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Editorials Parathyroid Hormone-Related Peptide MALIGNANCY-ASSOCIATED HYPERCALCEMIA has been recognized since the early 1920s.1 This syndrome was initially thought to be the result of local bone destruction mediated by malignant cells in direct contact with bone or boneresorbing cells. In 1941, Fuller Albright described a patient in whom hypercalcemia and hypophosphatemia resolved following irradiation of a solitary bone metastasis from a renal carcinoma; he proposed that the carcinoma was secreting parathyroid hormone (PTH) or a peptide with similar actions. By the mid-1950s, Albright's humoral hypothesis had been placed on a first-descriptive footing by the reporting of several series of cases in which hypercalcemia was eliminated by the removal or debulking of malignant tumors. In other patients hypercalcemia was clearly associated with an extensive tumor burden in bone. Thus, by 1960 or so there was agreement that malignancy-associated hypercalcemia could result from either of two general mechanisms, one local (referred to as local osteolytic hypercalcemia) and one systemic (referred to as humoral hypercalcemia of malignancy). Until recently, there has been agreement about little else in this field. The key points of controversy included the relative frequencies of the local and humoral mechanisms, reliable clinical criteria for invoking one or the other of these two mechanisms, and the identity of the humoral mediator(s) in patients with malignancy-associated hypercalcemia. For example, through the 1970s it was widely held that the local osteolytic syndrome was far more common than the humoral syndrome, that the presence of one or more bone metastases signified local osteolytic hypercalcemia by definition, and that humoral hypercalcemia was predominantly due to "ectopic" hyperparathyroidism. Those who hold to these beliefs today are in need of a refresher course and are referred to the excellent summary of the field provided elsewhere in this issue by Strewler and Nissenson.1 In the 1980s remarkable progress was made in this area in a series of studies that evolved rapidly through a number of interrelated phases. The first phase involved clinical studies which suggested that humoral hypercalcemia was

and, more important, provided a marker for this syndrome in the form of an increase in nephrogenous cyclic adenosine 3':5'-monophosphate (AMP) excretion. Because nephrogenous cyclic AMP was thought to reflect specifically the interaction of PTH with its receptors in the kidney, this effect of the putative tumor-derived peptide was regarded as "PTH-like." The second phase of work followed directly from this interpretation and involved the use of PTH-sensitive adenylate cyclase assays to detect the pepcommon

tide in tumor extracts and in the medium from cultured

malignant cells. Using these methods, it was possible to show that humoral hypercalcemia-associated tumors regularly contained PTH-like bioactivity whereas control tumors or those associated with local osteolytic hypercalcemia were devoid of such activity. The third phase involved isolating the PTH-like peptide, a formidable task because of its low abundance even in humoral hypercalcemia-associated tumors. Several groups were successful in purifying minute quantities of the tumor-derived peptide and in using this precious material to gain partial amino-terminal sequence information. Although partial, this sequence was a thing of beauty to those in the field in that it revealed that one portion of the molecule bore a remarkable similarity to

the sequence of PTH itself whereas another portion bore no resemblance whatsoever. The fourth phase of work involved the use of molecular techniques to identify complementary DNAs encoding the tumor-derived peptide, revealing its complete structure, and this was followed shortly by the isolation of the human gene. The peptide was found to be about twice the size of native PTH and to have a sequence similarity to PTH confined to its proximal amino terminus; the remainder of its sequence was unique. This structural information permitted the preparation of synthetic peptides that were found to be biologically active in vitro and in vivo and that have also been used to raise region-specific antisera. Although there has been no formal agreement in this field regarding nomenclature, the term PTH-related peptide (PTHrP) seems reasonable on the basis of what is known. Based on chromosomal localization findings and shared structural features, the PTH and PTHrP genes seem to have arisen by duplication from a common ancestral precursor and to therefore represent members of a gene family. Following this duplication event, the PTH and PTHrP genes have clearly evolved separately. The PTH gene has a comparatively simple structure and appears to be expressed exclusively by parathyroid cells. The parathyroid hormone has, of course, a well-defined, restricted job description and is associated with well-known syndromes of hormone deficiency and excess. In contrast, the human PTHrP gene has evolved a highly complex structure and appears to be expressed in a remarkable array of normal tissues. The structural complexities of the gene include alternatively spliced exons that give rise to three different PTHrP isoforms. The number of normal tissues that have been found to express the PTHrP gene seems to grow by the week and includes sites as diverse as keratinocytes, the endocrine pancreas, discrete regions of the central nervous system, and a number of reproductive tissues. In reproductive tissues such as lactating breast and preterm myometrium,2 the expression of the gene is clearly under the control of normal physiologic stimuli-such as a suckling in the case of a lactating breast. Exactly what the PTHrP is doing in all of these sites or circumstances is unknown, but its actions are almost certainly local (autocrine or paracrine) rather than systemic. In a number of sites, the role of the peptide may involve calcium translocation, signaling, or both. Presumably these actions are mediated by unique PTHrP receptors, but such receptors have yet to be identified. It may well be that the only circumstance in which the PTHrP enters the systemic circulation in sufficient quantities to exert a conventional "endocrine" effect is in the specific pathophysiologic setting of the syndrome of humoral hypercalcemia of malignancy. In this setting the peptide is clearly interacting or cross-reacting with classic PTH receptors in bone and kidney. In a nutshell, these receptor interactions explain the salient clinical and biochemical features of humoral hypercalcemia of malignancy. A number of these features-such as uncoupled bone turnover and reduced circulating levels of 1,25-dihydroxyvitamin D-differ from those in primary hyperparathyroidism and may result either from the severity of the process in humoral hypercalcemia or from the differing structures of circulating PTHrP and PTH. As noted above, it is doubtful that this scenario of PTHrP "cross-talk" with PTH receptors is relevant to the normal physiologic role of the PTHrP, in that

