Mechanism Of Bone Metastasis: The Role Of Osteoprotegerin And Of The Host-Tissue Microenvironment-Related Survival Factors

Main Category: Urology / Nephrology
Article Date: 26 Apr 2009 - 2:00 PDT

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Prostate cancer, the most frequently occurring cancer in men, very often metastasizes to bone, as more than 84% of patients demonstrate skeletal lesions ^{(1, 2-3)}. Although such metastases have been traditionally characterized to be osteoblastic, today it is well known that both bone formation and resorption are dysregulated and participate in the metastatic lesions ⁽⁴⁾. Therefore, it is interesting to investigate the role of osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, in the context of prostate cancer, as its overexpression by tumor cells could partly explain the osteoblastic phenotype of metastasis. ^{(1, 2-3)}

OPG has various biological functions including bone remodeling, as well as the protection of metastatic prostate cancer cells from apoptotic effects of TRAIL - and therefore provides tumor cells producing OPG with survival advantages. TRAIL (TNF- Related Apoptosis - Inducing Ligand) is secreted by monocytes and is responsible for their ability to induce the apoptotic mechanisms of tumor cells in vivo. OPG facilitates the survival of prostate cancer cells in vitro and this anti-apoptotic property seems to be due to its ability to bind to and inhibit the TRAIL death-activating receptors ⁽²⁾.

The first results of these investigations have revealed that prostate cancer cells produce and secrete OPG ⁽²⁾. Moreover, it has been shown that OPG can inhibit osteoclastogenesis ^(3,5). More specifically, prostate cancer cells can produce sRANKL, which may be responsible for the CaP-mediated osteoclastogenesis. OPG was shown to bind to sRANKL and completely prevent the establishment of mixed osteoblastic- osteolytic tumor lesions in bone, although it did not prevent the tumor growth. All together, these data show that the ability of OPG to prevent tumor growth in bone is affected by factors in the bone microenvironment. Moreover, inhibition of osteoclastic activity can prevent the establishment of prostate cancer in the skeleton ^(3,5).

Other in vitro studies ⁽⁶⁾ have revealed that OPG overexpression would decrease the growth of prostate metastatic tumors in the bone, without affecting the proliferation of cancer cells as a result of decreased bone lysis. Consequently, OPG influences the metastatic lesions in bone in an indirect manner.

Several studies have also been made to measure the levels of OPG in the serum of prostate cancer patients, in association with the progression of the disease. OPG serum levels are increased in patients with advanced prostate cancer and bone metastasis, compared with patients with primary disease, or without osseous lesions ⁽⁷⁾. These increased serum levels did not correlate well with serum PSA levels.

On the contrary, a more recent study ⁽⁸⁾ has revealed that human prostate cancer cells express RANK, RANKL and OPG in increased levels. In case of bone metastasis, the ratio OPG/RANKL was high. Interestingly, the overexpression of OPG/RANK/RANKL was observed in patients with other markers of advanced disease, such as Gleason score, TNM stage and serum PSA levels.

Several members of the TGF-_, such as TGF-_2, superfamily are also candidate mediators of osteoblastic metastasis, as in vivo they stimulate new bone formation ^(9-10). Prostate tumor cells express FGFs including FGF-1, -2 and -8 causing osteoblastic metastases.

Preventing a bone lesion from developing and limiting the progression of an established bone metastasis should be the primary goals of treating metastatic bone disease. However, the currently available therapies for bone metastasis such as bisphosphonates, radiotherapy, radiopharmaceuticals and surgery focus only on symptomatic management ^{(11, 12)}.



Figure: Mechanisms of osteoblastic lesions in cancer. Tumor cells directly contribute to osteoblastic lesions by producing ET-1 (endothelin-1), transforming growth factor _ (TGF-_), fibroblast growth factor (FGF), insulin-like growth factors (IGFs), platelet-derived growth factor (PDGF) and bone morphogenetic proteins (BMPs).


Written by Sofia Fili, Maria Karalakia, and Bernhard Schalle as part of Beyond the Abstract on UroToday.com

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