, 1348–1354 (2009).
Le Coadic, M. et al. Phg1/TM9 proteins control intracellular killing of bacteria by determining cellular levels of the Kil1 sulfotransferase in Dictyostelium. PLOS ONE 8, e53259 (2013).
Perrin, J. et al. The nonaspanins TM9SF2 and TM9SF4 regulate the plasma membrane localization and signalling activity of the peptidoglycan recognition protein PGRP-LC in Drosophila. J. Innate Immun. 7, 37–46 (2015).
Lozupone, F. et al. TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells. Oncogene 34, 5163–5174 (2015).
Fais, S., Venturi, G. & Gatenby, B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev. 33, 1095–1108 (2014).
Schwartz, L., Seyfried, T., Alfarouk, K. O., Da Veiga Moreira, J. & Fais, S. Out of Warburg effect: an effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin. Cancer Biol. 43, 134–138 (2017).
Sun, Q. et al. Competition between human cells by entosis. Cell Res. 24, 1299–1310 (2014).
Sun, Q., Cibas, E. S., Huang, H., Hodgson, L. & Overholtzer, M. Induction of entosis by epithelial cadherin expression. Cell Res. 24, 1288–1298 (2014).
Purvanov, V., Holst, M., Khan, J., Baarlink, C. & Grosse, R. G-Protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion. eLife https://doi.org/10.7554/eLife.02786 (2014).
Hinojosa, L. S., Holst, M., Baarlink, C. & Grosse, R. MRTF transcription and Ezrin-dependent plasma membrane blebbing are required for entotic invasion. J. Cell Biol. 216, 3087–3095 (2017).
Durgan, J. et al. Mitosis can drive cell cannibalism through entosis. eLife 6, e27134 (2017).
Ruan, B. et al. Cholesterol inhibits entotic cell-in-cell formation and actomyosin contraction. Biochem. Biophys. Res. Commun. 495, 1440–1446 (2018).
Wan, Q. et al. Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment. Mol. Biol. Cell 23, 2076–2091 (2012).
Hamann, J. C. et al. Entosis is induced by glucose starvation. Cell Rep. 20, 201–210 (2017).
Xia, P. et al. Aurora A orchestrates entosis by regulating a dynamic MCAK-TIP150 interaction. J. Mol. Cell. Biol. 6, 240–254 (2014).
Florey, O., Kim, S. E., Sandoval, C. P., Haynes, C. M. & Overholtzer, M. Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes. Nat. Cell Biol. 13, 1335–1343 (2011).
Ishikawa, F., Ushida, K., Mori, K. & Shibanuma, M. Loss of anchorage primarily induces non-apoptotic cell death in a human mammary epithelial cell line under atypical focal adhesion kinase signaling. Cell Death Dis. 6, e1619 (2015).
Diaz, B. & Moreno, E. The competitive nature of cells. Exp. Cell Res. 306, 317–322 (2005).
Claveria, C. & Torres, M. Cell competition: mechanisms and physiological roles. Annu. Rev. Cell Dev. Biol. 32, 411–439 (2016).
Merino, M. M., Levayer, R. & Moreno, E. Survival of the fittest: essential roles of cell competition in development, aging, and cancer. Trends Cell Biol. 26, 776–788 (2016).
Sun, Q., Huang, H. & Overholtzer, M. Cell-in-cell structures are involved in the competition between cells in human tumors. Mol. Cell. Oncol. 2, e1002707 (2015).
Huang, H., Chen, Z. & Sun, Q. Mammalian cell competitions, cell-in-cell phenomena and their biomedical implications. Curr. Mol. Med. 15, 852–860 (2015).
Patel, M. S., Shah, H. S. & Shrivastava, N. c-Myc-dependent cell competition in human cancer cells. J. Cell. Biochem. 118, 1782–1791 (2017).
Mackay, H. L. et al. Genomic instability in mutant p53 cancer cells upon entotic engulfment. Nat. Commun. 9, 3070 (2018).
Hamann, J. C. & Overholtzer, M. Entosis enables a population response to starvation. Oncotarget 8, 57934–57935 (2017).
Krajcovic, M., Krishna, S., Akkari, L., Joyce, J. A. & Overholtzer, M. mTOR regulates phagosome and entotic vacuole fission. Mol. Biol. Cell 24, 3736–3745 (2013).
