Parathyroid hormone-related protein promotes bone loss in T-cell leukemia as well as in solid tumors

Abstract

Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors that increase bone resorption and hypercalcemia in adult T-cell leukemia (ATL). We investigated the role of PTHrP and MIP-1α in the development of local osteolytic lesions in T-cell leukemia through overexpression in Jurkat T-cells. Injections of Jurkat-PTHrP and Jurkat-MIP-1α into the tibia and the left ventricle of NSG mice were performed to evaluate tumor growth and metastasis in vivo. Jurkat-pcDNA tibial neoplasms grew at a significantly greater rate and total tibial tumor burden was significantly greater than Jurkat-PTHrP neoplasms. Despite the lower tibial tumor burden, Jurkat-PTHrP bone neoplasms had significantly greater osteolysis than Jurkat-pcDNA and Jurkat-MIP-1α neoplasms. Jurkat-PTHrP and Jurkat-pcDNA cells preferentially metastasized to bone following intracardiac injection, though the overall metastatic burden was lower in Jurkat-PTHrP mice. These findings demonstrate that PTHrP induced pathologic osteolysis in T-cell leukemia but did not increase the incidence of skeletal metastasis.

Keywords:

• Cell lines and animal models
• T-cell leukemia
• PTHrP
• MIP-1α
• metastasis
• bone resorption

Acknowledgments

We thank the Target Validation Shared Resource (TVSR) at the Ohio State University Comprehensive Cancer Center for providing the NSG mice used in the preclinical studies described herein. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. We thank Alan Flechtner and Anne Saulsbery for tissue processing and preparation of slides. Finally, we thank our medical illustrator Tim Vojt for his invaluable assistance in creating all the figures.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was funded through grants from the National Cancer Institute (P01 CA100730 to TJR and KNW) and (T32 OD010429 to NAK). Animal research reported in this publication was supported by the Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number (P30 CA016058).