Hypercalcemia of malignancy revisited.

Abstract

In the three years since the last Perspectives article in the Journal of Clinical Investigation on this topic (1), there have been major advances in our understanding of the heterogeneous mechanisms responsible for the hypercalcemia of malignancy. Reports of many of these advances have appeared in the pages of the Journal of Clinical Investigation. These advances include discovery and characterization of the PTH-related protein (PTH-rP)' produced by many solid tumors, demonstration of tumor-derived transforming growth factor-alpha (TGF-alpha) as a bone-resorbing factor that can cause hypercalcemia, identification of lymphotoxin as thie major mediator of bone destruction in myeloma, and definitive demonstration of increased renal tubular reabsorption of calcium in hypercalcemia associated with solid tumors.One concept that has not changed in these last three years is that the mechanisms responsible for hypercalcemia ofmalignancy are heterogeneous. Different patterns of disturbances in calcium homeostasis occur in different types of malignancy. A simple diagram illustrating some of these different patterns is shown in Fig. 1. In all of the examples provided, increased bone resorption is an important feature. However, the importance of the net fluxes of calcium that occur across the other two major organs that guard calcium homeostasis (gut and kidney) depend on the type of tumor. PTH-related protein (PTH-rP) and solid tumorsIn the last 12 months, a succession of papers has described a protein isolated from solid tumors that has significant sequence homology in the NH2-terminal region to PTH. It was first suggested by Albright almost 50 years ago that hypercalcemia of malignancy could be related to PTH or a PTH-like peptide, but it was not appreciated just how PTH-like this factor was until it was purified from a variety of tumor cell lines and molecularly cloned (2)(3)(4)(5)(6) ceptor (3). Synthetic peptides that correspond to the NH2-terminal end of PTH-rP have now been tested in vitro and in vivo; these peptides appear to have effects essentially identical to those of PTH on the kidney and bone (7-12). Synthetic peptide analogues of PTH-rP enhance osteoclastic bone resorption in vitro (7, 9, 10), enhance renal tubular calcium reabsorption (7, 9), and cause hypercalcemia in vivo (8-10). Differences in potency with PTH have been suggested (7), although these have not been found by other workers (8-10). These observations provoke obvious questions about the normal physiologic role of this protein and its relationship to PTH and to the PTH receptor. The immediate question is whether this protein explains all of the manifestations of hypercalcemia of malignancy in patients with solid tumors. Based on current data, this is unlikely. The syndrome of humoral hypercalcemia of malignancy associated with solid tumors is quite distinct from that of primary hyperparathyroidism, and cannot be explained simply by what is known of the effects of synthetic peptides of PTH-rP on kidney, bone, and gut. For example, osteoclastic bo...

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