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The Role of PTHrP in Skeletal Metastases and Hypercalcemia of Malignancy

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Abstract

Since its discovery as the principal mediator of humoral hypercalcemia of malignancy, parathyroid hormone-related protein (PTHrP) has emerged as a key player in skeletal complications associated with solid tumor metastasis to bone. In addition to functioning as an endocrine factor, this pleiotropic peptide mediates its actions locally on tumor and stromal cells in paracrine, autocrine, and intracrine fashion when cancer metastasizes to the bone compartment. Multiple splice variants and newly described PTHrP fragments confer diverse functions to PTHrP that extend beyond binding to its common receptor with parathyroid hormone. Here, we summarize the causal role of PTHrP in humoral hypercalcemia of malignancy and its local involvement in the progression of osteolytic and osteoblastic cancer bone metastases. Clinical and preclinical findings describing how PTHrP regulates tumor and stromal cell interactions are summarized, with emphasis on emerging evidence of PTHrP’s role in tumorigenesis and cancer cell proliferation. Finally, we examine therapeutic opportunities and limitations to targeting PTHrP directly and indirectly in cancer patients.

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Acknowledgments

This work was supported by the Department of Defense Prostate Cancer Research Program postdoctoral training award PC101890 (LEW), the Jerry and Peggy Throgmartin Endowment (TAG), the Indiana Economic Development Fund, the National Cancer Institute (NCI/NIH) R01-CA69158 & U01-CA143057 (TAG), the V-Foundation (TAG), The Susan Komen Foundation (TAG), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS/NIH) R01-AR059221 (TAG).

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Laura E. Wright and Theresa A. Guise declare that they have no conflict of interest.

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This article does not include any studies with human or animal subjects performed by the author.

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Authors and Affiliations

  1. Division of Endocrinology, Indiana University Department of Medicine, 980 W. Walnut St., Walther Hall, R3, Room C122, Indianapolis, IN, 46202, USA

    Laura E. Wright

  2. Division of Endocrinology, Indiana University Department of Medicine, 980 W. Walnut St., Walther Hall, R3, Room C130, Indianapolis, IN, 46202, USA

    Theresa A. Guise

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  1. Laura E. Wright
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  2. Theresa A. Guise
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Correspondence to Theresa A. Guise.

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Wright, L.E., Guise, T.A. The Role of PTHrP in Skeletal Metastases and Hypercalcemia of Malignancy. Clinic Rev Bone Miner Metab 12, 119–129 (2014). https://doi.org/10.1007/s12018-014-9160-y

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  • DOI: https://doi.org/10.1007/s12018-014-9160-y

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