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Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis

Abstract

The causes of metastasis remain elusive despite vast information on cancer cells. We posit that cancer cell fusion with macrophages or other migratory bone marrow-derived cells (BMDCs) provides an explanation. BMDC–tumour hybrids have been detected in numerous animal models and recently in human cancer. Molecular studies indicate that gene expression in such hybrids reflects a metastatic phenotype. Should BMDC–tumour fusion be found to underlie invasion and metastasis in human cancer, new approaches for therapy would surely follow.

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Figure 1: Spontaneous in vivo fusion in melanoma52.
Figure 2: A renal cell carcinoma arising after allogeneic stem cell transplant.
Figure 3: Tumour β1,6-branched oligosaccharides after allogeneic stem cell transplant.
Figure 4: A model for generation of a metastatic phenotype following fusion of a melanoma cell with a macrophage.

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References

  1. Aichel, O. in Vorträge und Aufsätze über Entvickelungsmechanik Der Organismen Chapter XIII (ed Roux, W.) 92–111 (Wilhelm Engelmann, Leipzig, 1911).

    Google Scholar 

  2. Pawelek, J. M. Tumour cell hybridization and metastasis revisited. Melanoma Res. 10, 507–514 (2000).

    CAS  PubMed  Google Scholar 

  3. Pawelek, J. M. Tumour-cell fusion as a source of myeloid traits in cancer. Lancet Oncol. 6, 988–993 (2005).

    CAS  PubMed  Google Scholar 

  4. Pawelek, J. et al. Co-opting macrophage traits in cancer progression: a consequence of tumor cell fusion? Contrib. Microbiol. 13, 138–155 (2006).

    PubMed  Google Scholar 

  5. Mekler, L. B. [A general theory of oncogenesis.] Materials of Symposia on General Immunology. The Club of Immunologists of NF Gamaleya Inst of Epidemiology and Microbiology 3, 91–100 (1968) (in Russian).

    Google Scholar 

  6. Mekler, L. B. [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 (Bulletin of the USSR Acad Med Sci) 26, 80–89 (1971) (in Russian).

    CAS  Google Scholar 

  7. Goldenberg,.DM. [On the progression of malignity: a hypothesis.] Klin. Wschr. 46, 898 (1968) (in German).

    CAS  PubMed  Google Scholar 

  8. Goldenberg, D. M. & Gotz, H. On the 'human' nature of highly malignant heterotransplantable tumors of human origin. Europ. J. Cancer 4, 547–548 (1968).

    CAS  Google Scholar 

  9. Lagarde, A. E. & Kerbel, R. S. Somatic cell hybridization in vivo and in vitro in relation to the metastatic phenotype. Biochim. Biophys. Acta 823, 81–110 (1984).

    Google Scholar 

  10. Gupta, P. B., Mani, S., Yang, J., Hartwell, K. & Weinberg, R. A. The evolving portrait of cancer metastasis Cold Spring Harb. Symp. Quant. Biol. 6, 291–297 (2005).

    Google Scholar 

  11. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).

    CAS  Google Scholar 

  12. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    CAS  PubMed  Google Scholar 

  13. Fidler, I. J. & Kripke, M. L. Metastasis results from preexisting variant cells within a malignant tumor. Science 197, 893–895 (1977).

    CAS  PubMed  Google Scholar 

  14. Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).

    CAS  PubMed  Google Scholar 

  15. Chakraborty, A. K. & Pawelek, J. M. GnT-V, macrophages, and cancer metastasis: A common link. Clin. Exp. Metastasis 20, 365–373 (2003).

    CAS  PubMed  Google Scholar 

  16. Munzarova, M., Lauerova, L. & Capkova, J. Are advanced malignant melanoma cells hybrids between melanocytes and macrophages? Melanoma Res. 2, 127–129 (1992).

    CAS  PubMed  Google Scholar 

  17. Chakraborty, A. K., de Freitas Sousa, J., Espreafico, E. M. & Pawelek, J. M. Human monocyte × mouse melanoma fusion hybrids express human gene. Gene 275, 103–106 (2001).

    CAS  PubMed  Google Scholar 

  18. Duelli, D. & Lazebnik, Y. Cell-to-cell fusion as a link between viruses and cancer. Nature Rev. Cancer 7, 968–976

  19. Bjerkvig, R., Tysnes, B. B., Aboody, K. S., Najbauer, J. & Terzis, A. J. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nature Rev. Cancer 5, 899–904. Erratum in Nature Rev. Cancer 5, 995 (2005).

    CAS  Google Scholar 

  20. Sapir, A., Avinoam, O., Podbilewicz, B. & Chernomordik, L. V. Viral and developmental cell fusion mechanisms: conservation and divergence. Dev Cell. 14, 11–21 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, E. H. & Olson, E. N. Unveiling the mechanisms of cell–cell fusion. Science 308, 369–373 (2005).

