Prostate cancer mediates osteoclastogenesis through two different pathways

Inoue, Hitoshi; Nishimura, Kazuo; Oka, Daizo; Nakai, Yasutomo; Shiba, Masahiro; Tokizane, Takashi; Arai, Yasuyuki; Nakayama, Masashi; Shimizu, Kiyonori; Takaha, Natsuki; Nonomura, Norio; Okuyama, Äkïhïko

doi:10.1016/j.canlet.2004.09.053

Cited by 30 publications

(27 citation statements)

References 32 publications

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“…Furthermore, it has been recently reported that CM from DU145 cells increases the local RANKL/OPG ratio by stimulating RANKL expression without any change in OPG's [5]. These findings are all consistent with a high trend of prostate cancer metastases to bone.…”

Section: Discussionsupporting

confidence: 77%

“…Thus, RANK expressed on both osteoclasts and prostate cancer cells in tumoral bone microenvironment has a propensity for prostate cancer bone metastasis development by synergic effect. Indeed, despite its overall osteoblastic profile, recent evidences suggested the significant involvement of osteolytic lesion preceding osteoblastic prostate cancer bone metastasis development [4][5][6][7][8][9].…”

Section: Discussionmentioning

confidence: 99%

“…Unlike other solid tumors that are associated with osteolytic bone metastases, prostate cancer bone metastases stimulate an overall increase in both bone remodelling and bone volume [3]. In contrast, recent findings strongly suggest the importance of osteoclast function [4][5][6][7][8][9]; however the mechanisms underlining these processes are not fully determined.…”

Section: Introductionmentioning

confidence: 99%

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DU145 human prostate cancer cells express functional receptor activator of NFκB: New insights in the prostate cancer bone metastasis process

Mori

Goff

Charrier

et al. 2007

Bone

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. and PC3 express biologically functional RANK. Indeed, soluble human RANKL (shRANKL, 100ng/ml) treatment induced ERK 1/2, p38 and IκB phosphorylations in these cells. shRANKL administration also promoted DU145 and PC3 prostate cancer cell invasion in vitro. Whereas human OPG (hOPG) administration alone (100ng/ml) had no marked effect, combined association of both agents abolished the RANKL-induced DU145 cell invasion. As RANKL had no direct effect on DU145 cell proliferation, the observed effects were indeed related to RANKL-induced cell migration. DU145 human prostate cancer cells promoted osteoclastogenesis of osteoclast precursors generated from mouse bone marrow. Moreover, DU145 cells produced soluble factor(s) that up-regulate the proliferation of MC3T3-E1pre-osteoblasts through the activation of the ERK 1/2 and STAT3 signal transduction pathways.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DU145 human prostate cancer cells express functional receptor activator of NFκB: New insights in the prostate cancer bone metastasis process

Mori

Goff

Charrier

et al. 2007

Bone

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“…The treatment with gefitinib demonstrated to be very effective in the reduction of bone metastases generated by PCb2 cells, which developed in less than 20% of the mice (Table 1). Although PC3 and its sub-lines caused severe osteolytic metastases in vivo, their conditioned medium or co-culture had no effect on maturation of mouse osteoclasts from precursor cells in vitro (data not shown) (Inoue et al 2005). In order to address the role of osteoblasts in the gefitinib induced reduction of lytic lesions, we performed primary culture from mouse bone marrow and evaluated the mRNA expression levels of the receptor activator of Nf-kappa-B ligand (RANKL, osteoclastogenesis inducer) and osteoprotegerin (OPG, osteoclastogenesis repressor) in osteoblasts (Fig.…”

