Abstract
Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM.
Highlights
Epidermal growth factor receptor (EGFR, known as ErbB-1 and HER1) belongs to the ErbB family of receptor tyrosine kinases, together with ErbB-2, ErbB-3 (HER3) and ErbB-4(HER4) [1]
These results indicate that epidermal growth factor receptor (EGFR) is expressed by bone marrow endothelial cells, at low levels in MGUS patients and at higher levels in MM patients
This study revealed that EGFR is expressed on bone marrow endothelial cells from MGUS patients
Summary
Epidermal growth factor receptor (EGFR, known as ErbB-1 and HER1) belongs to the ErbB family of receptor tyrosine kinases, together with ErbB-2 (neu, HER2), ErbB-3 (HER3) and ErbB-4(HER4) [1]. Epidermal growth factor receptor (EGFR, known as ErbB-1 and HER1) belongs to the ErbB family of receptor tyrosine kinases, together with ErbB-2 (neu, HER2), ErbB-3 (HER3) and ErbB-4. EGFR overexpression or overactivation can result from mutations locking the receptor in a state of continual signaling or from abnormally high levels of EGFR ligands released from tumor cells or non-tumor cells of the tumor microenvironment [5]. These ligands include epidermal growth factor (EGF), transforming growth factor (TGF)-α, heparin-binding EGF-like growth factor (HB-EGF), betacellulin, amphiregulin (AREG), and epiregulin (EREG) [6]. Dimerization causes EGFR autophosphorylation at specific tyrosine residues in its intracellular domain, triggering downstream signaling pathways that are often overactivated in malignant cells during tumor progression [7]
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