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Tumor cells interact with red blood cells via galectin-4 - a short report

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Abstract

Background

The ability of tumor cells to invade and metastasize is relevant to the process of cancer progression and, as such, it represents an obstacle to cancer cure. So far, limited information is available on interactions between circulating tumor cells and blood cells. It is well-documented that galectin-4 is upregulated in many types of tumor cells and is involved in metastasis. Here, we address the hypothesis that tumor cells may interact with red blood cells (RBCs) via galectin-4.

Methods

High galectin-4 expressing colon, normal pancreatic and pancreatic cancer-derived cell lines (n = 5) were incubated with peripheral blood cells from different donors. Their interactions and associated proteins were examined by immunostaining and live cell imaging.

Results

We found that (endogenous or exogenous) galectin-4 expressing tumor cells interact directly with RBCs. We also observed an accumulation of galectin-4 and human blood group antigens at the contact sites between these cells. By comparing the number of RBCs attaching to each tumor cell, we found that cells with high pre-incubation expression levels of galectin-4 attached significantly more RBCs than those with low expression levels (p < 1 × 10−7). Conversely, we found that RBC attachment induces galectin-4 expression in tumor cells.

Conclusions

From our data we conclude that tumor cells directly interact with red blood cells via galectin-4.

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References

  1. A. Schroeder, D.A. Heller, M.M. Winslow, J.E. Dahlman, G.W. Pratt, R. Langer, T. Jacks, D.G. Anderson, Treating metastatic cancer with nanotechnology. Nat Rev Cancer 12, 39–50 (2012). doi:10.1038/nrc3180

    Article  CAS  Google Scholar 

  2. R. Paduch, The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol 39, 397–410 (2016). doi:10.1007/s13402-016-0281-9

  3. M. Labelle, S. Begum, R.O. Hynes, Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576–590 (2011). doi:10.1016/j.ccr.2011.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. B.Z. Qian, J. Li, H. Zhang, T. Kitamura, J. Zhang, L.R. Campion, E.A. Kaiser, L.A. Snyder, J.W. Pollard, Ccl2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011). doi:10.1038/nature10138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. J. Massague, A.C. Obenauf, Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016). doi:10.1038/nature17038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. M. Watanabe, I. Takemasa, N. Kaneko, Y. Yokoyama, E. Matsuo, S. Iwasa, M. Mori, N. Matsuura, M. Monden, O. Nishimura, Clinical significance of circulating galectins as colorectal cancer markers. Oncol Rep 25, 1217–1226 (2011). doi:10.3892/or.2011.1198

    PubMed  Google Scholar 

  7. H. Barrow, X. Guo, H.H. Wandall, J.W. Pedersen, B. Fu, Q. Zhao, C. Chen, J.M. Rhodes, L.G. Yu, Serum galectin-2, −4, and −8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res 17, 7035–7046 (2011a). doi:10.1158/1078-0432.CCR-11-1462

    Article  CAS  PubMed  Google Scholar 

  8. C. Chen, C.A. Duckworth, B. Fu, D.M. Pritchard, J.M. Rhodes, L.G. Yu, Circulating galectins −2, −4 and −8 in cancer patients make important contributions to the increased circulation of several cytokines and chemokines that promote angiogenesis and metastasis. Br J Cancer 110, 741–752 (2014). doi:10.1038/bjc.2013.793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. S.R. Stowell, C.M. Arthur, M. Dias-Baruffi, L.C. Rodrigues, J.P. Gourdine, J. Heimburg-Molinaro, T. Ju, R.J. Molinaro, C. Rivera-Marrero, B. Xia, D.F. Smith, R.D. Cummings, Innate immune lectins kill bacteria expressing blood group antigen. Nat Med 16, 295–301 (2010). doi:10.1038/nm.2103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. F.T. Liu, G.A. Rabinovich, Galectins as modulators of tumour progression. Nat Rev Cancer 5, 29–41 (2005). doi:10.1038/nrc1527

    Article  CAS  PubMed  Google Scholar 

  11. A.U. Newlaczyl, L.G. Yu, Galectin-3--a jack-of-all-trades in cancer. Cancer Lett 313, 123–128 (2011). doi:10.1016/j.canlet.2011.09.003

    Article  CAS  PubMed  Google Scholar 

  12. J. Dumic, S. Dabelic, M. Flogel, Galectin-3: An open-ended story. Biochim Biophys Acta 1760, 616–635 (2006). doi:10.1016/j.bbagen.2005.12.020