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mounting evidence suggests that this role is predominantly local. Despite the great progress that has been made in this area in the past decade, there is much of importance that remains unknown. We do not know what constitutes the final secretory form of the PTHrP for any cell type. This is a complicated question because different PTHrP isoforms exist and also because these isoforms may be subject to cleavage or other forms of processing. It is not unlikely that individual cell types may process PTHrP in a cell-specific manner and secrete quite different products. We do not know exactly how PTHrP acts, and unique PTHrP receptors have yet to be identified. Progress in this area has been hampered by the lack of information concerning the secretory form of the peptide. We do not understand the precise role(s) of the PTHrP in any of the many tissues in which it is produced, although there are some interesting leads in this regard. A peptide in search of a function is not an easy problem, particularly at a local level, so that this area of investigation may require many more years of study. We do not understand why certain malignant cells of a given cell type express the PTHrP gene whereas others do not. A related question is why the PTHrP gene is so commonly expressed and the PTH gene so rarely expressed by malignant cells. This is an important question of tumor cell biology that clearly cuts through previously simplistic concepts concerning eutopic versus ectopic gene expression. What effect will progress in this area have on clinical medicine? Immunoassays for PTHrP are already becoming available and should simplify the differential diagnosis. Second-generation assays of greater sensitivity may also prove useful in detecting low circulating concentrations of PTHrP that may serve as a tumor marker in patients who do not have hypercalcemia. Some interesting structure-function work is being done with hybrid PTH-PTHrP sequences, and there is the long-range hope that potent competitive

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inhibitors will be developed. Finally, if the PTHrP turns out to have widespread local actions, there is the possibility that other forms of disease may someday be explained on the basis of lesions in these local signaling pathways. In summary, a novel PTH-related peptide has been discovered by virtue of its production by tumors associated with the syndrome of humoral hypercalcemia of malignancy. In certain ways, this problem is reminiscent of the discovery of the growth hormone-releasing hormone (GRH) in human pancreatic tumors several years ago,3'4 the principal difference being that GRH had a defined role before its actual isolation whereas the normal role of the PTHrP is not yet known. The PTHrP problem has moved extremely rapidly and has been an exciting area in which to work; scarcely ten years passed between the initial identification of a viable marker for the effects of the peptide in vivo and the isolation of the human PTHrP gene. In addition to providing an answer to a rather old question, the solving of this problem stands as an excellent example of the power of the marriage between modern technology and clinical observation. ARTHUR E. BROADUS, MD, PhD Professor of Medicine and Cellular and Molecular Physiology Section Chief, Endocrinology and Metabolism Department of Internal Medicine Yale University School of Medicine New Haven, Connecticut REFERENCES

1. Strewler GJ, Nissenson RA: Hypercalcemia in malignancy. West J Med 1990; 153:635-640 2. Thiede MA, Daifotis AG, Weir EC, et al: Intrauterine occupancy controls expression of the parathyroid hormone-related eptide ene in preterm rat myometrium. Proc Natl Acad Sci USA 1990; 87:6969-6973 3. Rivier J, Spiess J, Thorner M, Vale W: Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature 1982; 300:276-278 4. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB: Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 1982; 218:585-587

Parathyroid hormone-related peptide.

660 Editorials Parathyroid Hormone-Related Peptide MALIGNANCY-ASSOCIATED HYPERCALCEMIA has been recognized since the early 1920s.1 This syndrome was...
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