    CAS  PubMed  Google Scholar 

  22. Vignery, A. Macrophage fusion: the making of osteoclasts and giant cells. J. Exp. Med. 202, 337–340 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Vignery, A. Macrophage fusion: are somatic and cancer cells possible partners? Trends Cell Biol. 4, 188–193 (2005).

    Google Scholar 

  24. Chen, E. H., Grote, E., Mohler, W. & Vignery, A. Cell–cell fusion. FEBS Lett. 581, 2181–2193 (2007).

    CAS  PubMed  Google Scholar 

  25. Pajcini, K. V., Pomerantz, J. H., Alkan, O., Doyonnas, R. & Blau, H. M. Myoblasts and macrophages share molecular components that contribute to cell–cell fusion. J. Cell Biol. 180, 1005–1019 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Holmgren, L., Bergsmedh, A. & Spetz, A. L. Horizontal transfer of DNA by the uptake of apoptotic bodies. Vox Sang. 83 (Suppl. 1), 305–306 (2002).

    PubMed  Google Scholar 

  27. Duelli, D. M. et al. A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr. Biol. 17, 431–437 (2007).

    CAS  PubMed  Google Scholar 

  28. Larsson, L. I., Bjerregaard, B., Wulf-Andersen, L. & Talts, J. F. Syncytin and cancer cell1 fusions. Sci. World J. 7, 1193–1197 (2007).

    CAS  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007).

    CAS  PubMed  Google Scholar 

  31. Yagi, M., Miyamoto, T., Toyama, Y. & Suda, T. Role of DC-STAMP in cellular fusion of osteoclasts and macrophage giant cells. J. Bone Miner. Metab. 24, 355–358 (2006).

    CAS  PubMed  Google Scholar 

  32. Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nature Rev. Genet. 4, 638–649 (2003).

    CAS  PubMed  Google Scholar 

  33. Han, X. et al. CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation. J. Biol. Chem. 275, 37984–37992 (2000).

    CAS  PubMed  Google Scholar 

  34. Kajita, M. et al. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J. Cell Biol. 153, 893–904 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kyriakides, T. R., et al. The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation. Am. J. Pathol. 165, 2157–2166 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim, M. S., Magno, C. L., Day, C. J. & Morrison, N. A. Induction of chemokines and chemokine receptors CCR2b and CCR4 in authentic human osteoclasts differentiated with RANKL and osteoclast like cells differentiated by MCP-1 and RANTES. J. Cell. Biochem. 97, 512–518 (2006).

    CAS  PubMed  Google Scholar 

  37. Marhaba, R. & Zöller, M. CD44 in cancer progression: adhesion, migration and growth regulation. J. Mol. Histol 35, 211–231 (2004).

    CAS  PubMed  Google Scholar 

  38. Götte, M. & Yip, G. W. Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. Cancer Res 66, 10233–10237 (2006).

    PubMed  Google Scholar 

  39. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zijlmans, H. J. et al. The absence of CCL2 expression in cervical carcinoma is associated with increased survival and loss of heterozygosity at 17q11.2. J. Pathol. 208, 507–517 (2006.

    CAS  PubMed  Google Scholar 

  41. Baier, P. K., Eggstein, S., Wolff-Vorbeck, G., Baumgartner, U. & Hopt, U. T. Chemokines in human colorectal carcinoma. Anticancer Res. 25, 3581–3584 (2005).

    CAS  PubMed  Google Scholar 

  42. Rendlew-Danielsen, J. M., et al. Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma. Br. J. Haematol. 138, 756–760 (2007).

    Google Scholar 

  43. Handerson, T. et al. Melanophages reside in hypermelanotic, aberrantly glycosylated tumor areas and predict improved outcome in primary cutaneous malignant melanoma. J. Cutaneous Pathol. 34, 667–738 (2007).

    Google Scholar 

  44. Jacobsen, B. M., et al. Spontaneous fusion with, and transformation of mouse stroma by, malignant human breast cancer epithelium. Cancer Res. 66, 8274–8279 (2006).

    CAS  PubMed  Google Scholar 

  45. Rizvi, A. Z., et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc. Natl Acad. Sci. USA 103, 6321–6325 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mortensen, K., Lichtenberg, J., Thomsen, P. D. & Larsson, L. I. Spontaneous fusion between cancer cells and endothelial cells. Cell. Mol. Life Sci. 61, 2125–2131 (2004).

    CAS  PubMed  Google Scholar 

  47. Bjerregaard, B., Holck, S., Christensen, I. J. & Larsson, L. I. Syncytin is involved in breast cancer-endothelial cell fusions. Cell. Mol. Life Sci. 63, 1906–1911 (2006).