Loike, J. D., Kozler, V. F. & Silverstein, S. C. Increased ATP and creatine phosphate turnover in phagocytosing mouse peritoneal macrophages. J. Biol. Chem. 254, 9558–9564 (1979).
Mazur, M. T. & Williamson, J. R. Macrophage deformability and phagocytosis. J. Cell Biol. 75, 185–199 (1977).
Kuiper, J. W. et al. Creatine kinase-mediated ATP supply fuels actin-based events in phagocytosis. PLOS Biol. 6, e51 (2008).
Humble, J. G., Jayne, W. H. & Pulvertaft, R. J. Biological interaction between lymphocytes and other cells. Br. J. Haematol. 2, 283–294 (1956).
Salvesen, G. S. Dying from within: granzyme B converts entosis to emperitosis. Cell Death Differ. 21, 3–4 (2014).
Chao, M. P., Weissman, I. L. & Majeti, R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr. Opin. Immunol. 24, 225–232 (2012).
Bansal, C., Tiwari, V., Singh, U., Srivastava, A. & Misra, J. Cell cannibalism: a cytological study in effusion samples. J. Cytol. 28, 57–60 (2011).
Gupta, K. & Dey, P. Cell cannibalism: diagnostic marker of malignancy. Diagn. Cytopathol. 28, 86–87 (2003).
Schwegler, M. et al. Prognostic value of homotypic cell internalization by nonprofessional phagocytic cancer cells. Biomed Res. Int. 2015, 359392 (2015).
Schenker, H., Buttner-Herold, M., Fietkau, R. & Distel, L. V. Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas. Radiat. Oncol. 12, 21 (2017).
Wang, S. et al. Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death. Cell Res. 19, 1350–1362 (2009).
Wang, X. Cell-in-cell phenomenon: a new paradigm in life sciences. Curr. Mol. Med. 15, 810–818 (2015).
Wang, M. et al. Impaired formation of homotypic cell-in-cell structures in human tumor cells lacking alpha-catenin expression. Sci. Rep. 5, 12223 (2015).
Abreu, M. & Sealy, L. Cells expressing the C/EBPbeta isoform, LIP, engulf their neighbors. PLOS ONE 7, e41807 (2012).
Balvan, J. et al. Oxidative stress resistance in metastatic prostate cancer: renewal by self-eating. PLOS ONE 10, e0145016 (2015).
Martins, I. et al. Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death. Cell Death Dis. 9, 716 (2018).
Liang, J. et al. CDKN2A inhibits formation of homotypic cell-in-cell structures. Oncogenesis 7, 50 (2018).
Ruan, B. et al. Expression profiling identified IL-8 as a regulator of homotypic cell-in-cell formation. BMB Rep. 51, 412–417 (2018).
Ibrahim-Hashim, A. et al. Defining cancer subpopulations by adaptive strategies rather than molecular properties provides novel insights into intratumoral evolution. Cancer Res. 77, 2242–2254 (2017).
Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat. Commun. 8, 1816 (2017).
Krajcovic, M. et al. A non-genetic route to aneuploidy in human cancers. Nat. Cell Biol. 13, 324–330 (2011).
Chen, Y. H. et al. Prevalence of heterotypic tumor/immune cell-in-cell structure in vitro and in vivo leading to formation of aneuploidy. PLOS ONE 8, e59418 (2013).
Kim, S. E. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat. Nanotechnol. 11, 977–985 (2016).
Zhao, H. et al. The key role of extracellular vesicles in the metastatic process. Biochim. Biophys. Acta 1869, 64–77 (2018).
Federici, C. et al. Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLOS ONE 9, e88193 (2014).
Iessi, E. et al. Acridine Orange/exosomes increase the delivery and the effectiveness of Acridine Orange in human melanoma cells: a new prototype for theranostics of tumors. J. Enzyme Inhib. Med. Chem. 32, 648–657 (2017).
Chao, K. C., Yang, H. T. & Chen, M. W. Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization. J. Cell. Mol. Med. 16, 1803–1815 (2012).
Onishi, T. et al. Tumor-specific delivery of biologics by a novel T cell line HOZOT. Sci. Rep. 6, 38060 (2016).
Sharma, N. & Dey, P. Cell cannibalism and cancer. Diagn. Cytopathol. 39, 229–233 (2011).
