Cancer Cells Responsible for Humoral Hypercalcemia Express mRNA Encoding a Secreted Form of ODF/TRANCE That Induces Osteoclast Formation

Nagai, Masazumi; Kyakumoto, Seiko; Sato, Nobuko

doi:10.1006/bbrc.2000.2314

Cited by 87 publications

(57 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The latter may be generated from cleavage of a cellular form by TACE 25 or may be a primary secreted form that has been described in activated T lymphocytes as well as in a squamous carcinoma cell line. 26 Our findings demonstrated that in SH-SY5Y both RANKL forms were detectable and active: indeed, osteoclast formation was induced not only by the juxtacrine cell-cell interaction but also by the paracrine activity of the culture medium. Analysis of the transcript from sRANKL did not reveal amplification.…”

Section: Discussionsupporting

confidence: 52%

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

Granchi

Amato

Battistelli

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

Proliferation and differentiation of osteoclasts are regulated by a cytokine system that includes RANKL, which binds 2 receptors: RANK, which activates osteoclast differentiation, and osteoprotegerin (OPG), a decoy receptor that limits RANKL action. We investigated the role of the OPG/ RANKL/RANK network in the pathogenesis of skeletal metastasis in neuroblastoma. Four different neuroblastoma cell lines (NB100, CHP212, SH-SY5Y, SJ-NK-P) showed a large amount of OPG and RANKL transcripts. Soluble RANKL was detectable in all cell lines, but poor release of OPG was observed. SH-SY5Y showed the lowest OPG-to-RANKL ratio and promoted osteoclastic differentiation of FLG29.1 and peripheral mononuclear cells, inducing expression of the osteoclast markers RANK, c-src, c-fos, cathepsin-K and TRAP. SJ-N-KP, which released both OPG and RANKL, did not show the same capability. OPG, neutralizing anti-RANKL antibody and antisense oligonucleotides were evaluated for their ability to inhibit RANKL activity. The neutralizing antibody hampered osteoclastic differentiation by blocking both the juxtacrine and the paracrine activity of RANKL. Our findings confirm that neuroblastoma cells induce osteoclastogenesis via RANKL and suggest that the RANKL expression associated with lack of the decoy receptor OPG could be a peculiarity of some tumors that makes them able to induce metastatic osteolysis. Moreover, our results suggest that RANKL could be a relevant target in the adjuvant therapy of bone metastatic neuroblastoma as proper neutralization revokes completely osteoclastic differentiation. © 2004 Wiley-Liss, Inc. Key words: neuroblastoma; bone metastasis; osteoclast; RANKL; osteoprotegerinMetastasis is the most relevant prognostic factor for survival in neuroblastoma patients, and bone is one of the target organs of metastasis in advanced neuroblastoma. Patients with bone metastasis are classified as stage IV, regardless of other clinical manifestations, since the presence of bone/bone marrow metastasis is responsible for poor prognosis despite high-dose chemotherapy and autologous hematopoietic stem cell transplantation. 1 One possible reason for this ominous prognosis is the difficulty in reaching cancer cells that have colonized the bone/bone marrow microenvironment. This suggests the need for effective therapeutic modalities for patients with skeletal metastases based on a precise understanding of the pathophysiology of bone colonization in neuroblastoma. Two classical theories are generally advocated to explain the invasion of tumor cells in bone, i.e., the soil hypothesis 2 and the circulation theory. 3 The first suggests that proper factors favor the implantation of metastatic cells, including nutrients, oxygen tension, hormonal environment and hydrogen ion concentrations. The second assumes that development of cancer metastases is dependent on the blood volume inside a target organ. This hemodynamic theory alone cannot explain the high frequency of skeletal metastasis from some neoplasms because blood flow in bone is very p...

show abstract

Section: Discussionsupporting

confidence: 52%

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

Granchi

Amato

Battistelli

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Several oral SCC cells in patients and oral SCC cell lines express RANKL (38)(39)(40). Recently, Chuang et al compared RANKL expression between buccal SCC without bone invasion (25 cases) and gingival SCC with invasion (15 cases).…”

Section: Rankl/rank Signaling Is Involved In Oral Scc Cell-induced Osmentioning

confidence: 99%

“…It has been reported that cancer cells expressing RANKL are able to induce osteoclastogenesis even in the absence of other accessory cells (38,42). On the other hand, not all cancers express RANKL, and cell-to-cell contact between cancer cells and host cells does not always lead to RANKL expression (43,44).…”

Section: Rankl/rank Signaling Is Involved In Oral Scc Cell-induced Osmentioning

confidence: 99%

The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma

Jimi

Shin

Furuta

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Squamous cell carcinomas (SCCs) of the gingiva frequently invade the mandible or maxilla; this invasion is associated with a worse prognosis. The bone destruction associated with carcinomal invasion is mediated by osteoclasts rather than directly by the carcinoma. Therefore, if the cellular and molecular mechanisms by which oral SCC regulates bone invasion were known, it could inform the development of new therapeutic targets. Recently, dysregulation of the functional equilibrium in the receptor activator of NF-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad has been shown to be responsible for osteolysis associated with the development of malignant tumors in bone sites. Furthermore, the administration of OPG or soluble RANK prevents bone metastasis by cancer cells. In this review, we discuss recent findings indicating that bone invasion by oral SCC is mediated via RANKL/RANK and may be successfully prevented by RANKL inhibition.