    CAS  PubMed  Google Scholar 

  48. Streubel, B. et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N. Engl. J. Med. 351, 250–259 (2004).

    CAS  PubMed  Google Scholar 

  49. Alison, M. R., Lovell, M. J., Direkze, N. C., Wright, N. A. & Poulsom, R. Stem cell plasticity and tumour formation. Eur. J. Cancer 42, 1247–1256 (2006).

    CAS  PubMed  Google Scholar 

  50. Herzog, E. L., et al. Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J. 21, 2592–12601 (2007).

    CAS  PubMed  Google Scholar 

  51. Kerbel, R. S., Lagarde, A. E., Dennis, J. W. & Donaghue, T. P. 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 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Chakraborty, A. K. et al. A spontaneous murine melanoma lung metastasis comprised of host × tumor hybrids. Cancer Res. 60, 2512–2519 (2000).

    CAS  PubMed  Google Scholar 

  53. Rachkovsky, M. S. et al. Melanoma × macrophage hybrids with enhanced metastatic potential. Clin. Exp. Metastasis 16, 299–312 (1998).

    CAS  PubMed  Google Scholar 

  54. Wiener, F., Fenyö, E. M. & Klein, G. Tumor-host cell hybrids in radiochimeras. Proc. Natl Acad. Sci. USA 7, 148–152 (1974).

    Google Scholar 

  55. Andersen, T. L. et al. 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 (2007).

    CAS  PubMed  Google Scholar 

  56. Chakraborty, A. et al. Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant recipient. Bone Marrow Transplant. 34, 183–186 (2004).

    CAS  PubMed  Google Scholar 

  57. Yilmaz, Y., Lazova, R., Qumsiyeh, M., Cooper, D. & Pawelek, J. 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 (2005).

    CAS  PubMed  Google Scholar 

  58. Salama, M. E., Worsham, M. J. & DePeralta-Venturina, M. Malignant papillary renal tumors with extensive clear cell change: a molecular analysis by microsatellite analysis and fluorescence in situ hybridization. Arch. Pathol. Lab. Med. 127, 1176–1181 (2003).

    CAS  PubMed  Google Scholar 

  59. Lau, L. C., Tan, P. H., Chong, T. W., Foo, K. T. & Yip, S. Cytogenetic alterations in renal tumors: a study of 38 Southeast Asian patients. Cancer Genet. Cytogenet. 175, 1–7 (2007).

    CAS  PubMed  Google Scholar 

  60. Guo, W., Lasky, J. L. 3rd & Wu, H. Cancer stem cells. Pediatr. Res. 59, 59R–64R (2006).

    PubMed  Google Scholar 

  61. Cogle, C. R. et al. Bone marrow contributes to epithelial cancers in mice and humans as developmental mimicry. Stem Cells 25, 1881–1887 (2007).

    PubMed  Google Scholar 

  62. Avital, I. et al. Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation. Stem Cells 25, 2903–2909 (2007).

    PubMed  Google Scholar 

  63. Wiener, F., Klein, G. & Harris, H. The analysis of malignancy by cell fusion. J. Cell Sci. 15, 177–183 (1974).

    CAS  PubMed  Google Scholar 

  64. Stanbridge, E. J. Suppression of malignancy in human cells. Nature 260, 17–20 (1976).

    CAS  PubMed  Google Scholar 

  65. Sidebottom, E., The analysis of malignancy by cell fusion. In Vitro 16, 77–86 (1980).

    CAS  PubMed  Google Scholar 

  66. Ramshaw, I. A., Carlsen, S., Wang, H. & Badenoch-Jones, P. The use of cell fusion to analyse factors involved in tumour cell metastasis. Int. J. Cancer 32, 471–478 (1983).

    CAS  PubMed  Google Scholar 

  67. Harris, H. The analysis of malignancy by cell fusion: the position in 1988. Cancer Res., 48, 3302–3306 (1988).

    CAS  PubMed  Google Scholar 

  68. Weinberg, A. S. Tumor suppressor genes. Science 254, 1138–1146 (1991).

    CAS  PubMed  Google Scholar 

  69. Levine, A. J. In The Molecular Basis of Cancer. (eds Mendelsohn, J., Howley, P. M., Israel, M. A. & Liotta, L. A) 86–104 (WB Saunders, Philadelphia, 1995).

    Google Scholar 

  70. Scaletta, L. J. & Ephrussi, B. Hybridization of normal and neoplastic cells in vitro. Nature 205, 1169 (1965).

    Google Scholar 

  71. Defendi, V., Ephrussi, B., Koprowski, H. & Yoshida, M. C. Properties of hybrids between polyoma-transformed and normal mouse cells. Proc. Natl Acad. Sci. USA 57, 299–305 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Jonasson, J., Povey, S. & Harris, H. The analysis of malignancy by cell fusion. VII. Cytogenetic analysis of hybrids between malignant diploid cells and of tumours derived from them. J. Cell Sci. 24, 217–254 (1977).

