WNT5A: a motility-promoting factor in Hodgkin lymphoma.
Classical Hodgkin lymphoma (cHL) has a typical clinical manifestation, with dissemination involving functionally neighboring lymph nodes. The factors involved in the spread of lymphoma cells are poorly understood. Here we show that cHL cell lines migrate with higher rates compared with non-Hodgkin lymphoma cell lines. cHL cell migration, invasion and adhesion depend on autocrine WNT signaling as revealed by the inhibition of WNT secretion with the porcupine inhibitors Wnt-C59/IWP-2, but did not affect cell proliferation. While application of recombinant WNT5A or WNT5A overexpression stimulates HL cell migration, neither WNT10A, WNT10B nor WNT16 did so. Time-lapse studies revealed an amoeboid type of cell migration modulated by WNT5A. Reduced migration distances and velocity of cHL cells, as well as altered movement patterns, were observed using porcupine inhibitor or WNT5A antagonist. Knockdown of Frizzled5 and Dishevelled3 disrupted the WNT5A-mediated RHOA activation and cell migration. Overexpression of DVL3-K435M or inhibition of ROCK (Rho-associated protein kinase) by Y-27632/H1152P disrupted cHL cell migration. In addition to these mechanistic insights into the role of WNT5A in vitro, global gene expression data revealed an increased WNT5A expression in primary HL cells in comparison with normal B-cell subsets and other lymphomas. Furthermore, the activity of both porcupine and WNT5A in cHL cells had an impact on lymphoma development in the chick chorionallantoic membrane assay. Massive bleeding of these lymphomas was significantly reduced after inhibition of WNT secretion by Wnt-C59. Therefore, a model is proposed where WNT signaling has an important role in regulating tumor-promoting processes.
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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F
Linke
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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S
Zaunig
Department of Medical Statistics, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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Nietert
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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von Bonin
Institute of Pharmacology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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S
Lutz
Institute of Diagnostic and Interventional Radiology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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Dullin
Faculty of Science, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic.
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Janovská
Department of Medical Statistics, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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Beissbarth
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.|Institute of Diagnostic and Interventional Radiology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.|Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
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Alves
Section Hematopathology, UKSH Campus Kiel, Kiel, Germany.
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W
Klapper
Faculty of Science, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic.|Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of Czech Republic, Brno, Czech Republic.
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V
Bryja
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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T
Pukrop
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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L
Trümper
Department of Anatomy and Cell Biology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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J
Wilting
Clinic of Hematology and Medical Oncology, University Medical Centre of the Georg-August University of Göttingen, Göttingen, Germany.
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Kube
D000818:Animals; D001706:Biopsy; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D000072261:Dishevelled Proteins / Q000378:metabolism; D051157:Frizzled Receptors / Q000378:metabolism; D015870:Gene Expression; D006689:Hodgkin Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D046328:Porcupines; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D000071818:Wnt-5a Protein / Q000235:genetics* / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C498589:FZD5 protein, human; D051157:Frizzled Receptors; D000071818:Wnt-5a Protein; D020742:rhoA GTP-Binding Protein