Abstract
The causes of metastasis remain unknown, however it has been proposed for nearly a century that metastatic cells are generated by fusion of tumor cells with tumor-associated leukocytes such as macrophages. Indeed, regardless of cell or tissue origin, when cancer cells in the original in situ tumor transform to malignant, invasive cells, they generally become aneuploid and begin to express molecules and traits characteristic of activated macrophages. This includes two key features of malignancy: chemotactic motility and the use of aerobic glycolysis as a metabolic energy source (the Warburg effect). Here we review evidence that these phenomena can be well-explained by macrophage-cancer cell fusion, as evidenced by studies of experimental macrophage-melanoma hybrids generated in vitro and spontaneous host-tumor hybrids in animals and more recently humans. A key finding to emerge is that experimental and spontaneous cancer cell hybrids alike displayed a high degree of constitutive autophagy, a macrophage trait that is expressed under hypoxia and nutrient deprivation as part of the Warburg effect. Subsequent surveys of 21 different human cancers from nearly 2,000 cases recently revealed that the vast majority (~85%) exhibited autophagy and that this was associated with tumor proliferation and metastasis. While much work needs to be done, we posit that these findings with human cancers could be a reflection of widespread leukocyte-cancer cell fusion as an initiator of metastasis. Such fusions would generate hybrids that express the macrophage capabilities for motility and survival under adverse conditions of hypoxia and nutrient deprivation, while at the same time maintaining the deregulated mitotic cycle of the cancer cell fusion partner.
References
Aichel O (1911) Über Zellverschmelzung mit Qualitativ Abnormer Chromosomenverteilung als Ursache der Geschwulstbildung. In Roux W (ed) Vorträge und Aufsätze über Entwickelungsmechanik Der Organism, pp. 1–115. Wilhelm Engelmann. Leipzig, Germany, Chapter XIII
Pawelek JM (2000) Tumor cell hybridization and metastasis revisited. Melanoma Res 10:507–514
Pawelek J (2005) Tumor cell fusion as a source of myeloid traits in cancer. Lancet Oncol 6:988–993
Pawelek JM, Chakraborty AK (2008) Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer 8:377–386
Pawelek JM, Chakraborty AK (2008) The cancer cell–leukocyte fusion theory of metastasis. Adv Cancer Res 101:397–444
Chakraborty A, Lazova R, Davies S et al (2004) Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant recipient. Bone Marrow Transplant 34:183–186
Yilmaz Y, Lazova R, Qumsiyeh M et al (2005) Donor Y chromosome in renal carcinoma cells of a female BMT recipient: visualization of putative BMT-tumor hybrids by FISH. Bone Marrow Transplant 35:1021–1024
Andersen TL, Boissy P, Sondergaard TE et al (2007) Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership? J Pathol 211:10–17
Andersen TL, Søe K, Sondergaard TE et al (2010) Myeloma cell-induced disruption of bone remodelling compartments leads to osteolytic lesions and generation of osteoclast-myeloma hybrid cells. Br J Haematol 148:551–561
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51
Lin EY, Nguyen AV, Russell RG et al (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740
Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78
Handerson T, Berger A, Harigopol M et al (2007) Melanophages reside in hypermelanotic, aberrantly glycosylated tumor areas and predict improved outcome in primary CMM. J Cutan Pathol 34:667–738
Mekler LB (1968) A general theory of oncogenesis. Materials of symposia on general immunol. The club of immunologists of NF Gamaleya. Inst of Epidemiol and Microbiol 3:91–100
Mekler LB (1971) Hybridization of transformed cells with lymphocytes as 1 of the probable causes of the progression leading to the development of metastatic malignant cells. Vestn Acad Med Nauk SSR 26:80–89
Goldenberg DM (1968) On the progression of malignity: a hypothesis. Klin Wochenschr 46:898–899
Goldenberg DM, Götz H (1968) On the ‘human’ nature of highly malignant heterotransplantable tumors of human origin. Eur J Cancer 4:547–548
Rachkovsky MS, Sodi S, Chakraborty A et al (1998) Melanoma×macrophage hybrids with enhanced metastatic potential. Clin Exp Metastasis 16:299–312
Sodi SA, Chakraborty AK, Platt JT et al (1998) Melanoma × macrophage fusion hybrids acquire increased melanogenesis and metastatic potential: altered N-glycosylation as an underlying mechanism. Pigment Cell Res 11:299–309
