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Int. J. Mol. Sci. 2019, 20(2), 292; https://doi.org/10.3390/ijms20020292

Hepatocyte Growth Factor: A Microenvironmental Resource for Leukemic Cell Growth

1
Stem Cell Laboratory, Department of Experimental Medicine, University of Genoa, V. Pastore 3, 16132 Genova, Italy
2
Molecular Pathology Unit, IRCCS Polyclinic Hospital San Martino, L.go R. Benzi n.10, 16132 Genova, Italy
*
Author to whom correspondence should be addressed.
Received: 25 October 2018 / Revised: 7 January 2019 / Accepted: 9 January 2019 / Published: 12 January 2019
(This article belongs to the Special Issue Hepatocyte Growth Factor (HGF))
PDF [570 KB, uploaded 12 January 2019]

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the progressive expansion of B lymphocytes CD5+/CD23+ in peripheral blood, lymph-nodes, and bone marrow. The pivotal role played by the microenvironment in disease pathogenesis has become increasingly clear. We demonstrated that bone marrow stromal cells and trabecular bone cells sustain survival of leukemic B cells through the production of hepatocyte growth factor (HGF). Indeed the trans-membrane kinase receptor for HGF, c-MET, is expressed on CLL cells and STAT3 TYR705 or AKT phosphorylation is induced after HGF/c-MET interaction. We have further observed that c-MET is also highly expressed in a peculiar type of cells of the CLL-microenvironment showing nurturing features for the leukemic clone (nurse-like cells: NLCs). Since HGF treatment drives monocytes toward the M2 phenotype and NLCs exhibit features of tumor associated macrophages of type 2 we suggested that HGF, released either by cells of the microenvironment or leukemic cells, exerts a double effect: i) enhances CLL cells survival and ii) drives differentiation of monocytes-macrophages to an oriented immune suppressive phenotype. We here discuss how paracrine, but also autocrine production of HGF by malignant cells, may favor leukemic clone expansion and resistance to conventional drug treatments in CLL, as well as in other hematological malignancies. Novel therapeutic approaches aimed to block HGF/c-MET interactions are further proposed.
Keywords: HGF; c-MET; hematological neoplasia; microenvironment HGF; c-MET; hematological neoplasia; microenvironment
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Giannoni, P.; Fais, F.; Cutrona, G.; Totero, D.D. Hepatocyte Growth Factor: A Microenvironmental Resource for Leukemic Cell Growth. Int. J. Mol. Sci. 2019, 20, 292.

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