Two decades ago, researchers identified numerous members of the tumor necrosis factor (TNF) superfamily of cytokine receptors. Among them, the receptor activator of nuclear factor kappa B (RANK) has since emerged as a central player in bone physiology and beyond.
Inhibiting RANK signaling has proved a useful strategy in preventing the debilitating skeletalrelated events (SREs) that are associated with bone metastases in many patients with cancer.
Researchers are now uncovering hints of the importance of the RANK pathway at different stages of tumor development, from the early steps of tumorigenesis to the establishment and maintenance of the metastatic niche, in addition to its role in other physiological processes linked to cancer development, such as inflammation and immunity.
As a result, investigators are turning their focus to the study of patient outcomes beyond bone health, and early results have raised the possibility that exploiting this strategy can help treat and possibly even prevent the development of certain cancers. Thus far, denosumab (Xgeva) is the only FDA-approved drug that directly inhibits RANK pathway activity. Ongoing studies are exploring a wider role for the agent as part of therapeutic regimens in a number of tumor types (Table)
Maintaining the Bone Niche
In order to repair and maintain the skeleton and ensure adequate levels of calcium in the body, bone is constantly being synthesized and destroyed. This complex process of remodeling is orchestrated by 2 major cell types: the osteoblasts (which build up the bone) and the osteoclasts (which break it down).
Osteoblasts are derived from mesenchymal stem cells and they synthesize and secrete type I collagen, which is the main structural component of the bone matrix, while osteoclasts originate from hematopoietic stem cells and produce hydrogen ions and protease enzymes that digest the bone matrix.
Table. Selected Clinical Trials of Denosumab in Cancer
aTrial ongoing but not recruiting participants.
bTrial not yet open for recruitment.
A plethora of different molecules produced by the bone and its surrounding environment maintain a tight balance of osteoblast and osteoclast function. As researchers sought to tease out the underlying molecular mechanisms, the RANK receptor, a member of the TNF superfamily, and its only known receptor RANKL, emerged front and center in the bone remodeling process through their effects on osteoclasts.
RANKL, in its membrane-bound form, is found on the surface of osteoblasts and various cells within the bone microenvironment. The ligand can also be cleaved from the membrane by proteases and found in a soluble form. Both forms of the ligand are able to activate the receptor and it is unclear whether the 2 have different functions, although it is suspected their roles may be dependent upon the context in which RANK activation is required.
RANK is expressed on the surface of osteoclast precursors and mature osteoclasts. Similar to other members of this family of receptors, RANK itself does not possess any enzymatic activity.
Instead, upon RANKL binding, the receptor recruits a range of adaptor molecules that propagate the signal—central among them, the TNF receptor associated factors (TRAFs)—by activating downstream signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen- activated protein kinase (MAPK) cascades.
Ultimately, this initiates a transcriptional program within the nucleus that coordinates the differentiation, activation, and survival of osteoclasts. RANK and RANKL are 2 members of a triad of molecules that keep the process of osteoclastogenesis tightly in check. The third member is osteoprotegerin (OPG), a natural decoy receptor for RANKL. It competes with RANKL for binding to RANK and thus helps to propagate a feedback loop that balances osteoclast activation and inhibition (Figure)
Master of Bone Metastasis
Tumor metastases are responsible for the vast majority of all cancer-related deaths. Although the bone is not the most common site of metastasis, some tumor types show a striking preference for metastasizing to the skeletal system; in particular, bone metastases occur in more than 70% of breast and prostate cancers. Bone metastasis is associated with particularly poor quality of life for patients because of its painful effects on the skeletal and nervous systems.
High levels of RANK and RANKL expression have been noted in a variety of different cancers, including breast, prostate, and lung cancer, as well as multiple myeloma and melanoma. RANK is frequently found to be expressed by cancer cells, while RANKL is often upregulated in the tumor microenvironment. It is now widely thought that RANK signaling may, in part, explain the tendency of some tumors to metastasize to the bone.