Inhibition of bone-derived insulin-like growth factors by a ligand-specific antibody suppresses the growth of human multiple myeloma in the human adult bone explanted in NOD/SCID mouse.
Multiple myeloma (MM) is a fatal disease that affects plasma cells. Patients with MM have 1 or more osteolytic lesions in their bone tissues, where insulin-like growth factors (IGFs; IGF-I and IGF-II) are mainly stored. The role of bone-derived IGFs in the development of MM has not been extensively studied because reliable animal models are lacking. We established an animal model using a human MM cell line, RPMI8226, in nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice implanted with human adult bone (HAB) fragments. Treatment with an anti-human IGF-neutralizing monoclonal antibody, KM1468, inhibited the IGF-I-stimulated phosphorylation of type-I IGF receptors (IGF-IR) in RPMI8226 cells and the activation of the downstream PI3-K/Akt signaling pathway in vitro. KM1468 inhibited IGF-I-mediated RPMI8226 cell growth in a dose-dependent manner. In the NOD/SCID-HAB model, treatment with KM1468 significantly inhibited the growth of RPMI8226 cells (p<0.02). These results indicated that the growth of MM cells was predominantly stimulated not by serum-derived IGFs, but by bone-derived IGFs. Furthermore, the targeting of bone-derived IGFs, using a neutralizing antibody, may offer a new therapeutic strategy for MM.
Araki
Kazuhiro
K
Pathology Division, National Cancer Center Research Institute East, Chiba, Japan.
Sangai
Takafumi
T
Miyamoto
Shin'ichi
S
Maeda
Hiroyuki
H
Zhang
Shi-Chuan
SC
Nakamura
Michio
M
Ishii
Genichiro
G
Hasebe
Takahiro
T
Kusaka
Hideaki
H
Akiyama
Tadakazu
T
Tokuda
Yoshimi
Y
Nagai
Kanji
K
Minami
Hironobu
H
Ochiai
Atsushi
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001842:Bone and Bones / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000503:physiopathology*; D010766:Phosphorylation; D015398:Signal Transduction; D013002:Somatomedins / Q000096:biosynthesis* / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D008024:Ligands; D013002:Somatomedins