CALCIUM HOMEOSTASIS IN THE HOST-TUMOR RELATIONSHIP

31 May

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

Interleukin-1

Tumor necrosis factor-α

Lymphotoxin Prostaglandins

Colony-stimulating factors

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.

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