This investigation addresses a theoretical concept of
tumor pathogenesis proposed over 40 years ago, namely that
malignancy-associated
hypercalcemia can result from endocrine secretion by
tumors of a PTH-like factor. These studies demonstrate that a fragment of hHCF alone, without added or
tumor-secreted cofactors or
hormones, can produce
hypercalcemia and other biochemical abnormalities associated with HHM. The
hypercalcemia can be generated by hHCF-(1-34)NH2 action on bone, although kidney and gut could contribute to the HHM syndrome when it occurs naturally. No other
tumor-secreted
peptide displays this
biological profile. These studies establish one (PTH-like) mechanism by which human
tumors could produce
hypercalcemia. Furthermore, the finding that hHCF-(1-34)NH2 is more potent than PTH in some systems is of considerable interest for the future design of
hormone analogs. A broad spectrum of
biological properties of hHCF-(1-34)NH2, including production of components of the HHM syndrome, can be inhibited by a PTH antagonist. Because [Tyr-34]
bPTH-(7-34)NH2 selectively and competitively occupies PTH receptors, our studies demonstrate formally that hHCF-(1-34)NH2 mediates some (and perhaps all) of its actions via receptors conventionally regarded as intended for interaction with PTH, but which actually may be present to allow for expression of bioactivity of both secreted
proteins. Although some structural homology is shared by the two
hormones and many contribute to interaction with receptors, the disparity in structure, especially within the 1-34 domains responsible for bioactivity in both
hormones, is more pronounced. The similarity in
biological profiles despite structural differences between hHCF and PTH is emphasized by the inhibitory action of [Tyr-34]
bPTH-(7-34)NH2 against the
tumor peptide even in the absence of much of the homologous region in the PTH antagonist. This investigation provides impetus for designing more potent antagonists, which must now be regarded more appropriately as inhibitors of both PTH and hHCF. Such antagonists may best be generated from hybrid structures of the two
hormones. In any case, these studies establish a promising new approach to
therapy of
tumor-associated
hypercalcemia.