Departments of Surgery (I.W.Y.M., N.E., and M.G.), Pathology and Molecular Science (S.P.), and Oncology (R.T.), McMaster University, 711 Concession Street, Hamilton, ON L8V 1C3, Canada. E-mail addresses for I.W.Y. Mak:
J Bone Joint Surg Am. 2014 Aug 6;96(15):e127. doi: 10.2106/JBJS.M.01332.
Giant cell tumor of bone is a primary bone tumor that is treated surgically and is associated with high morbidity in many cases. This tumor consists of giant cells expressing RANK (receptor activator of nuclear factor-κB) and mesenchymal spindle-like stromal cells expressing RANKL (RANK ligand); the interaction of these cells leads to bone resorption. Denosumab is a monoclonal antibody that binds RANKL and directly inhibits osteoclastogenesis. Clinical studies have suggested clinical and histological improvement when denosumab was administered to patients with a giant cell tumor. However, no studies have yet examined the viability and functional characteristics of tumor cells following denosumab treatment.
Specimens were obtained from six patients with a histologically confirmed giant cell tumor. Two of the patients had been treated with denosumab for six months. Primary cultures of stromal cells from fresh tumor tissue were established. Cell proliferation was measured over a two-day time course. The expression of RANKL and osteoprotegerin was analyzed with use of real-time PCR (polymerase chain reaction).
Histological specimens from both patients who had completed denosumab treatment showed the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. The expression of RANKL in the specimens from the treated patients was almost completely eliminated.
Once the giant cell tumor tissue was no longer exposed to denosumab, the stromal cells continued to proliferate in vitro, albeit to a lesser degree. However, they also showed almost complete loss of RANKL expression.
It is clear that treatment with denosumab only partially addresses the therapeutic need of patients with a giant cell tumor by wiping out the osteoclasts but leaving the neoplastic stromal cells proliferative.
骨巨细胞瘤是一种原发性骨肿瘤，通过手术治疗，在许多情况下与高发病率相关。这种肿瘤由表达 RANK（核因子-κB 受体激活物）的巨细胞和表达 RANKL（RANK 配体）的间质梭形基质细胞组成；这些细胞的相互作用导致骨质吸收。地舒单抗是一种单克隆抗体，与 RANKL 结合并直接抑制破骨细胞生成。临床研究表明，地舒单抗给药可改善巨细胞瘤患者的临床和组织学表现。然而，目前尚无研究检测地舒单抗治疗后肿瘤细胞的活力和功能特征。
从六例经组织学证实的巨细胞瘤患者中获得标本。其中两名患者接受地舒单抗治疗六个月。从新鲜肿瘤组织中建立基质细胞的原代培养物。在两天的时间过程中测量细胞增殖。使用实时 PCR（聚合酶链反应）分析 RANKL 和骨保护素的表达。
两名完成地舒单抗治疗的患者的组织学标本均显示巨细胞消失但基质细胞持续存在。细胞增殖研究表明，与未经治疗的患者相比，经地舒单抗治疗后培养的临床标本中的基质细胞增殖速度约慢 50%。治疗患者标本中的 RANKL 表达几乎完全消除。
一旦巨细胞瘤组织不再接触地舒单抗，基质细胞在体外继续增殖，尽管程度较轻。然而，它们也表现出几乎完全丧失 RANKL 表达。
很明显，用地舒单抗治疗仅通过消灭破骨细胞部分解决了巨细胞瘤患者的治疗需求，但使肿瘤性基质细胞仍具有增殖性。
