Hypercalcaemia of malignancy

Abstract

Hypercalcaemia in malignancy is a major clinical problem. It contributes significantly to morbidity and mortality and can present difficult diagnostic and management dilemmas. Direct bony invasion by tumour cells rather than humorally mediated hypercalcaemia is probably the most common cause of malignant hypercalcaemia. Yet even in this situation the mechanism of bone resorption or the reason that the normal homeostatic mechanisms cannot cope with the calcium load are poorly understood. It is likely that the humoral and paracrine factors produced by tumours which result in hypercalcaemia or in osteosclerotic bone metastases, are interposing themselves into the normal regulatory processes and deranging them. Humoral hypercalcaemia of malignancy is an important model for studying these questions, and it also provides some insight into the normal regulation of bone turnover. This review will examine the animal models and human syndromes of malignant hypercalcaemia and show how animal models, although helpful, fail to delineate the relative importance of the various potential humoral factors. A most interesting recent development in this area is the description of a new hormone, the parathyroid hormone-related peptide, which may explain many of the cases of humoral hypercalcaemia of malignancy. It is also a useful model with multiple sites of action within the bone and calcium homeostatic process. The active hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, may also be involved in a small proportion of cases, but again it is a useful model of some of the factors that may operate. Of considerable interest are the tumour derived factors, such as the transforming growth factors, and the cytokines, such as tumour necrosis factors, interleukins, and haemopoietic colony stimulating factors. Prostanoids are seldom of major importance, but may be important in certain tumour types. Osteosclerotic metastases, although seldom associated with hypercalcaemia, may provide insight into osteoblast regulating factors. Treatment of hypercalcaemia is discussed to show ways in which response to treatment may shed light on underlying pathophysiological mechanisms. Most effective treatments have many potential modes of action, and further study of the interactions of these agents and tumour types may help to unravel some of the enigmas in this human syndrome. The major advances in this complex problem involve the realisation of the necessity of multiple sites of action, including renal calcium handling as well as relative increases in bone resorption and/or intestinal calcium absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Osseous and Intestinal Compartments in the Humoral Hypercalcemia of Malignancy Associated to Walker 256 Tumor in Rats

“…With respect to the possible role of the gut in the path ogenesis of HHM, an elevation of 1,25(OH)2D levels has been observed in Walker 256 tumor-bearing rats [7,8] and in other animal models [18]. There is a discrepancy be tween these results and the human HHM syndrome re ports in which 1,25(OH)2D levels are often, but not always, depressed [5,6].…”

Immunocytochemical demonstration of PTHrP protein in neoplastic tissue of HTLV-1 positive human adult T cell leukaemia/lymphoma: implications for the mechanism of hypercalcaemia

“…and varied from weakly (Figure lb tor a metabolism have all been proposed (Cohn et al, 1987;Kiyokawa et al, 1987;Fukumoto et al, 1988;Adams et al, 1989;Matsuda et al, 1990). Recent studies have suggested a role for PTHrP, a new parathyroid hormone-like protein (Suva et al, 1987;Mangin et al, 1988) which is involved in normal calcium homeostasis in the foetus and implicated in the development of humoral hypercalcaemia of malignancy syndrome seen associated with epithelial tumours Danks et al, 1989;Burtis et al, 1990;and reviewed in Martin & Suva, 1989;Kelly & Eisman, 1989). Thus, HTLV-1 positive T cell lines and tissue from three cases of ATLL expressed PTHrP mRNA and bioactive PTHrP was isolated from cells or conditioned media (Motokura et al, 1988(Motokura et al, , 1989Fukumoto et al, 1989).…”