    Article  CAS  PubMed  Google Scholar 

  13. V. Balan, P. Nangia-Makker, A. Raz, Galectins as cancer biomarkers. Cancers 2, 592–610 (2010). doi:10.3390/cancers2020592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. S. Nakahara, A. Raz, Regulation of cancer-related gene expression by galectin-3 and the molecular mechanism of its nuclear import pathway. Cancer Metastasis Rev 26, 605–610 (2007). doi:10.1007/s10555-007-9095-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. R.C. Hughes, Secretion of the galectin family of mammalian carbohydrate-binding proteins. Biochim Biophys Acta 1473, 172–185 (1999)

    Article  CAS  PubMed  Google Scholar 

  16. S. Nakahara, N. Oka, A. Raz, On the role of galectin-3 in cancer apoptosis. Apoptosis 10, 267–275 (2005). doi:10.1007/s10495-005-0801-y

    Article  CAS  PubMed  Google Scholar 

  17. H. Barrow, J.M. Rhodes, L.G. Yu, The role of galectins in colorectal cancer progression. Int J Cancer 129, 1–8 (2011b). doi:10.1002/ijc.25945

    Article  CAS  PubMed  Google Scholar 

  18. F.T. Liu, R.J. Patterson, J.L. Wang, Intracellular functions of galectins. Biochim Biophys Acta 1572, 263–273 (2002)

    Article  CAS  PubMed  Google Scholar 

  19. Y. Takenaka, T. Fukumori, A. Raz, Galectin-3 and metastasis. Glycoconj J 19, 543–549 (2004). doi:10.1023/B:GLYC.0000014084.01324.15

    Article  Google Scholar 

  20. H. Rechreche, G.V. Mallo, G. Montalto, J.C. Dagorn, J.L. Iovanna, Cloning and expression of the mrna of human galectin-4, an s-type lectin down-regulated in colorectal cancer. Eur J Biochem 248, 225–230 (1997)

    Article  CAS  PubMed  Google Scholar 

  21. A.A. El Leithy, R. Helwa, M.M. Assem, N.H. Hassan, Expression profiling of cancer-related galectins in acute myeloid leukemia. Tumour Biol 36, 7929–7939 (2015). doi:10.1007/s13277-015-3513-0

    Article  CAS  PubMed  Google Scholar 

  22. H. Barrow, J.M. Rhodes, L.G. Yu, Simultaneous determination of serum galectin-3 and -4 levels detects metastases in colorectal cancer patients. Cell Oncol 36, 9–13 (2013). doi:10.1007/s13402-012-0109-1

  23. R. Helwa, M. Ramadan, A.A. Abdel-Wahab, S. Knappskog, A.S. Bauer, Promoter snps rs116896264 and rs73933062 form a distinct haplotype and are associated with galectin-4 overexpression in colorectal cancer (2015). doi:10.1093/mutage/gev086Mutagenesis

    Google Scholar 

  24. K. Flatmark, G.M. Maelandsmo, M. Martinsen, H. Rasmussen, O. Fodstad, Twelve colorectal cancer cell lines exhibit highly variable growth and metastatic capacities in an orthotopic model in nude mice. Eur J Cancer 40, 1593–1598 (2004). doi:10.1016/j.ejca.2004.02.023

    Article  PubMed  Google Scholar 

  25. N. Liu, T. Furukawa, M. Kobari, M.S. Tsao, Comparative phenotypic studies of duct epithelial cell lines derived from normal human pancreas and pancreatic carcinoma. Am J Pathol 153, 263–269 (1998). doi:10.1016/S0002-9440(10)65567-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. T. Furukawa, W.P. Duguid, L. Rosenberg, J. Viallet, D.A. Galloway, M.S. Tsao, Long-term culture and immortalization of epithelial cells from normal adult human pancreatic ducts transfected by the e6e7 gene of human papilloma virus 16. Am J Pathol 148, 1763–1770 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. G. Reyes, A. Villanueva, C. Garcia, F.J. Sancho, J. Piulats, F. Lluis, G. Capella, Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. Cancer Res 56, 5713–5719 (1996)

    CAS  PubMed  Google Scholar 

  28. W.H. Chen, J.S. Horoszewicz, S.S. Leong, T. Shimano, R. Penetrante, W.H. Sanders, R. Berjian, H.O. Douglass, E.W. Martin, T.M. Chu, Human pancreatic adenocarcinoma: In vitro and in vivo morphology of a new tumor line established from ascites. In Vitro 18, 24–34 (1982)

    Article  CAS  PubMed  Google Scholar 

  29. R.S. Metzgar, M.T. Gaillard, S.J. Levine, F.L. Tuck, E.H. Bossen, M.J. Borowitz, Antigens of human pancreatic adenocarcinoma cells defined by murine monoclonal antibodies. Cancer Res 42, 601–608 (1982)

