Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy.
Rhabdomyosarcomas (RMSs) are frequently characterized by bone marrow involvement. Recently, we reported that human RMS cells express the CXC chemokine receptor-4 (CXCR4) and postulated a role for the CXCR4 stromal-derived factor (SDF)-1 axis in the metastasis of RMS cells to bone marrow. Because RMS cells also express the tyrosine kinase receptor c-MET, the specific ligand hepatocyte growth factor (HGF) that is secreted in bone marrow and lymph node stroma, we hypothesized that the c-MET-HGF axis modulates the metastatic behavior of RMS cells as well. Supporting this concept is our observation that conditioned media harvested from expanded ex vivo human bone marrow fibroblasts chemoattracted RMS cells in an HGF- and SDF-1-dependent manner. Six human alveolar and three embryonal RMS cell lines were examined. We found that although HGF, similar to SDF-1, did not affect the proliferation of RMS cells, it induced in several of them: (a) locomotion; (b) stress fiber formation; (c) chemotaxis; (d) adhesion to human umbilical vein endothelial cells; (e) trans-Matrigel invasion and matrix metalloproteinase secretion; and (f) phosphorylation of mitogen-activated protein kinase p42/44 and AKT. Moreover HGF, but not SDF-1, increased the survival of RMS cells exposed to radio- and chemotherapy. We also found that the more aggressive alveolar RMS cells express higher levels of c-MET than embryonal RMS cell lines and "home/seed" better into bone marrow after i.v. injection into immunocompromised mice. Because we could not find any activating mutations in the kinase region of c-MET or any evidence for HGF autocrine stimulation, we suggest that the increased response of RMS cell lines depends on overexpression of functional c-MET. We conclude that HGF regulates the metastatic behavior of c-MET-positive RMS cells, directing them to the bone marrow and lymph nodes. Signaling from the c-MET receptor may also contribute to the resistance of RMS cells to conventional treatment modalities.
Jankowski
Kacper
K
Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, 529 South Jackson Street, Louisville, KY 40202, USA.
Kucia
Magda
M
Wysoczynski
Marcin
M
Reca
Ryan
R
Zhao
Dongling
D
Trzyna
Ela
E
Trent
John
J
Peiper
Stephen
S
Zembala
Marek
M
Ratajczak
Janina
J
Houghton
Peter
P
Janowska-Wieczorek
Anna
A
Ratajczak
Mariusz Z
MZ
D000199:Actins / Q000378:metabolism; D019046:Bone Marrow Neoplasms / Q000473:pathology / Q000556:secondary; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D011836:Radiation Tolerance; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy
D000199:Actins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D017228:Hepatocyte Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C494918:AKT1 protein, human