Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

Abstract

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is produced by mesenchymal cells, including bone marrow (BM) stromal cells, and has mitogenic and motogenic effects on a variety of cell types. Recently, a role has been assigned to HGF/SF and its receptor, c-MET, in both normal and malignant hemopoiesis. We investigated the function of HGF/SF on hemopoietic mononuclear cells (MNC) from patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with circulating blasts. In contrast to results with normal MNC, HGF/SF alone stimulated the proliferation and colony formation of MNC from these patients. MNC from some (4/13) of the AML patients also produced HGF/SF (0.1-0.2 ng/ml/day), while we could not detect HGF/SF in cultures from normal MNC. Furthermore, it appeared that HGF/SF induced migration of leukemic cells in Boyden using KG1a cells as a model for leukemic blasts. The membranes dividing the two compartments of the Boyden chambers were coated with fibronectin. HGF/SF significantly promoted migration in 3/5 samples of MDS patients and in 5/7 samples of AML patients. Supernatant of human BM stromal cells, which is chemoattractive for normal human hemopoietic progenitor cells, also promoted migration of MNC from 4/5 MDS patients and 6/7 AML patients. Since HGF/SF is one of the growth factors produced by BM stromal cells, a neutralizing antibody directed against HGF/SF was added to the BM stroma supernatant, which reduced migration significantly in 2/3 MDS and in 3/6 AML responders to BM stroma supernatant. In conclusion, HGF/SF promotes proliferation and migration of hemopoietic cells from AML and MDS patients in vitro and may therefore contribute to the malignant potential of these cells.

Efficacy and safety of imatinib in adult patients with c-kit–positive acute myeloid leukemia

“…Interactions between AML cells and bone marrow stromal cells have been described to play an important role in inhibition of apoptosis and in increased proliferation observed in AML clonogenic cells. 66,[69][70][71][72][73] Thus, we assume that reductions in leukemic blasts observed are due to suppression of c-kit signaling. However, the data obtained did not detect an obvious correlation between expression and/or activation of c-kit on leukemic blasts and clinical response to imatinib.…”

Plasma hepatocyte growth factor is a prognostic factor in patients with acute myeloid leukemia but not in patients with myelodysplastic syndrome

“…40 Furthermore, the possibility that HGF was produced by leukemic cells in vivo was suggested by the detection of HGF expression and production by freshly prepared AML blasts. Based on these observations, it is not surprising that HGF plasma levels in our study group correlated strongly with the white blood cell counts.…”

The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation

“…Other interesting gene changes between 2 and 3.5-fold include (Supplementary Table S2) the c-met proto-oncogene (c-met, 3.1-fold) that is the receptor for hepatocyte growth factor, 26 which is also induced eightfold, suggesting that this known oncogenic signaling pathway is putatively upregulated. In addition, as no increased apoptosis was observed associated with decreased Bcl2 (À2.6-fold), it could be suggested that the HGF/c-met signaling pathway may be blocking such a cellular response.…”