Singhal, N., Handa, U., Bansal, C. & Mohan, H. Neutrophil phagocytosis by tumor cells — a cytological study. Diagn. Cytopathol. 39, 553–555 (2011).
Singh, G., Mathur, S. R., Iyer, V. K. & Jain, D. Cytopathology of neoplastic meningitis: a series of 66 cases from a tertiary care center. Cytojournal 10, 13 (2013).
Ferreira, F. C. et al. Four cases of cell cannibalism in highly malignant feline and canine tumors. Diagn. Pathol. 10, 199 (2015).
Kale, A. Cellular cannibalism. J. Oral Maxillofac. Pathol. 19, 7–9 (2015).
Huang, H. et al. Detecting cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 triple staining. Oncotarget 6, 20278–20287 (2015).
Melendez-Lazo, A. et al. Cell cannibalism by malignant neoplastic cells: three cases in dogs and a literature review. Vet. Clin. Pathol. 44, 287–294 (2015).
Morales-Camacho, R. M. et al. Leukaemic blast cannibalism in acute megakaryoblastic leukaemia with myeloid sarcoma. Br. J. Haematol. 173, 336 (2016).
Jeon, Y. K., Kim, H. W., Choi, H. J. & Park, I. A. Fine needle aspiration cytology of epithelioid angiosarcoma. Report of a case with nuclear grooves and indentations. Acta Cytol. 48, 223–228 (2004).
Fujii, M. et al. Cytologic diagnosis of male breast cancer with nipple discharge. A case report. Acta Cytol. 30, 21–24 (1986).
Abodief, W. T., Dey, P. & Al-Hattab, O. Cell cannibalism in ductal carcinoma of breast. Cytopathology 17, 304–305 (2006).
Almeida, S. M. & Rotta, I. Cerebrospinal fluid cell cannibalism in metastatic breast adenocarcinoma. Arq. Neuropsiquiatr. 73, 469 (2015).
Kinoshita, M. et al. Cytological diagnostic clues in poorly differentiated squamous cell carcinomas of the breast: streaming arrangement, necrotic background, nucleolar enlargement and cannibalism of cancer cells. Cytopathology 29, 22–27 (2018).
Nakajima, T. et al. Multivariate statistical analysis of bile cytology. Acta Cytol. 38, 51–55 (1994).
Sarode, S. C. & Sarode, G. S. Cellular cannibalism in central and peripheral giant cell granuloma of the oral cavity can predict biological behavior of the lesion. J. Oral Pathol. Med. 43, 459–463 (2014).
Azzi, L. et al. A giant-cell lesion with cellular cannibalism in the mandible: case report and review of brown tumors in hyperparathyroidism. Case Rep. Dent. 2017, 9604570 (2017).
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).
Gamez, R. G., Jessurun, J., Berger, M. J. & Pambuccian, S. E. Cytology of metastatic cervical squamous cell carcinoma in pleural fluid: report of a case confirmed by human papillomavirus typing. Diagn. Cytopathol. 37, 381–387 (2009).
AbdullGaffar, B. Clear cell carcinoma first suspected in Pap smear. The value of neutrophil cannibalism by tumor cells. Diagn. Cytopathol. 45, 176–178 (2017).
Kalele, K. P., Patil, K. P., Nayyar, A. S. & Sasane, R. S. Atypical lymphocytes and cellular cannibalism: a phenomenon, first of its kind to be discovered in chronic periapical lesions. J. Clin. Diagn. Res. 10, ZC01–4 (2016).
Caruso, R. A., Famulari, C., Giuffre, G. & Mazzeo, G. Pleomorphic carcinoma of the gallbladder: report of a case. Tumori 77, 523–526 (1991).
Caruso, R. A., Muda, A. O., Bersiga, A., Rigoli, L. & Inferrera, C. Morphological evidence of neutrophil-tumor cell phagocytosis (cannibalism) in human gastric adenocarcinomas. Ultrastruct. Pathol. 26, 315–321 (2002).
Caruso, R. A. et al. Neutrophil-rich gastric carcinomas: light and electron microscopic study of 9 cases with particular reference to neutrophil apoptosis. Ultrastruct. Pathol. 37, 164–170 (2013).