    CAS  PubMed  Google Scholar 

  73. Davidson, R. L., Ephrussi, R. L. B. & Yamamoto, K. Regulation of pigment synthesis in mammalian cells, as studied by somatic hybridization. Proc. Natl Acad. Sci. USA 56, 1437–1440 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Powers, T. P. & Davidson, R. L. Coordinate extinction of melanocyte-specific gene expression in hybrid cells. Som. Cell Mol. Gen. 22, 41–56 (1996).

    CAS  Google Scholar 

  75. Gourdeau, H. & Fournier, R. E. K. Genetic analysis of mammalian cell differentiation. Ann. Rev. Cell Biol. 6, 69–94 (1990).

    CAS  PubMed  Google Scholar 

  76. Powers, T. P., Shows, T. B. & Davidson, R. L. Pigment-cell-specific genes from fibroblasts are transactivated after chromosomal transfer into melanoma cells. Mol. Cell Biol. 14, 1179–1190 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Darlington, G. J., Bernhard, H. P. & Ruddle, F. H. Human serum albumin phenotype activation in mouse hepatoma — human leukocyte cell hybrids. Science 185, 859–862 (1974).

    CAS  PubMed  Google Scholar 

  78. Malawista, S. E. & Weiss, M. C. Expression of differentiated function in hepatoma cell hybrids: high frequency of induction of mouse albumin production in rat hepatoma-mouse lymphoblast hybrids. Proc. Natl Acad. Sci. USA 71, 927–931 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Giacomoni, D. Tumorigenicity and intracisternal A-particle expression of hybrids between murine myeloma and lymphocytes. Cancer Res. 39, 4481–4484 (1979).

    CAS  PubMed  Google Scholar 

  80. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    CAS  PubMed  Google Scholar 

  81. Gottesman, M. M. & Ling, V. The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 580, 998–1009 (2006).

    CAS  PubMed  Google Scholar 

  82. Lemaire, S., Van Bambeke, F., Mingeot-Leclercq, M. P. & Tulkens, P. M. Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells. Antimicrob. Agents Chemother. 51, 2748–2757 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Rachkovsky, M. & Pawelek, J. Acquired melanocyte stimulating hormone-inducible chemotaxis following macrophage fusion with Cloudman S91 melanoma cells. Cell Growth Differ. 10, 515–524 (1999).

    Google Scholar 

  84. Pawelek, J. et al. Altered N-glycosylation in macrophage x melanoma fusion hybrids. Cell. Mol. Biol. 45, 1011–1027 (2000).

    Google Scholar 

  85. Roos, E., La Riviere, G., Collard, J. G., Stukart, M. J. & De Baetselier, P. Invasiveness of T-cell hybridomas in vitro and their metastatic potential in vivo. Cancer Res. 45, 6238–6243 (1985).

    CAS  PubMed  Google Scholar 

  86. Larizza, L., Schirrmacher, V., Stöhr, M., Pflüger, E. & Dzarlieva, R. 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 (1984).

    CAS  PubMed  Google Scholar 

  87. Larizza, L. et al. 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 (1984).

    CAS  PubMed  Google Scholar 

  88. Lane, T. F. & Sage, E. H. The biology of SPARC, a protein that modulates cell-matrix interactions. FASEB J. 8, 163–173 (1994).

    CAS  PubMed  Google Scholar 

  89. Bradshaw, A. D. & Sage, E. H. SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. J. Clin. Invest. 107, 1049–1054 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Martinek, N., Shahab, J., Sodek, J. & Ringuette, M. Is SPARC an evolutionarily conserved collagen chaperone? J. Dent. Res. 86, 296–305 (2007).

    CAS  PubMed  Google Scholar 

  91. Damjanovski, S., Huynh, M. H., Motamed, K., Sage, E. H & Ringuette, M. Regulation of SPARC expression during early Xenopus development: evolutionary divergence and conservation of DNA regulatory elements between amphibians and mammals. Dev. Genes Evol. 207, 453–461 (1998).

    CAS  PubMed  Google Scholar 

  92. Fujita, T. et al. SPARC stimulates the synthesis of OPG/OCIF, MMP-2 and DNA in human periodontal ligament cells. J. Oral Pathol. Med. 31, 345–352 (2002). Erratum in J. Oral Pathol. Med. 31, 504 (2002).

    CAS  PubMed  Google Scholar 

  93. Mansergh, F. C. et al. Osteopenia in Sparc (osteonectin)-deficient mice: characterization of phenotypic determinants of femoral strength and changes in gene expression. Physiol. Genomics. 32, 64–73 (2007).

    CAS  PubMed  Google Scholar 

  94. Reed, M. J. et al. Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization. J. Histochem. Cytochem. 41, 1467–1477 (1993).

