Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Abstract

Abstract. Receptor activator of nuclear factor κB (RANK), a member of the tumour necrosis factor family, is activated by its ligand and regulates the differentiation of osteoclasts and dendritic cells. Local growth of osteosarcoma involves destruction of the host bone by osteoclasts and proteolytic mechanisms. Although the prognosis of patients with osteosarcoma has been improved by advances in chemotherapy over the last four decades, the issues of non-responders, and the lack of effective prognostic markers have remained. The present study aimed to investigate the prognostic and predictive value of RANK expression in human osteosarcoma. The expression of RANK was immunohistochemically evaluated in biopsies of 43 patients (mean age 25.4 years) with high-grade osteosarcoma, and was found to be correlated with histological response to chemotherapy, disease-free status and overall survival. RANK expression was detected in eight of the 43 osteosarcoma specimens (18%), whereas the remaining specimens were negative for RANK. A statistically significant correlation was detected between RANK expression and the overall survival of patients. A total of 7/8 patients with RANK-expressing tumours succumbed to the disease (88% mortality rate amongst patients with RANK-positive tumours vs. 37% with RANK-negative tumours; P<0.05). No significant difference was found when comparing RANK expression status with response to chemotherapy; 50% of RANK-positive patients exhibited a poor response to chemotherapy, compared with 66% in the RANK negative group. In addition, the appearance of metastases was not correlated with RANK expression status (38% metastases in RANK-positive tumours vs. 34% in RANK-negative tumours). In conclusion, the results of the present study suggested that RANK expression is likely to be of prognostic, but not of predictive, value.

RANK–RANKL signalling in cancer

“…Bago-Horvath et al revealed that RANKL expression was significantly more common in osteosarcoma of the lower extremity than in any other location and did not find any significant correlation between RANKL and disease-free or osteosarcoma-specific survival. However, they did report that RANK expression is a negative prognostic factor regarding disease-free survival, confirming the data obtained by Trieb and Windehager [ 89 ]. Interestingly, in 2012, Papanastasiou et al [ 91 ] identified a new isoform of RANK (named RANK-c) generated by alternative splicing and expressed in breast cancer samples.…”

“…RANK expression was also described as being predictive of poor prognosis in bone metastatic patients but not in patients with visceral metastases [ 88 ]. Similarly, sarcoma cells also express RANK (18–69% depending on the series) [ 79 , 89 , 90 ] and expression is correlated with clinical parameters. Trieb and Windhager [ 89 ] described a reverse correlation between RANK expression and the overall survival of patients with osteosarcoma, but not with the response to chemotherapy.…”

“…Similarly, sarcoma cells also express RANK (18–69% depending on the series) [ 79 , 89 , 90 ] and expression is correlated with clinical parameters. Trieb and Windhager [ 89 ] described a reverse correlation between RANK expression and the overall survival of patients with osteosarcoma, but not with the response to chemotherapy. These authors observed lower disease-free and overall survival rates in patients presenting RANK positive tumours.…”

The RANK–RANKL axis: an opportunity for drug repurposing in cancer?

“…Additionally, high RANK expression has been linked to a shorter PFS (p = 0.01) and OS (p = 0.02) in endometrial cancer [36]. RANK-positive osteosarcomas are also associated with higher mortality than RANKnegative cases (p < 0.05) [41]. A high RANKL expression has been associated with higher stage disease (p = 0.035) and a shorter OS (p = 0.008) in gastric cancer [37].…”

“…The relative levels of RANK/RANKL/OPG expression may influence prognosis in numerous cancer types including breast, lung, endometrial, renal cell and gastric cancers, osteosarcoma and multiple myeloma (Fig. 4a, b) [34][35][36][37][38][39][40][41]. In breast cancer, microarray analysis demonstrated that low RANK and high OPG expression were associated with longer OS (p = 0.0078 and p = 0.034, respectively) and disease-free survival (p = 0.059 and p = 0.040, respectively) [34].…”