RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

Department of Hematology, Amgen Inc., Seattle, Washington 98119, USA.
The Prostate (Impact Factor: 3.57). 01/2008; 68(1):92-104. DOI: 10.1002/pros.20678
Source: PubMed

ABSTRACT Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-kappaB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells.
Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro.
OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix.
These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner.

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Available from: Allison Jacob, Jun 17, 2014
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    • "Interestingly, numerous tumour cells expressed functional RANK as shown by the signal transduction (P-ERK1/2, P-P38, P-IkB, etc.) induced by RANKL [39] [47] [50]. The first evidence of this mechanism has been established by Jones et al. [45] and has been now described as prostate carcinoma [45] [47] [48], breast carcinoma [45], oral squamous carcinoma [50], lung cancer cells [52] and melanoma [45]. The implication of RANK/RANKL axis in tumour cell migration has been confirmed by exploration in human samples. "
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    ABSTRACT: Bone remodelling is related to coordinated phases of bone resorption and bone apposition allowing the maintenance of bone integrity, the phosphocalcic homoeostasis all along the life and consequently the bone adaptation to mechanical constraints or/and to endocrine fluctuations. Unfortunately, bone is a frequent site of tumour development originated from bone cell lineages (primary bone tumours: bone sarcomas) or from nonosseous origins (bone metastases: carcinomas). These tumour cells disrupt the balance between osteoblast and osteoclast activities resulting in a disturbed bone remodelling weakening the bone tissue, in a strongly altered bone microenvironment and consequently facilitating the tumour growth. At the early stage of tumour development, osteoclast differentiation and recruitment of mature osteoclasts are strongly activated resulting in a strong bone matrix degradation and release of numerous growth factors initially stored into this organic/calcified matrix. In turn these soluble factors stimulate the proliferation of tumour cells and exacerbate their migration and their ability to initiate metastases. Because Receptor Activator of NFκB Ligand (RANKL) is absolutely required for in vivo osteoclastogenesis, its role in the bone tumour growth has been immediately pointed out and has consequently allowed the development of new targeted therapies of these malignant diseases. The present review summarises the role of RANKL in the bone tumour microenvironment, the most recent pre-clinical and clinical evidences of its targeting in bone metastases and bone sarcomas. The following sections position RANKL targeted therapy among the other anti-resorptive therapies available and underline the future directions which are currently under investigations.
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    • "Numerous studies have shown that the underlying influence of these cellular transitions is a consequence of tumorstromal interactions [15] [16]. Coculture studies have found that the survival and proliferation of cancer cells are intimately linked to the soluble factors in the microenvironment, such as EGF, TGF-β, IGF-l that contribute to survival and the subsequent formation of macrometastasis [17] [18] [19] [20]. However, these factors are not likely to have a direct effect during initial metastatic colonization, and thus heterotypic and homotypic cellular adhesion has been proposed to provide the necessary survival signals for successful colonization [21] [22]. "
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    Journal of Oncology 07/2010; 2010. DOI:10.1155/2010/232831
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    • "Growth of prostate tumors in bone and the accompanying metastatic bone disease presents an imbalance in the normal process of bone remodeling (formation and resorption) as a result of factors secreted by the tumor cells (Guise et al., 2006). These signaling proteins include the receptor activator of NF-κB ligand (RANKL) (Brown et al., 2001; Armstrong et al., 2008), parathyroid hormone related protein (PTHrP) and interleukin 8 (IL8) (Bendre et al., 2005; Araki et al., 2007), that promote bone resorption, while endothelin and Wnt pathway factors promote osteoblastic lesions (Li et al., 2008b; Clines et al., 2007). "
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