Bortezomib Suppresses Giant Cell Tumor Of Bone In Vivo And In Vitro

Comprising approximately 6% of all primary bone tumors, giant cell tumor of bone (GCT) is a kind of tumor with unknown etiology. It is a prominent lesion that presents with significant local osteolysis. The tumors arise predominantly in the epiphyses of long bones in the appendicular skeleton, but GCTs can occur in any other areas of the skeleton. Although it is rare for GCT to have distant metastases, the tumor is locally aggressive with large areas of bone damage. Surgical removal of the tumor is often the preferred treatment of GCT, although it is sometimes impractical or otherwise not desirable, and there is 15%-25% for GCTs to locally recur in many cases following surgery even 50% of some areas such as spine. GCT patients usually present with pain and limited range of motion caused by tumor’s proximity to the joint space. There may be swelling and pain as well, if the tumor has been growing for a long time. As the prevalence of GCT peaks during the 3rd decade, patients have to endure great pain for half of life.Because of complicated and unknown pathology GCT is still the one of most difficult clinical disease to overcome currently. Although surgical removal of a large area of tumor tissue is a recipe for giant cell tumor of bone, but the subsequent reconstruction of bone function is complex and often accompanied by various complications. When GCT is multicentric or arise in locations where surgical removal is very difficult, adjuvant medical treatment is needed. But no effective chemotherapy has been explored. There are only clinical drugs have been used which aimed at reducing bone resorption of giant cell including bisphosphonates and the monoclonal antibody denosumab.To exploring new treatment drug for GCT, we detected abnormal activated cytokine in serum by ELISA which highly expression of TNF-a and IL-la which could active NF-κB signaling pathway were observed in GCT patients VS normal person. Not surprisingly, abundantly activated NF-κB complex were assessed in GCT tumor tissues.Logically, we exposed GCT cells to NF-κB signaling pathway inhibitors and subject them to cell activity assay. All GCT primary cultured cells exhibited decreased cell activity induced with NF-κB signaling pathway inhibitors with strongly inhibition by 26S proteasome inhibitor bortezomib.GCTs are heterogeneous tumors that are composed of several cell types. A defining feature of the lesion is the presence of numerous multinucleated giant cells that are uniformly distributed amongst mononuclear spindle-like stromal cells and other monocytes. The spindle-like stromal cells are actually the neoplastic component of the tumor, owing to their ability to readily proliferate in culture. And the osteoclasts like giant cells are the bone-resorbing element of GCT, so it is also called "osteoclastomas." Theoretically, drugs that inhibit the osteoclast-like giant cells (and thus the extensive osteolysis) and the proliferating stromal cells should be effective against giant cell tumor of tumor.We exposed GCT primary cultured cells to bortezomib, regarding that it will be a potential chemotherapy for GCT.1. Bortezomib prevented differentiation and formation of giant cell with reducing functional bone resorption;2. Bortezomib reduced secretion of GCT condition medium which could promote recruitment and differentiation of monocytes;3. Bortezomib inhibited the giant cell formation which was induced by GCT condition medium;4. Bortezomib inhibited the migration of BMM induced by stromal cell which was not inhibited by reducing cell activity;5. Bortezomib promote stromal cell apoptosis by reducing NF-κB downstream anti-apoptotic gene expression and P53 accumulation;6. Bortezomib inhibited giant cell formation and promoted stromal cell apoptosis in GCT tibial injection mouse model.In summary, a new treatment option for GCT may have been explored because that bortezomib not only inhibit the osteoclast-like giant cells formation but also promote stromal cell apoptosis. Besides bortezomib reduces the number of giant cells and proliferative stromal cells in GCT tibial injection mouse model with better effect than zoledronic acid which could induce hyperostosis.