    CAS  PubMed  Google Scholar 

  30. K. Bum-Erdene, H. Leffler, U.J. Nilsson, H. Blanchard, Structural characterization of human galectin-4 c-terminal domain: Elucidating the molecular basis for recognition of glycosphingolipids, sulfated saccharides and blood group antigens. FEBS J 282, 3348–3367 (2015). doi:10.1111/febs.13348

    Article  CAS  PubMed  Google Scholar 

  31. O.A. Vokhmyanina, E.M. Rapoport, S. Andre, V.V. Severov, I. Ryzhov, G.V. Pazynina, E. Korchagina, H.J. Gabius, N.V. Bovin, Comparative study of the glycan specificities of cell-bound human tandem-repeat-type galectin-4, −8 and −9. Glycobiology 22, 1207–1217 (2012). doi:10.1093/glycob/cws079

    Article  CAS  PubMed  Google Scholar 

  32. C.J. Dimitroff, Galectin-binding o-glycosylations as regulators of malignancy. Cancer Res 75, 3195–3202 (2015). doi:10.1158/0008-5472.CAN-15-0834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. T. Hayashi, T. Saito, T. Fujimura, K. Hara, K. Takamochi, K. Mitani, R. Mineki, S. Kazuno, S. Oh, T. Ueno, K. Suzuki, T. Yao, Galectin-4, a novel predictor for lymph node metastasis in lung adenocarcinoma. PLoS One 8, e81883 (2013). doi:10.1371/journal.pone.0081883

    Article  PubMed  PubMed Central  Google Scholar 

  34. L.M. Machesky, Lamellipodia and filopodia in metastasis and invasion. FEBS Lett 582, 2102–2111 (2008). doi:10.1016/j.febslet.2008.03.039

    Article  CAS  PubMed  Google Scholar 

  35. D. Schumacher, B. Strilic, K.K. Sivaraj, N. Wettschureck, S. Offermanns, Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via p2y2 receptor. Cancer Cell 24, 130–137 (2013). doi:10.1016/j.ccr.2013.05.008

    Article  CAS  PubMed  Google Scholar 

  36. K. Knight, S. Wade, L. Balducci, Prevalence and outcomes of anemia in cancer: A systematic review of the literature. Am J Med 116(Suppl 7A), 11S–26S (2004). doi:10.1016/j.amjmed.2003.12.008

    Article  PubMed  Google Scholar 

  37. K. Hu, L.B. Harrison, Impact of anemia in patients with head and neck cancer treated with radiation therapy. Curr Treat Options in Oncol 6, 31–45 (2005)

    Article  Google Scholar 

  38. Y.S. Choi, C.M. Yi, J.I. Sin, G.W. Ye, I.H. Shin, T.S. Lee, Impact of hemoglobin on survival of cervical carcinoma patients treated with concurrent chemoradiotherapy is dependent on lymph node metastasis findings by magnetic resonance imaging. Int J Gynecol Cancer 16, 1846–1854 (2006). doi:10.1111/j.1525-1438.2006.00666.x

    Article  CAS  PubMed  Google Scholar 

  39. M. Grogan, G.M. Thomas, I. Melamed, F.L. Wong, R.G. Pearcey, P.K. Joseph, L. Portelance, J. Crook, K.D. Jones, The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 86, 1528–1536 (1999)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The PancoBank (Prof. Dr. M.W. Büchler) is supported by the Heidelberger Stiftung Chirurgie/HSC and the Biomaterial Bank Heidelberg/BMBH (Prof. Dr. P. Schirmacher; BMBF grant 01EY1101). Reham Helwa was funded by the German Cancer Research Center as a visiting scholar. This work was funded by the Deutsche Krebsforschungszentrum (DKFZ), Heidelberg, Germany. Also some experiments were carried out at Ain Shams and Bergen universities.

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Author notes

  1. Reham Helwa

    Present address: Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway

Authors and Affiliations

  1. Molecular Cell Biology Lab, Zoology Department, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt

    Reham Helwa

  2. Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Reham Helwa & Andrea S. Bauer

  3. Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway

    Stian Knappskog

  4. Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany

    Anette Heller

  5. Department of Oncology, Haukeland University Hospital, Bergen, Norway

    Stian Knappskog

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  1. Reham Helwa
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Correspondence to Reham Helwa.

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Reham Helwa and Anette Heller equally contributing authors.

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Helwa, R., Heller, A., Knappskog, S. et al. Tumor cells interact with red blood cells via galectin-4 - a short report. Cell Oncol. 40, 401–409 (2017). https://doi.org/10.1007/s13402-017-0317-9

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