Pawelek JM, Chakraborty AK, Rachkovsky ML et al (2000) Altered N-glycosylation in macrophage×melanoma fusion hybrids. Cell Mol Biol (Noisy-Le-Grand) 45:1011–1027
Chakraborty AK, Funasaka Y, Ichihashi M et al (2009) Upregulation of alpha and beta integrin subunits in metastatic macrophage-melanoma fusion hybrids. Melanoma Res 19:343–349
Rachkovsky M, Pawelek J (1999) Acquired melanocyte stimulating hormone-inducible chemotaxis following macrophage fusion with cloudman S91 melanoma cells. Cell Growth Diff 10:515–524
Roos E, La Rivière G, Collard JG et al (1985) Invasiveness of T-cell hybridomas in vitro and their metastatic potential in vivo. Cancer Res 45:6238–6243
Kerbel RS, Lagarde AE, Dennis JW et al (1983) Spontaneous fusion in vivo between normal host and tumor cells: possible contribution to tumor progression and metastasis studied with a lectin-resistant mutant tumor. Mol Cell Biol 3:523–538
Larizza L, Schirrmacher V, Stöhr M (1984) Inheritance of immunogenicity and metastatic potential in murine cell hybrids from the T-lymphoma ESb08 and normal spleen lymphocytes. J Natl Cancer Inst 72:1371–1381
Larizza L, Schirrmacher V, Graf L et al (1984) Suggestive evidence that the highly metastatic variant ESb of the T-cell lymphoma eb is derived from spontaneous fusion with a host macrophage. Int J Cancer 34:699–707
Robert G, Gaggioli C, Bailet O et al (2006) SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. Cancer Res 66:7516–7523
Alonso SR, Tracey L, Ortiz P et al (2007) A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Cancer Res 67:3450–3460
Reed MJ, Puolakkainen P, Lane TF et al (1993) Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization. J Histochem Cytochem 41:1467–1477
Charest A, Pépin A, Shetty R et al (2006) Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart 92:1844–1849
Chakraborty AK, de Freitas Sousa J, Espreafico EM et al (2001) Human monocyte×mouse melanoma fusion hybrids express human gene. Gene 275:103–106
Handerson T, Pawelek JM (2003) β1,6-Branched oligosaccharides and coarse vesicles: a common and pervasive phenotype in melanoma and other human cancers. Cancer Res 63:5363–5369
Handerson T, Camp R, Harigopal M et al (2005) β1,6-Branched oligosaccharides are associated with metastasis and predict poor outcome in breast carcinoma. Clin Cancer Res 11:2969–2973
Fukuda M, Spooncer E, Oates JE et al (1984) Structure of sialylated fucosyl lactosaminoglycan isolated from human granulocytes. J Biol Chem 25:10925–10935
Sawada R, Lowe JB, Fukuda M (1993) E-selectin-dependent adhesion efficiency of colonic carcinoma cells is increased by genetic manipulation of their cell surface lysosomal membrane glycoprotein-1 expression levels. J Biol Chem 268:12675–12681
Sarafian V, Jadot M, FoidartJ M et al (1998) Expression of lamp-1 and lamp-2 and their interactions with galectin-3 in human tumor cells. Int J Cancer 75:105–111
Chakraborty AK, Pawelek J, Ikeda Y et al (2001) Fusion hybrids with macrophage and melanoma cell up-regulate N-acetylglucosaminyltransferase V, β1-6 branching, and metastasis. Cell Growth Diff 12:623–630
Dennis JW, Waller CA, Schirrmacher V (1984) Identification of asparagine-linked oligosaccharides involved in tumor cell adhesion to laminin and type IV collagen. J Cell Biol 99:1416–1423
Chang MH, Hua CT, Isaac EL et al (2004) Transthyretin interacts with the lysosome-associated membrane protein (LAMP-1) in circulation. Biochem J 382:481–489
Rupani R, Handerson T, Pawelek J (2004) Co-localization of β1,6-branched oligosaccharides and coarse melanin in macrophage-melanoma fusion hybrids and human melanoma cells in vitro. Pigment Cell Res 17:281–288
Chakraborty A, Sodi S, Rachkovsky M et al (2000) A spontaneous murine melanoma lung metastasis comprised of host×tumor hybrids. Cancer Res 60:2512–2519
Warburg O (1930) Ãœber den Stoffwechsel der Tumoren. Constable: London
Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17: 596–603
Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822
Ogata M, Hino S, Saito A et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231
Yorimitsu T, Klionsky DJ (2007) Endoplasmic reticulum stress: a new pathway to induce autophagy. Autophagy 3:160–162
Vander Heiden MG et al (2009) Understanding the warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033
Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23:537–548
Santore MT, McClintock DS, Lee VY et al (2002) Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 282:L727–734
Lee VY, McClintock DS, Santore MT et al (2002) Hypoxia sensitizes cells to nitric oxide-induced apoptosis. J Biol Chem 277:16067–16074