    CAS  PubMed  Google Scholar 

  95. Charest, A. et al. Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart 92, 1844–1849 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Robert, G. et al. SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. Cancer Res. 66, 7516–7523 (2006).

    CAS  PubMed  Google Scholar 

  97. Alonso, S. R. et al. A high-throughput study in melanoma identifies epithelial–mesenchymal transition as a major determinant of metastasis. Cancer Res. 67, 3450–3460 (2007).

    CAS  PubMed  Google Scholar 

  98. Barrallo-Gimeno, A. & Nieto, M. A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132, 3151–3161 (2005).

    CAS  PubMed  Google Scholar 

  99. Chakraborty, A. K. & Yamaga, S. Differential gene expression in genetically matched mouse melanoma cells with different metastatic potential. Gene 315, 165–175 (2003).

    CAS  PubMed  Google Scholar 

  100. Sharif, M. N. et al. Twist mediates suppression of inflammation by type I IFNs and Axl. J. Exp. Med. 203, 1891–1901 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Sosi, D., Richardson, J. A., Yu, K., Ornitz, D. M. & Olson, E. N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell 112, 169–180 (2003).

    Google Scholar 

  102. Carlson, J. A., Linette, G. P., Aplin, A., Ng, B. & Slominski, A. Melanocyte receptors: clinical implications and therapeutic relevance. Dermatol. Clin. 25, 541–557, viii–ix (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Kanetsky, P. A. et al. Population-based study of natural variation in the melanocortin-1 receptor gene and melanoma. Cancer Res. 66, 9330–9337 (2006).

    CAS  PubMed  Google Scholar 

  104. McGill, G. G., Haq, R., Nishimura, E. K. & Fisher, D. E. c-Met expression is regulated by Mitf in the melanocyte lineage. J. Biol. Chem. 281, 10365–10373 (2006).

    CAS  PubMed  Google Scholar 

  105. Beuret, L. et al. Up-regulation of MET expression by α-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis. J. Biol. Chem. 282, 14140–14147 (2007).

    CAS  PubMed  Google Scholar 

  106. Boccaccio, C. & Comoglio, P. M. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nature Rev. Cancer. 6, 637–645 (2006).

    CAS  Google Scholar 

  107. Chakraborty, A. K. et al. Upregulation of mRNA for the melanocortin-1 receptor but not for melanogenic proteins in macrophage x melanoma fusion hybrids exhibiting increased melanogenic and metastatic potential. Pig. Cell Res. 12, 355–366 (1999).

    CAS  Google Scholar 

  108. Chakraborty, A. K. et al. Expression of c-Met proto-oncogene in metastatic macrophage × melanoma fusion hybrids: implication of its possible role in MSH-induced motility. Oncol. Res. 14, 163–174 (2003).

    CAS  PubMed  Google Scholar 

  109. Levy, C., Khaled, M. & Fisher, D. E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol. Med. 12, 406–414 (2006).

    CAS  PubMed  Google Scholar 

  110. Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).

    CAS  PubMed  Google Scholar 

  111. Bronisz, A. et al. Microphthalmia-associated transcription factor interactions with 14–3–3 modulate differentiation of committed myeloid precursors. Mol. Biol. Cell 17, 3897–3906 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Beilmann, M. et al. Neoexpression of the c-met/hepatocyte growth factor-scatter factor receptor gene in activated monocytes. Blood 90, 4450–4458 (1997).

    CAS  PubMed  Google Scholar 

  113. Gaasch, J. A., Bolwahnn, A. B. & Lindsey, J. S. Hepatocyte growth factor-regulated genes in differentiated RAW 264.7 osteoclast and undifferentiated cells. Gene 369, 142–152 (2006).

    CAS  PubMed  Google Scholar 

  114. Lam, C. W., Getting, S. J. & Perretti, M. In vitro and in vivo induction of heme oxygenase 1 in mouse macrophages following melanocortin receptor activation. J. Immunol. 174, 2297–2304 (2005).

    CAS  PubMed  Google Scholar 

  115. Lam, C. W., Perretti, M. & Getting, S. J. Melanocortin receptor signaling in RAW264.7 macrophage cell line. Peptides 27, 404–412 (2006).

    CAS  PubMed  Google Scholar 

  116. Manna, S. K., Sarkar, A. & Sreenivasan, Y. α-Melanocyte-stimulating hormone down-regulates CXC receptors through activation of neutrophil elastase. Eur. J. Immunol. 36, 754–769 (2006).

    CAS  PubMed  Google Scholar 

  117. Taylor, A. W. The immunomodulating neuropeptide α-melanocyte-stimulating hormone (α-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages. J. Neuroimmunol. 162, 43–50 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Fernandes, B., Sagman, U., Auger, M., Demetrio, M. & Dennis, J. W. β1,6-branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia. Cancer Res. 51, 718–723 (1991).