Barresi, V. et al. Phagocytosis (cannibalism) of apoptotic neutrophils by tumor cells in gastric micropapillary carcinomas. World J. Gastroenterol. 21, 5548–5554 (2015).
Sarode, G. S. et al. Cellular cannibalism in giant cells of central giant cell granuloma of jaw bones and giant cell tumors of long bones. J. Investig. Clin. Dent. 8, e12214 (2017).
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).
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).
Conway, A. B., Hart, M. K., Jessurun, J. & Pambuccian, S. E. “Cannonballs” and psammoma bodies: unusual cytologic features of metastatic pulmonary small-cell carcinoma in a pleural effusion. Diagn. Cytopathol. 41, 247–252 (2013).
Escamilla, V. et al. Bone marrow cellular cannibalism by medulloblastoma. Am. J. Hematol. 90, 466–467 (2015).
Beaty, M. W., Fetsch, P., Wilder, A. M., Marincola, F. & Abati, A. Effusion cytology of malignant melanoma. A morphologic and immunocytochemical analysis including application of the MART-1 antibody. Cancer 81, 57–63 (1997).
Ehya, H. The cytologic diagnosis of mesothelioma. Semin. Diagn. Pathol. 3, 196–203 (1986).
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).
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).
Kimura, N., Dota, K., Araya, Y., Ishidate, T. & Ishizaka, M. Scoring system for differential diagnosis of malignant mesothelioma and reactive mesothelial cells on cytology specimens. Diagn. Cytopathol. 37, 885–890 (2009).
Cakir, E., Demirag, F., Aydin, M. & Unsal, E. Cytopathologic differential diagnosis of malignant mesothelioma, adenocarcinoma and reactive mesothelial cells: a logistic regression analysis. Diagn. Cytopathol. 37, 4–10 (2009).
Matsumoto, S. et al. Morphology of 9p21 homozygous deletion-positive pleural mesothelioma cells analyzed using fluorescence in situ hybridization and virtual microscope system in effusion cytology. Cancer Cytopathol. 121, 415–422 (2013).
Abati, A., Cajigas, A. & Hijazi, Y. M. Metastatic epithelioid hemangioendothelioma in a pleural effusion: diagnosis by cytology. Diagn. Cytopathol. 11, 64–67 (1994).
Sarode, G. S., Sarode, S. C. & Karmarkar, S. Complex cannibalism: an unusual finding in oral squamous cell carcinoma. Oral Oncol. 48, e4–e6 (2012).
Sarode, S. C. & Sarode, G. S. Neutrophil-tumor cell cannibalism in oral squamous cell carcinoma. J. Oral Pathol. Med. 43, 454–458 (2014).
Jose, D. et al. Evaluation of cannibalistic cells: a novel entity in prediction of aggressive nature of oral squamous cell carcinoma. Acta Odontol. Scand. 72, 418–423 (2014).
Jain, M. An overview on “cellular cannibalism” with special reference to oral squamous cell carcinoma. Exp. Oncol. 37, 242–245 (2015).
Jain, M. et al. Assessment of tumor cell cannibalism as a predictor of oral squamous cell carcinoma — a histopathologic correlation. Gulf J. Oncolog. 1, 52–56 (2017).
Sarode, S. C., Sarode, G. S., Chuodhari, S. & Patil, S. Non-cannibalistic tumor cells of oral squamous cell carcinoma can express phagocytic markers. J. Oral Pathol. Med. 46, 327–331 (2017).
Kosaka, N. et al. Cytological findings of ascitic fluid with a malignant ovarian steroid cell tumor: a case report and literature review. Acta Cytol. 61, 165–171 (2017).
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).
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).
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).
Khayyata, S., Basturk, O. & Adsay, N. V. Invasive micropapillary carcinomas of the ampullo-pancreatobiliary region and their association with tumor-infiltrating neutrophils. Mod. Pathol. 18, 1504–1511 (2005).
Wen, S., Shang, Z., Zhu, S., Chang, C. & Niu, Y. Androgen receptor enhances entosis, a non-apoptotic cell death, through modulation of Rho/ROCK pathway in prostate cancer cells. Prostate 73, 1306–1315 (2013).
Gilloteaux, J., Ruffo, C., Jamison, J. M. & Summers, J. L. Modes of internalizations of human prostate carcinoma (DU145) cells in vitro and in murine xenotransplants. Ultrastruct. Pathol. 40, 231–239 (2016).
