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Targeting RANKL in metastasis.

Dougall WC, Holen I, González Suárez E - Bonekey Rep (2014)

Bottom Line: Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival.In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts.Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells.

View Article: PubMed Central - PubMed

Affiliation: Therapeutic Innovation Unit, Amgen Inc , Seattle, WA, USA.

ABSTRACT
Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival. Preclinical data have now firmly established that blockade of tumor-induced osteoclastogenesis by RANKL inhibition will not only protect against bone destruction but will also inhibit the progression of established bone metastases and delay the formation of de novo bone metastases in cancer models. In patients with bone metastases, skeletal complications are driven by increased osteoclastic activity and may result in pathological fractures, spinal cord compression and the need for radiotherapy to the bone or orthopedic surgery (collectively known as skeletal-related events (SREs)). Denosumab, a fully human monoclonal antibody against RANKL, has been demonstrated to prevent or delay SREs in patients with solid tumors that have metastasized to bone. In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts. For example, RANKL also stimulates metastasis via activity on RANK-expressing cancer cells, resulting in increased invasion and migration. Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells. This review describes these distinct but potentially overlapping mechanisms by which RANKL may promote metastases.

No MeSH data available.


Related in: MedlinePlus

Interaction with the bone microenvironment supports tumor metastasis. OPG, osteoprotegerin; RANKL, RANK ligand.
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License
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f1: Interaction with the bone microenvironment supports tumor metastasis. OPG, osteoprotegerin; RANKL, RANK ligand.

Mentions: Skeletal metastasis results from reciprocal engagement between tumor cells and normal host cells of the bone microenvironment (for example, osteoclasts, stromal cells, vascular cells and so on; Figure 1). The resultant bone destruction and skeletal complications are mediated by a pathologically increased rate of bone remodeling driven by marked increases in osteoclast activity. This cooperative interaction between the bone microenvironment and tumor is known as the vicious cycle and is critical for metastatic establishment and progression.6 Thus, the increased bone turnover driven by osteoclastic bone resorption not only contributes to skeletal morbidity, but has also been hypothesized to contribute to both early tumor colonization and later progression in bone. Data supporting this hypothesis have been comprehensively described in a recent review by Weilbaecher et al.7 Given that RANKL is essential for osteoclastogenesis, it is also an attractive therapeutic target for the prevention and treatment of metastatic bone disease.


Targeting RANKL in metastasis.

Dougall WC, Holen I, González Suárez E - Bonekey Rep (2014)

Interaction with the bone microenvironment supports tumor metastasis. OPG, osteoprotegerin; RANKL, RANK ligand.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4007167&req=5

f1: Interaction with the bone microenvironment supports tumor metastasis. OPG, osteoprotegerin; RANKL, RANK ligand.
Mentions: Skeletal metastasis results from reciprocal engagement between tumor cells and normal host cells of the bone microenvironment (for example, osteoclasts, stromal cells, vascular cells and so on; Figure 1). The resultant bone destruction and skeletal complications are mediated by a pathologically increased rate of bone remodeling driven by marked increases in osteoclast activity. This cooperative interaction between the bone microenvironment and tumor is known as the vicious cycle and is critical for metastatic establishment and progression.6 Thus, the increased bone turnover driven by osteoclastic bone resorption not only contributes to skeletal morbidity, but has also been hypothesized to contribute to both early tumor colonization and later progression in bone. Data supporting this hypothesis have been comprehensively described in a recent review by Weilbaecher et al.7 Given that RANKL is essential for osteoclastogenesis, it is also an attractive therapeutic target for the prevention and treatment of metastatic bone disease.

Bottom Line: Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival.In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts.Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells.

View Article: PubMed Central - PubMed

Affiliation: Therapeutic Innovation Unit, Amgen Inc , Seattle, WA, USA.

ABSTRACT
Acting through its cognate receptor, receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) is an essential mediator of osteoclast function and survival. Preclinical data have now firmly established that blockade of tumor-induced osteoclastogenesis by RANKL inhibition will not only protect against bone destruction but will also inhibit the progression of established bone metastases and delay the formation of de novo bone metastases in cancer models. In patients with bone metastases, skeletal complications are driven by increased osteoclastic activity and may result in pathological fractures, spinal cord compression and the need for radiotherapy to the bone or orthopedic surgery (collectively known as skeletal-related events (SREs)). Denosumab, a fully human monoclonal antibody against RANKL, has been demonstrated to prevent or delay SREs in patients with solid tumors that have metastasized to bone. In addition to its central role in tumor-induced osteolysis, bone destruction and skeletal tumor progression, there is emerging evidence for direct pro-metastatic effects of RANKL, independent of osteoclasts. For example, RANKL also stimulates metastasis via activity on RANK-expressing cancer cells, resulting in increased invasion and migration. Pharmacological inhibition of RANKL may also reduce bone and lung metastasis through blockade of the direct action of RANKL on metastatic cells. This review describes these distinct but potentially overlapping mechanisms by which RANKL may promote metastases.

No MeSH data available.


Related in: MedlinePlus