    CAS  PubMed  Google Scholar 

  119. Handerson, T., Camp, R., Harigopal, M., Rimm, D. & Pawelek, J. β1,6-Branched oligosaccharides are associated with metastasis and predict poor outcome in breast carcinoma. Clin. Cancer Res. 11, 2969–2973 (2005).

    CAS  PubMed  Google Scholar 

  120. Seelentag, W. K. et al. Pronostic value of β1,6-branched oligosaccharides in human colorectal carcinoma. Cancer Res. 58, 5559–5564 (1998).

    CAS  PubMed  Google Scholar 

  121. Murata, K. et al. Expression of N-acetylglucosaminyltransferase V in colorectal cancer correlates with metastasis and poor prognosis. Clin. Cancer Res. 6, 1772–1777 (2000).

    CAS  PubMed  Google Scholar 

  122. Dosaka-Akita, H. et al. Expression of N-acetylglucosaminyltransferase V is associated with prognosis and histology in non-small cell lung cancers. Clin. Cancer Res. 10, 1773–1779 (2004).

    CAS  PubMed  Google Scholar 

  123. Fukuda, M., Spooncer, E., Oates, J. E., Dell, A. & Klock, J. C. Structure of sialylated fucosyl lactosaminoglycan isolated from human granulocytes. J. Biol. Chem. 25 10925–10935 (1984).

  124. Yamamoto, E. et al. Expression of N-acetylglucosaminyltransferase V in endometrial cancer correlates with poor prognosis. Br. J. Cancer 97, 1538–1544 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fukuda, M., Spooncer, E., Oates, J. E., Dell, A. & Klock, J. C. Structure of sialylated fucosyl lactosaminoglycan isolated from human granulocytes. J. Biol. Chem. 259, 10925–10935 (1984).

    CAS  PubMed  Google Scholar 

  126. Mizoguchi, A., Takasaki, S., Maeda, S. & Kobata, A. Changes in asparagine-linked sugar chains of human promyelocytic leukemic cells (HL-60) during monocytoid differentiation and myeloid differentiation. Decrease of high-molecular-weight oligosaccharides in acidic fraction. J. Biol. Chem. 259, 11949–11957 (1984).

    CAS  PubMed  Google Scholar 

  127. Chakraborty, A. K. et al. Fusion hybrids with macrophage and melanoma cells up-regulate N-acetylglucosaminyltransferase V, β1–6 branching, and metastasis. Cell Growth Differentiation 12, 623–630 (2001).

    CAS  PubMed  Google Scholar 

  128. Dennis, J., Waller, C. A. & Schirrmacher, V. Identification of asparagine-linked oligosaccharides involved in tumor cell adhesion to laminin and type IV collagen. J. Cell Biol. 99, 1034–1044 (1984).

    CAS  PubMed  Google Scholar 

  129. Demetriou, M., Nabi, I. R., Coppolino, M., Dedhar, S. & Dennis, J. W. Reduced contact-inhibition and substratum adhesion in epithelial cells expressing GlcNAc-transferase, V. J. Cell Biol. 130, 383–392 (1995).

    CAS  PubMed  Google Scholar 

  130. Saitoh, O., Wang, W. C., Lotan, R. & Fukuda, M. Differential glycosylation and cell surface expression of lysosomal membrane glycoproteins in sublines of a human colon cancer exhibiting distinct metastatic potentials. J. Biol. Chem. 267, 5700–5711 (1992).

    CAS  PubMed  Google Scholar 

  131. Chammas, R., Veiga, S. S., Travassos, L. R. & Brentani, R. R. Functionally distinct roles for glycosylation of α and β integrin chains in cell matrix interactions. Proc. Natl Acad. Sci. USA 90, 1795–1799 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Zheng, M., Fang, H. & Hakomori, S. Functional role of N-glycosylation in α5β1 integrin receptor. De-N-glycosylation induces dissociation or altered association of α5 and β1 subunits and concomitant loss of fibronectin binding activity. J. Biol. Chem. 269, 12325–12331, (1994).

    CAS  PubMed  Google Scholar 

  133. Leppa, S., Heino, J. & Jalkanen, M. Increased glycosylation of β1 integrin affects the interaction of transformed s115 mammary epithelial cells with laminin-1. Cell Growth Differ. 6, 853–861, (1995).

    CAS  PubMed  Google Scholar 

  134. Dennis, J. W., Granovsky, M. & Warren, C. E. Glycoprotein glycosylation and cancer progression. Biochim. Biophys. Acta 1473, 21–34 (1999).

    CAS  PubMed  Google Scholar 

  135. Yamamoto, H. et al. β1,6 N-acetyl-glucosamine bearing N-glycans in human gliomas; implications for role in regulating invasivity. Cancer Res. 60, 134–142 (2000).