Kong, Y., Liang, Y. & Wang, J. Foci of entotic nuclei in different grades of noninherited renal cell cancers. IUBMB Life 67, 139–144 (2015).
Arya, P., Khalbuss, W. E., Monaco, S. E. & Pantanowitz, L. Salivary duct carcinoma with striking neutrophil-tumor cell cannibalism. Cytojournal 8, 15 (2011).
Fernandez-Flores, A. Cannibalism in a benign soft tissue tumor (giant-cell tumor of the tendon sheath, localized type): a study of 66 cases. Rom. J. Morphol. Embryol. 53, 15–22 (2012).
Huang, C. C. & Michael, C. W. Cytomorphological features of metastatic squamous cell carcinoma in serous effusions. Cytopathology 25, 112–119 (2014).
Logothetou-Rella, H. Glycosaminoglycan-sac formation in vitro. Interactions between normal and malignant cells. Histol. Histopathol. 9, 243–249 (1994).
Kojima, S., Sekine, H., Fukui, I. & Ohshima, H. Clinical significance of “cannibalism” in urinary cytology of bladder cancer. Acta Cytol. 42, 1365–1369 (1998).
Dey, P., Amir, T., Jogai, S. & Al Jussar, A. Fine-needle aspiration cytology of metastatic transitional cell carcinoma. Diagn. Cytopathol. 32, 226–228 (2005).
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).
Ohsaki, H. et al. Can cytological features differentiate reactive renal tubular cells from low-grade urothelial carcinoma cells? Cytopathology 21, 326–333 (2010).
Ahmed Wani, F. & Bhardwaj, S. Cytological evaluation and significance of cell cannibalism in effusions and urine cytology. Malays. J. Pathol. 37, 265–270 (2015).
Acknowledgements
This work was supported by grants from the Ministry of Health, Italy (S.F.) and the US National Institutes of Health (CA154649; M.O.). The authors included many different examples of published reports of cell-in-cell activity in cancer in Box 1 of this review to show the breadth of this activity; the authors apologize to those whose work was not included owing to space limitations.
Reviewer information
Nature Reviews Cancer thanks E. Moreno, M. Olson and A. Thorburn for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
Both authors contributed equally to this work.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Cannibalism
-
The engulfment of live or dead cells or debris by cancer cells as described in metastatic melanoma; also used frequently as a general term for engulfment.
- Cell-in-cell
-
A general term used to describe the appearance of whole, typically live, cells ingested into other cells.
- Emperipolesis
-
A general term that describes the uptake of live cells and their movement inside host cells. Suicidal emperipolesis is the mechanism of invasion of live T cells into hepatocytes.
- Emperitosis
-
A mechanism resembling entosis and involving natural killer cells that invade into cancer cells and die by granzyme B-mediated cell death.
- Entosis
-
The uptake of live cells into other cells through an invasive mechanism; entosis typically involves cell–cell adhesion proteins and actomyosin-mediated contraction within invading cells regulated by RHO GTPases and RHO-associated coiled-coil-containing protein kinase (ROCK).
- Homotypic cell cannibalism
-
A term describing a homotypic engulfment mechanism suggested to involve pancreatic cancer cells.
- Phagocytosis
-
The engulfment of dying or dead cells or microorganisms through receptor-mediated mechanisms.
- Phagoptosis
-
The uptake and killing of live cells through phagocytosis.
Rights and permissions
About this article
Cite this article
Fais, S., Overholtzer, M. Cell-in-cell phenomena in cancer. Nat Rev Cancer 18, 758–766 (2018). https://doi.org/10.1038/s41568-018-0073-9
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41568-018-0073-9
This article is cited by
-
Non-mitotic proliferation of malignant cancer cells revealed through live-cell imaging of primary and cell-line cultures
Cell Division (2024)
-
Entosis: the core mechanism and crosstalk with other cell death programs
Experimental & Molecular Medicine (2024)
-
Mechanisms and significance of entosis for tumour growth and progression
Cell Death Discovery (2024)
-
Cell-in-cell phenomena across the tree of life
Scientific Reports (2024)
-
Tumor malignancy by genetic transfer between cells forming cell-in-cell structures
Cell Death & Disease (2023)