Section: Reduction Of Experimental Bone Metastasis By Gefitinibmentioning

confidence: 97%

Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice

Angelucci¹,

Gravina²,

Rucci³

et al. 2006

Endocr Relat Cancer

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The activation of epidermal growth factor receptor (EGF-R) plays a key role in the promotion of proliferation and invasion in prostatic carcinoma (PCa). Gefitinib (Iressa; ZD1839), an orally active EGF-R tyrosine kinase inhibitor, has shown an important anti-proliferative activity in tumors expressing EGF-R both in vitro and in vivo. Our aim was to elucidate the role of gefitinib in the modulation of the metastatic spread of PCa cells. The therapeutic role of gefitinib was investigated by evaluating the proliferative and invasive ability of the PCa cell line PC3 and of its high metastatic sub-line, PCb2, by in vitro assays and intracardiac injection in nude mice. The inhibitory effect of gefitinib was tested in vivo by injecting PCa cells subcutaneously or in the left ventricle of nude mice and by administrating daily 150 mg/kg of gefitinib. While xenograft growth was equally reduced in all PCa lines (about 50%), the bone metastasis formation was inhibited especially for the high metastatic PCb2 sub-line (81%) in comparison to PC3 cells (47%). The comparative in vitro analysis among PCa cell lines showed that PCb2 cells were more sensitive to the inhibitory effect of gefitinib in their invasive ability compared to parental PC3 cells but not in their proliferation rate. Moreover, PCb2 cells demonstrated an increased invasive ability in vitro in response to bone stromal cell conditioned medium (BCM). The simultaneous presence of 0.1 ng/ml gefitinib was sufficient to reduce the number of invaded cells in the presence of both EGF and BCM. The molecular characterization of the highly aggressive PCa sub-lines demonstrated that this phenomenon was associated with an increment in uPA/uPAR axis but not in EGF-R expression. In conclusion, our data suggest that the use of gefitinib as a therapeutic agent may be indicated in the control of PCa spreading to bone.

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“…Increased osteoclastogenesis has been detected in prostate cancer bone metastases (3). The initial osteoclast-mediated osteolytic process is critical to the subsequent osteoblastic lesions, and a metastatic phenotype consists of a combination of both bone resorption and formation (4)(5)(6). A vicious cycle in the tumor cell-bone interface drives the metastasis, whereby growth factors secreted by tumor cells stimulate osteoclast formation and matrix turnover.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model

Yang

Bai

Yap

et al. 2010

Molecular Cancer Therapeutics

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The hematogenous metastatic spread of prostate cancer is preferentially to bone and can result in significant patient morbidity. Although these metastatic lesions are typically osteoblastic, bone resorption is believed to have a prerequisite role in their development. Src kinase has been identified to contribute to prostate cancer tumor growth and metastasis. In addition, Src is also essential in bone metabolism, especially in bone resorption. We hypothesized that inhibiting Src activity with the specific Src family kinase inhibitor saracatinib (AZD0530) would inhibit tumor cell growth and osteoclast differentiation in the tumor-bone interface, thus providing a new approach for advanced prostate cancer. We found that saracatinib inhibited PC-3 cell growth and invasion in a dose-dependent manner. Phosphorylation of Src, focal adhesion kinase, and P38 kinases was inhibited by saracatinib at the submicromolar range. Saracatinib also inhibited the expression and secretion of invasion-related molecules interlukin-8, urokinase-type plasminogen activator, and matrix metalloprotease-9. Receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and signaling were inhibited by saracatinib in both macrophages and PC-3 cells. In in vivo studies, control mice developed more severe osteolytic lesions compared with the treatment group. Immunohistochemical and biochemical assays of bone metabolites confirmed that saracatinib preserved bone architecture in the presence of prostate cancer tumor cells. In summary, we have shown the inhibition of PC3 cell growth and invasion by saracatinib. Src inhibition also blocked the RANKL stimulatory pathway in osteoclasts and PC3 cells. The inhibition of Src thus targets multiple sites involved in prostate cancer bone metastasis, which may offer a therapeutic advantage in treating advanced prostate cancer. Mol Cancer Ther; 9(6); 1629-37. ©2010 AACR.

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Prostate cancer mediates osteoclastogenesis through two different pathways

Cited by 30 publications

References 32 publications

DU145 human prostate cancer cells express functional receptor activator of NFκB: New insights in the prostate cancer bone metastasis process

DU145 human prostate cancer cells express functional receptor activator of NFκB: New insights in the prostate cancer bone metastasis process

Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice

Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model

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