Humoral hypercalcemia of malignancy

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Humoral hypercalcemia of malignancy (HHM) is often caused by tumor-secreted proteins acting on parathyroid hormone (PTH) receptors.
• A protein distinct from PTH has been suspected to mediate HHM.

Purpose of the Study:

• To identify and characterize the protein responsible for HHM.
• To investigate the biological activity and tissue distribution of this novel protein.

Main Methods:

• Purification and cloning of parathyroid hormone-related protein (PTHrP) from a human lung cancer cell line.
• Amino acid sequencing and cDNA analysis to determine protein structure.
• In vitro and in vivo bioassays using synthetic PTHrP peptides.
• Immunohistochemical localization of PTHrP in tumor and normal tissues.

Main Results:

• PTHrP was purified and cloned, encoding a 141-amino acid mature protein with sequence homology to PTH in the N-terminus.
• Synthetic PTHrP(1-34) demonstrated 2-4 times greater potency than PTH(1-34) in stimulating cAMP and plasminogen activity.
• PTHrP(1-34) was more potent than hPTH(1-34) in stimulating cAMP and altering phosphate and calcium excretion in rat kidneys.
• PTHrP was localized in squamous cell carcinomas and normal keratinocytes, with activity found in ovine placenta and parathyroids.

Conclusions:

• PTHrP is a novel hormone responsible for HHM, acting via the PTH receptor.
• The N-terminal region of PTHrP is crucial for its biological activity, similar to PTH.
• PTHrP has a broader tissue distribution than previously thought, including normal tissues.