    CAS  PubMed  Google Scholar 

  136. Ochwat, D., Hoja-Lukowicz, D. & Litynska, A. N-glycoproteins bearing β1,6-branched oligosaccharides from the A375 human melanoma cell line analysed by tandem mass spectrometry. Melanoma Res. 14, 479–485 (2004).

    CAS  PubMed  Google Scholar 

  137. Guo, H.-B., Lee, I., Kamar, M., Akiyama, S. K. & Pierce, M. Aberrant N-glycosylation of β1 integrin causes reduced α5β1 integrin clustering and stimulates cell migration. Cancer Res. 62, 6837–6845 (2002).

    CAS  PubMed  Google Scholar 

  138. Poche, E., Litysk, A., Amoresano, A. & Casbarra, A. Glycosylation profile of integrin α3β1 changes with melanoma progression. Biochim. Biophys. Acta Mol. Cell Res. 1643, 113–123 (2003).

    Google Scholar 

  139. Jasiulionis, M. G., Chammas, R., Ventura, A. M., Travassos, L. R. & Brentani, R. R. α6β1-Integrin, a major cell surface carrier of β1-6-branched oligosaccharides, mediates migration of EJ-ras-transformed fibroblasts on laminin-1 independently of its glycosylation state. Cancer Res. 56, 1682–1689 (1996).

    CAS  PubMed  Google Scholar 

  140. Giannelli, G. et al. Role of the α3β1 and α6β4 integrins in tumor invasion. Clin. Exp. Metastasis 19, 217–230 (2002).

    CAS  PubMed  Google Scholar 

  141. Danen, E. H. J. et al. Emergence of α5β1 fibronectin- and αvβ3 vitronectin-receptor expression in melanocytic tumour progression. Histopathology 24, 249–256 (1994).

    CAS  PubMed  Google Scholar 

  142. Natali, P. G., Nicotra, M. R., Di Filippo, F. & Bigotti, A. Expression of fibronectin, fibronectin isoforms and integrin receptors in melanocytic lesions. Br. J. Cancer 71, 1243–1247 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Galbraith, C. G., Yamada, K. M. & Galbraith, J. A. Polymerizing actin fibers position integrins primed to probe for adhesion sites. Science 315, 992–995 (2007).

    CAS  PubMed  Google Scholar 

  144. Gladson, C. L. & Cheresh, D. A. Glioblastoma expression of vitronectin and the αvβ3 integrin. Adhesion mechanism for transformed glial cells. J. Clin. Invest. 88, 1924–1932 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Natali, P. G., et al. Clinical significance of αvβ3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. Cancer Res. 57, 1554–1560 (1997).

    CAS  PubMed  Google Scholar 

  146. Wong, N. C. et al. αv integrins mediate adhesion and migration of breast carcinoma cell lines. Clin. Exp. Metastasis 16, 50–61 (1998).

    CAS  PubMed  Google Scholar 

  147. Juliano, R. L. The role of β1 integrins in tumors. Semin. Cancer Biol. 4, 277–283 (1993).

    CAS  PubMed  Google Scholar 

  148. Ammon, C. et al. Comparative analysis of integrin expression on monocyte-derived macrophages and monocyte-derived dendritic cells. Immunology 100, 364–369 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Aplin, A. E., Howe, A., Alahari, S. K. & Juliano, R. L. Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol. Rev. 50, 197–263 (1998).

    CAS  PubMed  Google Scholar 

  150. Elsegood, C. L. et al. M-CSF induces the stable interaction of cFms with αVβ3 integrin in osteoclasts. Int. J. Biochem. Cell Biol. 38, 1518–1529 (2006).

    CAS  PubMed  Google Scholar 

  151. Shinji, H. et al. Expression and distribution of very late antigen-5 in mouse peritoneal macrophages upon ingestion of fibronectin-bound Staphylococcus aureus. Microbiol. Immunol. 51, 63–171 (2007).

    CAS  PubMed  Google Scholar 

  152. Kurita-Taniguchi, M. et al. Molecular assembly of CD46 with CD9, α3-β1 integrin and protein tyrosine phosphatase SHP-1 in human macrophages through differentiation by GM-CSF. Mol. Immunol. 38, 689–700 (2002).

    CAS  PubMed  Google Scholar 

  153. Chang, M. H. et al. Transthyretin interacts with the lysosome-associated membrane protein (LAMP-1) in circulation. Biochem. J. 382, 481–489 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Sawada, R., Lowe, J. B. & Fukuda, M. 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 (1993).

    CAS  PubMed  Google Scholar 

  155. Sarafian, V. et al. Expression of Lamp-1 and Lamp-2 and their interactions with galectin-3 in human tumor cells. Int. J. Cancer 75, 105–111 (1998).

