Aside from distinct technical approaches used the

Aside from distinct technical approaches used, the well-established RANKL and RANK expression patterns in the bone further substantiates the expression patterns defined in the current study of OS. RANKL and RANK play major roles in bone metabolism due to the critical role of this pathway in osteoclastogenesis [4]. That is, RANK is expressed with the hematopoietic myeloid compartment contributing to myeloid-derived osteoclasts and their precursors consistent with the observed compartmentalization of RANK expression within giant cells, osteoclasts and osteoclast precursors found within OS samples in the present study. Given that OS tumors may arise from a mesenchymal-osteoblast origin [1,2], it is unlikely that RANK would be expressed in the tumor ginsenoside rh2 while expression of RANKL in OS tumor cells is perhaps not surprising. In normal and pathologic bone, RANKL expression is confined to the cells of the osteoblast lineage, including osteocytes and has also been observed in certain tumor cells [33]. The observation herein of RANKL within reactive bone stroma in OS tumors as well as many OS cells themselves suggests that RANKL may stimulate osteoclast differentiation and activation potentially via multiple sources. Molyneux et al. [35] has reported that human and mouse OS with reduced expression of the gene encoding the regulatory subunit α (RIa) of PKA have high RANKL levels suggesting that pathways regulating RANKL expression may be dysfunctional in some OS. For any RANKL-positive OS, it remains unclear why RANKL is not expressed uniformly in all OS tumor cells as observed in the present study, suggesting that perhaps some element of local regulation observed in normal osteoblast-lineage cells (e.g. responsiveness to PTH1r) is retained by OS tumor cells. In mouse models of OS, pharmacologic inhibition of RANKL is protective against bone destruction and also decreases tumor burden [18–20]. This is likely related to osteoclast inhibition, as treatment with bisphosphonates lead to essentially similar responses [21]. The reduction in skeletal tumor burden observed with osteoclast inhibitors results from interruption of the vicious cycle in which decreased osteoclastic bone resorption and subsequent reduction in localized bone matrix and growth factors indirectly reduces tumor growth and survival. These pharmacology observations demonstrating similar anti-tumor activity of bisphosphonates and RANKL inhibitors are consistent with the absence of RANK on OS tumor cells and a contribution of RANK-positive osteoclasts associated with OS tumors (this study and Avnet et al. [10]) to the bone pathologies observed in OS and potential indirect feedback to the skeletal tumor. The observation that RANKL is expressed in OS cells themselves suggests that these tumors may mediate an osteoclastic response independently of (or in addition to) RANKL within the normal or tumor-reactive bone stroma. However, the absence of RANK expression in OS tumor cells indicates that an autocrine RANKL/RANK response in human OS tumor cells is unlikely to be operative. While anti-RANKL therapy may influence the bone microenvironment and may be protective against bone pathologies in OS, the lack of RANK expression in tumor cells suggests that this approach would not directly affect the tumor.
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Introduction There is an estimated 330,000 new cases of renal cell carcinoma (RCC) diagnosed each year worldwide, with over 100,000 deaths, and a rising incidence of 3% per year [1]. Although several advances in the treatment of metastatic RCC have occurred in the last decade, this disease remains one of the most deadly cancers with a 5-year survival rate of ∼10% [2–4]. The primary treatment for localized RCC is surgical resection alone. Although systemic therapies in the form of receptor tyrosine kinase (RTK) inhibitors and targets of the mTOR protein have improved length of survival for patients found to have advanced metastatic disease, there is a reluctance to start these treatments with significant side effects in patients with only localized disease [5,6], as many patients will not go on to develop metastatic disease if treated with surgery alone. Two important trends in RCC have been noted in the past decade. The first is that the incidence of localized disease has been increasing, despite a plateau in the number of abdominal CT scans performed that would normally detect such disease [7]. Secondly, the mortality rate for patients with localized disease has also increased. This is in the setting of no improvements in incidence or mortality rates for patients with advanced disease [7]. Despite our best efforts to detect and surgically treat early stage RCC, approximately 30% of patients will go on to develop advanced metastatic disease [1]. An area in which major improvements could be made is diagnostic radiology for those patients with localized disease and a high risk of developing metastases, as early-aggressive treatments could then be justified. To this end, we aim to identify novel-clinically relevant radiologic and molecular biomarkers that can differentiate the metastatic potential of RCC in patients with local disease. This may alter surveillance and possibly the indications for starting systemic treatment.