Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis.
Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.
Chen
Haiming
H
Institute for Myeloma & Bone Cancer Research, West Hollywood, CA 90069, USA.
Campbell
Richard A
RA
Chang
Yunchao
Y
Li
Mingjie
M
Wang
Cathy S
CS
Li
Jennifer
J
Sanchez
Eric
E
Share
Michael
M
Steinberg
Jeffrey
J
Berenson
Ariana
A
Shalitin
Dror
D
Zeng
Zhaohui
Z
Gui
Dorina
D
Perez-Pinera
Pablo
P
Berenson
Ronald J
RJ
Said
Jonathan
J
Bonavida
Benjamin
B
Deuel
Thomas F
TF
Berenson
James R
JR
D000818:Animals; D002352:Carrier Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000209:etiology*; D014183:Transplantation, Heterologous; D020298:U937 Cells
D002352:Carrier Proteins; D016207:Cytokines; D004338:Drug Combinations; C066845:pleiotrophin; D049452:Green Fluorescent Proteins; D016173:Macrophage Colony-Stimulating Factor