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.