PTHrP Induces Autocrine/Paracrine Proliferation of Bone Tumor Cells through Inhibition of Apoptosis

Abstract

Giant Cell Tumor of Bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates and metastatic potential. Previous work in our lab has shown that the neoplastic cell of GCT is a proliferating pre-osteoblastic stromal cell in which the transcription factor Runx2 plays a role in regulating protein expression. One of the proteins expressed by these cells is parathryroid hormone-related protein (PTHrP). The objectives of this study were to determine the role played by PTHrP in GCT of bone with a focus on cell proliferation and apoptosis. Primary stromal cell cultures from 5 patients with GCT of bone and one lung metastsis were used for cell-based experiments. Control cell lines included a renal cell carcinoma (RCC) cell line and a human fetal osteoblast cell line. Cells were exposed to optimized concentrations of a PTHrP neutralizing antibody and were analyzed with the use of cell proliferation and apoptosis assays including mitochondrial dehydrogenase assays, crystal violet assays, APO-1 ELISAs, caspase activity assays, flow cytometry and immunofluorescent immunohistochemistry. Neutralization of PTHrP in the cell environment inhibited cell proliferation in a consistent manner and induced apoptosis in the GCT stromal cells, with the exception of those obtained from a lung metastasis. Cell cycle progression was not significantly affected by PTHrP neutralization. These findings indicate that PTHrP plays an autocrine/paracrine neoplastic role in GCT by allowing the proliferating stromal cells to evade apoptosis, possibly through non-traditional caspase-independent pathways. Thus PTHrP neutralizing immunotherapy is an intriguing potential therapeutic strategy for this tumor.

Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation

“…Mak et al . has used the neutralized PTHLH antibodies to prevent in vitro bone tumor proliferation and induced apoptosis39. Target to PTHLH may provide a new therapy niche for HNSCC patients.…”

Evaluating the Role of PTH in Promotion of Chondrosarcoma Cell Proliferation and Invasion by Inhibiting Primary Cilia Expression

“…PTHrP protein plays a crucial role in the process of normal bone tissue development [ 7 , 8 , 9 , 10 , 11 , 12 ]. Abnormal expression of PTHrP has been found in various tumor types.…”

“…Parathyroid hormone-related protein (PTHrP) is a crucial factor in regulating calcium balance in the internal environment, and it plays an indispensable role in the processes of bone and cartilage growth and differentiation [ 7 , 8 , 9 , 10 , 11 ]. In normal cartilage, PTHrP can inhibit cartilage cell differentiation and promote proliferation by a PTHrP/Ihh feedback loop [ 12 ].…”

“…However, a high level of PTHrP may not only lead to teratogenesis, but it also may induce malignancies, such as giant cell tumor of bone and various bone metastasis tumors. These tumors were detected in high expression of PTHrP that leads to metastatic osteolytic destruction accompanied with hypercalcemia [ 8 , 9 , 10 , 11 ]. In the current study, we confirmed that human chondrosarcoma tissues expressed a high level of PTHrP, compared with adjacent tissues, and this protein contributes to positive facilitation in promoting proliferation and invasion.…”

Developmental Cues for Bone Formation from Parathyroid Hormone and Parathyroid Hormone-Related Protein in anEx VivoOrganotypic Culture System of Embryonic Chick Femora

“…[33][34][35][36] Ablation of PTHrP in mice or humans leads to a lethal skeletal dysplasia, caused by abnormal chondrocyte proliferation and differentiation, 37,38 and PTHrP has been implicated in the progression and bone metastases of a number of cancers. 39,40 In E11 femurs, higher dose of PTHrP resulted in slightly different effects to PTH, with increased formation of bone and marrow cavities within the inner diaphyseal region as well as the bone collar. This may be due to the ability of PTHrP to influence proliferation, differentiation, and apoptosis of multiple cell types, including osteoblasts, chondrocytes, and marrow cells.…”