show abstract

“…28 On the other hand, cancer cells expressing RANKL directly were able to induce osteoclastogenesis even in the absence of other accessory cells. 25,29 It has been reported that BHY cells, a human oral SCC cell line, invaded mandibular bone when these cells were mixed with human gingival fibroblasts and injected into the masseter muscle. 30 In our present study, we examined how oral SCC cells regulate osteoclast formation using in vitro culture systems.…”

mentioning

confidence: 99%

“…18 The RANKL/RANK signaling pathway regulates bone invasion or bone metastasis by several types of human cancer, such as breast cancer, 19,20 prostate cancer, 21,22 myeloma 23,24 and oral SCC. 25 Interesting and controversial new questions have arisen concerning the direct expression and production of RANKL by human cancer cells: Some evidence suggests that RANKL/OPG expression ratio in osteoblasts/stromal cells is the critical factor regulating osteoclastogenesis under both physiological and pathological conditions. 9,26,27 Moreover, T lymphocytes appear to play a role in the regulation of bone resorption through RANKL expression.…”

mentioning

confidence: 99%

Oral squamous cell carcinoma cells induce osteoclast differentiation by suppression of osteoprotegerin expression in osteoblasts

Tada

Jimi

Okamoto

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

The invasion of oral squamous cell carcinoma (SCC) cells into the mandibular bone is a common clinical problem. It has been reported that BHY cells, a human oral SCC cell line, are capable of invading mandibular bone of nude mice. These results led us to examine possible mechanisms of osteoclastogenesis induced by BHY cells using in vitro culture systems. When BHY cells were cocultured with mouse bone marrow cells (BMCs), only few osteoclasts were formed, even though BHY cells express the receptor activator of NF-jB ligand (RANKL). However, adding BHY cells to a coculture of mouse primary osteoblasts (POBs) and BMCs markedly induced osteoclastogenesis in the absence of osteotropic factors. Furthermore, another oral SCC cell line, HSC-2, which does not express RANKL, also induced osteoclastogenesis in our cocultures. These effects were significantly, but not completely, inhibited by adding osteoprotegerin (OPG). In addition, we also found that TNFa released from these cells partially contributes to osteoclastogenesis via a RANKL-independent mechanism. Adding BHY or HSC-2 cells suppressed mouse OPG mRNA expression and protein production by POBs in cocultures of POBs and human oral SCC cells. This finding is consistent with the result that BHY cells and HSC-2 cells did not enhance osteoclastogenesis in cocultures of BMCs and POBs from OPG-deficient mice. Immunohistochemical analysis showed a reduction of OPG expression in osteolytic lesions as compared to normal lesions from oral SCC patients. Therefore, oral SCC-induced suppression of OPG expression in POBs appears critical for osteoclastogenesis, rather than expression of RANKL in SCC cells. ' 2005 Wiley-Liss, Inc.Key words: squamous cell carcinoma; RANKL; OPG; osteoclastogenesis Oral cancer most commonly involves the tissue of the tongue and the lips, and it can also occur on the floor of the mouth, gingiva or plate.1,2 The vast majority of oral cancers are squamous cell carcinomas (SCCs) 1,2 and oral SCCs frequently invade the mandibular bone. Advanced oral SCC has a high mortality and treatment is complicated by the disruption of speech and swallowing after surgical resection. It is generally agreed that patients with mandibular invasion should be treated surgically, but the extent of mandibular resection required remains controversial. Resection of the mandibular bone leads to physical damage as well as frequent psychological problems for the patients.It is well known that oral SCC invades the mandibular bone by direct extension and not by metastasis.3,4 Previous studies have suggested that the bone destruction associated with carcinoma invasion is mediated by osteoclasts rather than directly by the carcinoma.3,4 Invasion of the mandible by oral SCC is currently established only by radiological inspection. The cellular and molecular mechanisms regulating bone invasion and osteoclastic bone resorption by oral SCC are poorly understood.Osteoclasts are multinucleated cells that are responsible for bone resorption. [5][6][7] Osteoclastic bone resorption consists...

show abstract

Cancer Cells Responsible for Humoral Hypercalcemia Express mRNA Encoding a Secreted Form of ODF/TRANCE That Induces Osteoclast Formation

Cited by 87 publications

References 36 publications

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

In vitro blockade of receptor activator of nuclear factor‐κB ligand prevents osteoclastogenesis induced by neuroblastoma cells

The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma

Oral squamous cell carcinoma cells induce osteoclast differentiation by suppression of osteoprotegerin expression in osteoblasts

Contact Info

Product

Resources

About