    CAS  PubMed  Google Scholar 

  156. Chakraborty, A. K. & Pawelek, J. M. β1,6-branched oligosaccharides regulate melanin content and motility in macrophage-melanoma fusion hybrids. Melanoma Res. 17, 9–16 (2007).

    CAS  PubMed  Google Scholar 

  157. Rupani, R., Handerson, T. & Pawelek, J. Co-localization of β1,6-branched oligosaccharides and coarse melanin in macrophage-melanoma fusion hybrids and human melanoma cells in vitro. Pig. Cell Res. 17, 281–288 (2004).

    CAS  Google Scholar 

  158. Hariri, M. et al. Biogenesis of multilamellar bodies via autophagy. Mol. Biol. Cell 11, 255–268 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Handerson, T. & Pawelek, J. β1,6-branched oligosaccharides and coarse vesicles: A common and pervasive phenotype in melanoma and other human cancers. Cancer Res. 63, 5363–5369 (2003).

    CAS  PubMed  Google Scholar 

  160. Clark, W. H. et al. Current concepts of the biology of human cutaneous malignant melanoma. Adv. Cancer Res. 24, 267–338 (1977).

    PubMed  Google Scholar 

  161. Hait, W. N., Jin, S. & Yang, J.-M. A matter of life or death (or both): understanding autophagy in cancer. Clin. Cancer Res. 12, 1961–1965 (2006).

    CAS  PubMed  Google Scholar 

  162. Hait, W. N., Wu, H., Jin, S. & Yang, J. M. Elongation factor-2 kinase: its role in protein synthesis and autophagy. Autophagy 2, 294–296 (2006).

    CAS  PubMed  Google Scholar 

  163. Hait, W. N., Jin, S. & Yang, J. M. Elongation factor-2 kinase regulates autophagy in human glioblastoma cells. Clin. Cancer Res. 12, 1961–1965 (2006).

    CAS  PubMed  Google Scholar 

  164. Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nature Rev. Cancer 7, 961–967 (2007).

    CAS  Google Scholar 

  165. Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Levine, B. Cell biology: autophagy and cancer. Nature 446, 745–747 (2007).

    CAS  PubMed  Google Scholar 

  167. Amer, A. O. & Swanson, M. S. Autophagy is an immediate macrophage response to Legionella pneumophila. Cell Microbiol. 7, 765–778 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Amer, A. O., Byrne, B. G. & Swanson, M. S. Macrophages rapidly transfer pathogens from lipid raft vacuoles to autophagosomes. Autophagy 1, 53–58 (2005).

    CAS  PubMed  Google Scholar 

  169. Lugini, L. et al. Cannibalism of live lymphocytes by human metastatic but not primary melanoma cells. Cancer Res. 66, 3629–3638 (2006).

    CAS  PubMed  Google Scholar 

  170. 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).

    CAS  PubMed  Google Scholar 

  171. Damiani, M. T. & Colombo, M. I. Microfilaments and microtubules regulate recycling from phagosomes. Exp. Cell Res. 289, 152–161 (2003).

    CAS  PubMed  Google Scholar 

  172. Coopman, P. J., Do, M. T., Thompson, E. W. & Mueller, S. C. Phagocytosis of cross-linked gelatin matrix by human breast carcinoma cells correlates with their invasive capacity. Clin. Cancer Res. 4, 507–515 (1998).

    CAS  PubMed  Google Scholar 

  173. Montcourrier, P. et al. Characterization of very acidic phagosomes in breast cancer cells and their association with invasion. J. Cell Sci. 107, 2381–2391 (1994).

    PubMed  Google Scholar 

  174. Houghton, J. et al. Gastric cancer originating from bone marrow-derived cells. Science 306, 1568–1571 (2004).

    CAS  PubMed  Google Scholar 

  175. Parris, G. E. 2-Deoxy-D-glucose as a potential drug against fusogenic viruses including HIV. Med. Hypotheses 70, 776–782 (2008).

    CAS  PubMed  Google Scholar 

  176. Halaban, R. et al. Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells. Proc. Natl Acad. Sci. USA 94, 6210–6215 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully acknowledge the many and invaluable contributions of D. Bermudes, J. Bolognia, D. Brash, D. Cooper, T. Henderson, R. Lazova, L. Margulis, J. Pawelek, J. Platt, M. Rachkovsky, S. Sodi and Y. Yilmaz. We thank R. Sorensen, D. Schafer and L. Hummel for their critical readings of the manuscript. Supported in part by a gift from Vion Pharmaceuticals (J.M.P.), and a grant from Avon Pharmaceuticals (A.K.C.).

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DATABASES

National Cancer Institute

breast cancer

colorectal carcinoma

endometrial cancer

lung carcinoma

melanoma

ovarian carcinoma

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Pawelek, J., Chakraborty, A. Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer 8, 377–386 (2008). https://doi.org/10.1038/nrc2371

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