We review the current state of knowledge of the molecular properties and actions of parathyroid hormone-related protein (PTHrP) both in cancer patients and in normal physiology. PTHrP is a common product of squamous cancers and is the major mediator of the syndrome of humoral hypercalcemia of malignancy (HHM) by its actions through parathyroid hormone receptors in bone and kidney. Recently developed radioimmunoassays and tissue localization techniques indicate that PTHrP is produced by many more cancers than was originally indicated by clinical studies and that it contributes significantly to malignancy-related hypercalcemia associated with other etiologies, for example, cancers metastatic to bone and hematological malignancies. The gene encoding PTHrP is complex, with multiple exons coding for up to 12 alternate transcripts and three different length proteins, potentially in a tissue-specific manner, by the use of three promoters. Its expression is regulated by hormones and growth factors, and the untranslated exons display features in common with many cytokine genes. Although potential endocrine actions of PTHrP are evident in fetal development, further evidence suggesting that the normal physiological role of PTHrP is predominantly as a locally produced regulator/cytokine comes from localization studies and investigations of its actions in a variety of tissues. Such studies indicate that in addition to its parathyroid hormone-like actions, PTHrP has multiple activities, including those in fetal development, placental calcium transfer, lactation, smooth muscle relaxation, and on epithelial cell growth. Although PTHrP was discovered because of its production by cancers, evidence for its actions as a local regulator highlights the importance of understanding its roles not only in the etiology of HHM in cancer patients but also in normal tissues. PTHrP was discovered because of clinical features resembling hyperparathyroidism displayed by some cancer patients in whom circulating PTH was not detectable. Subsequently, PTHrP has been shown to be produced by a far broader spectrum of cancers than was appreciated on the basis of clinical studies, and it is becoming clear that it has a significant role in the etiology of hypercalcemia associated with many types of malignancy. PTHrP has also been shown to be parent to a number of biological actions relevant in normal physiology, both endocrine and paracrine/autocrine in nature. Evidence indicates major roles for PTHrP in smooth muscle relaxation, fetal calcium regulation, and milk production during lactation. As a potential cytokine produced by many normal as well as malignant cells, its actions may be far reaching and understanding the precise nature of its role on cell growth will be of paramount importance.
- Fetal development
- Humoral hypercalcemia of malignancy (HHM)
- Smooth muscle