Targeting of Bone-Derived Insulin-Like Growth Factor-II by a Human Neutralizing Antibody Suppresses the Growth of Prostate Cancer Cells in a Human Bone Environment

Abstract

Purpose: Advanced prostate cancer frequently involves the bone, where the insulin-like growth factor (IGF)-II is abundant. However, the importance of IGF-II in bone metastasis from prostate cancer is uncertain. The present study was aimed at examining the therapeutic importance of targeting IGF-II in bone metastases from prostate cancer.Experimental Design: We investigated whether inhibiting IGF-II using a human neutralizing antibody (m610) suppresses the growth of prostate cancer cells in a human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of nonobese diabetic/severe combined immunodeficient mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody (m102.4) once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells.Results: Histomorphologic examination indicated that m610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. m610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. m610 prevented the in vitro IGF-II-induced proliferation of MDA PCa 2b cells.Conclusions: Our results indicate that IGF-II plays an important role in the prostate cancer cell growth in human bone, suggesting that targeting it by neutralizing antibodies offers a new therapeutic strategy for bone metastasis from prostate cancer. Clin Cancer Res; 16(1); 121-9. ©2010 AACR.Bone has long been recognized as the most common target organ for prostate cancer metastasis (1, 2). Bone metastasis causes skeletal complications and results in poor prostate cancer outcome in patients (3). Unfortunately, the efficacy of conventional therapies, including androgen deprivation, for the bone metastasis is limited. Despite extensive efforts to develop new therapeutic approach, more efficient treatment of bone metastases from prostate cancer has not been established.Although the precise reason why prostate cancer cells prefer bone tissue is not fully understood, one hypothesis is that the bone is a source of abundant growth factors required for the growth and survival of prostate cancer cells (4). Previously, we established a bone-specific metastasis model of human prostate cancer to investigate the mechanism of bone metastasis from prostate cancer (5). Using this model, in which human adult bones (HAB) were engrafted in mice, we showed previously that the release of growth factors, such as insulin-like growth factors (IGF), arising from bone resorption induced by the tumor cells was important for bone metastasis from prostate cancer (6, 7).IGFs are the most abundant growth factors stored in bone matrix (8). The actions of IGFs are inhibited when they bind to IGF-binding proteins. Prostate cancer cells are known to secrete certa...

Impaired mesenchymal stem cell differentiation and osteoclastogenesis in mice deficient for Igf2-P2 transcripts

“…We showed that the OPN mRNA level was completely dependent on IGF2 signaling during differentiation of MSCs into CFU-ALP. Establishing the link between IGF2 signaling and OPN is of major interest, as these two molecules are strongly involved in many physiological processes, such as proliferation, cell survival, cell migration and tissue remodeling (Suzuki et al, 2002;Bellahcène et al, 2008), and also in many pathological processes, such as dissemination of cancer cells, in particular breast or prostate cancer cells (Wai and Kuo, 2008), which are highly IGFdependent and form metastasis preferentially in the bone (Kimura et al, 2010). OPN secreted by osteoblasts has also been shown to be a hematopoietic stem cell niche component (Stier et al, 2005).…”

The Role of Signaling Pathway on Osteoprogenitor Cell Behavior and Bone Formation

“…Researchers for the first time showed an origin of human mesenchyme stem cells, which is from the perivascular area (1)(2)(3). Furthermore, HMSC with special cluster of differentiation, such as CD 37 , CD 90 , and CD 40 with little increased expression of CD 14 , CD 34 , CD 45 , and human leucocyte-DR (HLA-DR) can differentiate to osteoblast cells (4). Researchers exploit HMSC from different sources, such as dental tissue, endometria menstrual, blood, peripheral blood, placenta and fetal membrane salivary gland, skin, synovial fluid, foreskin, endometrium amniotic fluid, subamniotic umbilical cord lining membrane, and Wharton jelly (5).…”

Human Monoclonal Antibodies Targeting Nonoverlapping Epitopes on Insulin-like Growth Factor II as a Novel Type of Candidate Cancer Therapeutics

“…We identified previously a human mAb to IGF-II, m610, which potently inhibited IGF-IR and IR signaling pathways and cancer cell growth in vitro (5) and in a mouse model with implanted human bone (6). To further increase its affinity, an Fab library with shuffled light chains was generated and panned against hIGF-II.…”

“…Although IR is also functionally important for glucose homeostasis, targeting IGF-II may be an ideal strategy, which could leave the insulin-IR interactions unaffected. Recently, several mAbs specific to IGF-II or cross-reactive against IGF-I and IGF-II have been identified that potently inhibit the growth and migration of human cancer cells in vitro and in vivo (4)(5)(6)(7)(8).…”