Our discussion thus far of the nutritional aspects of the host-tumor relationship has included only organic nutrients as well as humoral factors of an organic nature. However, studies have demonstrated the inhibition of neoplastic growth by the depletion of essential inorganic constitu- ents such as zinc (Mills et al., 1984a) and magnesium (Mills et al., 1984b). While such parame- ters are of undoubted importance in the nutrition of the tumor-bearing host, a far more significant inorganic constituent is calcium. A diagram of normal adult calcium homeostasis is seen in Figure 17.9. Since calcium, unlike organic nutritional components, is not “degraded” by the organism, a balance, just as with nitrogen, is established by the organism. In the adult, where bone growth has essentially ceased, calcium balance is neutral, as shown in the figure. However, in the young, growing individual, there is a positive calcium balance with greater retention of ingested calcium than excretion, while individuals critically ill from a variety of different dis- eases as well as those with renal insufficiency sometimes occurring as a complication of chemo- therapy will be in a negative calcium balance (Abramson et al., 1990). Hypercalcemia, an increase in serum calcium concentration, is probably the most common metabolic complication of malignant disease (Ralston, 1994). This condition occurs in about one-third of patients with multiple myeloma and in five or more percent of all patients with solid neoplasms (Glover and Glick, 1987). Of patients with breast cancer, 30% to 40% exhibit this complication (Muggia,1990). In fact, the most frequent metabolic oncological emergency is hypercalcemia (Glover and
Figure 17.9 Pathways leading to calcium homeostasis in the adult organism. (Modified from Seymour,1995, with permission of the author and publisher.)
Glick, 1987). From the pathways noted in Figure 17.9, one may note that hypercalcemia can result from at least one of three mechanisms acting alone or in combination. These are increased calcium absorption from the gut, decreased excretion of calcium in the kidney, and accelerated calcium resorption into the serum from bone (Warrell, 1992). In cancer patients exhibiting hy- percalcemia, calcium absorption from the gut is generally suppressed and contributes relatively little calcium to the systemic circulation (Coombes et al., 1976). An interesting exception to this generalization is seen with some lymphomas in which the neoplasm itself synthesizes the vita- min 1,25-dihydroxyvitamin D, which regulates the absorption of calcium from the gut (Davies et al., 1994).
During the first two-thirds of the twentieth century and earlier, hypercalcemia due to ma- lignant disease was thought to be primarily a function of the effects of metastases in bone, caus- ing resorption of the skeleton and increase in serum calcium. The three most common neoplasms in humans—breast, prostate, and lung cancer—frequently affect the skeleton with metastases to bone. Since these three types of neoplasms are diagnosed in almost three-quarters of a million new individuals each year, the 5% suffering from hypercalcemia becomes a very significant figure. However, it was not until some 15 years ago that a better understanding of the mechanism of hypercalcemia became apparent. The major internal hormone that regulates cal- cium metabolism is secreted by the parathyroid gland, parathyroid hormone. Neoplasms of the parathyroid gland in many cases secrete excessive amounts of this hormone, as discussed in Chapter 18. This leads to hypercalcemia but may be considered a special case, although occa- sionally neoplasms of other tissues may secrete parathyroid hormone ectopically and result in hypercalcemia (Nussbaum et al., 1990). However, in 1987, several laboratories reported the iso- lation of a polypeptide significantly larger than the parathyroid hormone but having at least some of the sequences of this hormone at its amino terminal end (cf. Broadus et al., 1988). Fig- ure 17.10 shows the organization of the human parathyroid hormone (PTH) gene and that of the parathyroid hormone-related protein (PTHRP) gene. While at first PTHRP and its product were felt to be exclusively produced in neoplasms, it was rapidly shown that PTHRP is a normal hor- mone essential both for normal development of the mammal as well as for normal homeostasis in the adult. Figure 17.11 lists tissues in the fetus and the adult in which PTHRP is produced and exerts its hormonal effect. Interestingly, the parathyroid glands of both the fetus and the adult produce PTHRP. Furthermore, many of the tissues noted produce the hormone, and it has a para- crine effect on adjacent tissues as well as endocrine effects on distant tissues. Furthermore, as noted from Figure 17.10, there are two promoters for the PTHRP gene, resulting in several forms produced in different tissues (Burtis, 1992). PTH is a polypeptide of 84 amino acids in the human, whereas the various forms of PTHRP range from 139 to 173 amino acids in length (Sey- mour, 1995). The first 34 amino acids beginning from the N-terminal are structurally similar and functionally equivalent in PTH and the forms of PTHRP. However, the remainder of the polypeptides are different, and in PTHRP there is a region involved in calcium transport in the middle of the polypeptide, whereas the C-terminal domains are involved in osteoclast metabo- lism in bone (Seymour, 1995; Strewler, 2000). Figure 17.12 gives the plasma levels of PTHRP in normal individuals as well as in those exhibiting the humoral hypercalcemia of malignancy (HHM), several different types of neoplasms, as well as two non-neoplastic conditions. Essen- tially, it is only neoplasms that exhibit higher than normal levels of PTHRP in the plasma (Mar- tin and Grill, 1992).
As already noted, the secretion of PTHRP, while accounting for the vast majority of hyper- calcemia of malignancy, is not the only hormone that can trigger or affect this parameter of the host-tumor relationship. In Table 17.8 is a short list of other factors that induce hypercalcemia, primarily through their action on bone. Notably in this list are the growth factors TGF-α and
Figure 17.10 Diagram of organization of human parathyroid hormone (PTH) and parathyroid hor- mone–related protein (PTHRP) genes. The PTH gene has three exons that encode a pre-pro region (light shading) and the mature protein (dark shading). A more complex PTHRP gene possesses two promoters (P1, P2), either of which can initiate transcription. The distal three of its eight exons can be alternatively spliced (arrows) to yield at least three different mRNA transcripts, encoding different lengths of the mature protein. (Reproduced from Burtis, 1992, with permission of the author and publisher.)
Figure 17.11 Diagrammatic summary of the sites of parathyroid hormone–related protein (PTHRP) production and action. PTHRP can function either in an endocrine or paracrine manner in normal adult and fetal tissues depending on whether it acts locally or is secreted into the circulation. Neoplasms which pro- duce this hormone primarily do so in an endocrine manner. (Reproduced from Rosol and Capen, 1992, with permission of the authors and publisher.)
Figure 17.12 Plasma levels of PTHRP in patients with neoplasms and other disease states as well as normal controls. HHM, humoral hypercalcemia of malignancy; SCC, squamous cell carcinoma. (Repro- duced from Martin and Grill, 1992, with permission of the authors and publisher.)
Table 17.8 Other Factors Contributing to the Hypercalcemia of Malignancy
Transforming growth factor-α .
Transforming growth factor-β
Tumor necrosis factor-α
TGF-β, which act on osteoblasts and osteoclasts, two cell types critical in bone formation and resorption (Mundy, 1989). Not surprisingly, IL-1 and TNF-α, as well as lymphotoxin, also cause hypercalcemia and probably play a significant role in hypercalcemia seen with multiple my- eloma and various lymphomas. One of the earlier fashionable theories for the pathogenesis of hypercalcemia was the production of prostaglandins of the E series, which were shown to stimu- late osteoclastic bone resorption (cf. Gutierrez et al., 1990).
While all of these factors may be important in certain types of neoplasms, such as those of the immune system and some epithelial neoplasms, all of the evidence argues that PTHRP is the primary stimulator of the hypercalcemia in the majority of neoplasms.