van Loo G, Saelans X, van Gurp M et al (2002) The role of mitochondrial factors in apoptosis: a russian roulette with more than one bullet. Cell Death Differ 10:1031–1042
Roiniotis J, Dinh H, Masendycz P et al (2009) Hypoxia prolongs monocyte/macrophage survival and enhanced glycolysis is associated with their maturation under aerobic conditions. J Immunol 182:7974–7981
Plas DR, Talapatra S, Edlinger AL et al (2001) Akt and bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J Biol Chem 276:12041–12048
Lewis JS, Lee JA, Underwood JC et al (1999) Macrophage responses to hypoxia: relevance to disease mechanisms. J Leukoc Biol 66:889–900
Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899
Czernin J, Phelps ME (2002) Positron emission tomography scanning: current and future applications. Annu Rev Med 53:89–112
Nair-Gill E, Wiltzius SM, Wei XX et al (2010) PET probes for distinct metabolic pathways have different cell specificities during immune responses in mice. J Clin Invest 120:2005–2015
Laing R, Nair-Gill E, Witte ON et al (2010) Visualizing cancer and immune cell function with metabolic positron emission tomography. Curr Opin Genet Dev 20:100–105
Radu CG, Shu CJ, Nair-Gill E et al (2008) Molecular imaging of lymphoid organs and immune activation by positron emission tomography with a new [18f]-labeled 2′-deoxycytidine analog. Nat Med 14:783–738
Nair-Gill ED, Shu CJ, Radu CG et al (2008) Non-invasive imaging of adaptive immunity using positron emission tomography. Immunol Rev 221:214–228
Garedew A, Henderson SO, Moncada S (2010) Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death Differ 17:1540–1550
Butterick CJ, Williams DA, Boxer LA et al (1981) Changes in energy metabolism, structure and function in alveolar macrophages under anaerobic conditions. Br J Haematol 48:523–532
Hannah S, Mecklenburgh K, Rahmen I et al (1995) Hypoxia prolongs neutrophil survival in vitro. FEBS Lett 372:233–237
Murdoch C, Muthana M, Lewis CE (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175:6257–6263
Murdoch C, Lewis CE (2005) Macrophage migration and gene expression in response to tumor hypoxia. Int J Cancer 117:701–708
Walmsley SR, Print C, Farahi N et al (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201:105–115
Semenza GL (2010) Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 2:336–361
Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 810:105–120
Elstrom RL, Bauer DE, Buzzai M et al (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899
Lazova R, Klump V, Pawelek J (2010) Autophagy in cutaneous malignant melanoma. J Cutan Pathol 37:256–268
Lazova R, Pawelek J (2009) Why do melanomas get so dark? Exp Dermatol 18:934–938
Klionsky DJ, Abeliovich H, Agostinis P et al (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151–175
Martinou JC, Kroemer G (2009) Autophagy: evolutionary and pathophysiological insights. Biochim Biophys Acta 1793:1395–1396
Amer AO, Swanson MS (2009) Autophagy is an immediate macrophage response to legionella pneumophila. Cell Microbiol 7:765–778
Amer AO, Byrne BG, Swanson MS (2005) Macrophages rapidly transfer pathogens from lipid raft vacuoles to autophagosomes. Autophagy 1:53–58
Sanjuan MA, Dillon CP, Tait SW et al (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–1257
Sanjuan MA, Green DR (2008) Eating for good health: linking autophagy and phagocytosis in host defense. Autophagy 4:607–611
Shui W, Sheu L, Liu J et al (2008) Membrane proteomics of phagosomes suggests a connection to autophagy. Proc Natl Acad Sci USA 105:16952–16957
Deretic V (2008) Autophagosome and phagosome. Methods Mol Biol 445:1–10
Bjerkvig R, Tysnes BB, Aboody KS et al (2005) Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer 5:899–904
Simsek T, Kocabas F, Zheng J et al (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7:380–390
Acknowledgments
We thank Vincent Klump, Yale Dermatopathology for the excellent immunohistochemistry. Funded in part by a generous gift from the Amway Corporation.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Lazova, R., Chakraborty, A., Pawelek, J.M. (2011). Leukocyte-Cancer Cell Fusion: Initiator of the Warburg Effect in Malignancy?. In: Dittmar, T., Zänker, K. (eds) Cell Fusion in Health and Disease. Advances in Experimental Medicine and Biology, vol 950. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0782-5_8
Download citation
DOI: https://doi.org/10.1007/978-94-007-0782-5_8
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-0781-8
Online ISBN: 978-94-007-0782-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)