Endocrine Abstracts (2006) 11 S19

Mechanisms of malignant hypercalcaemia

P Clezardin

INSERM, U.664, Lyon, France.

Malignancy is the most common cause of hypercalcaemia. Hypercalcaemia in solid tumours involves the secretion of humoral factors by tumour cells that act systemically on target organs (bone, kidney) to alter calcium homeostasis. Parathyroid hormone-related protein (PTHrP) is a major humoral factor. It is produced by a variety of solid tumours and acts on PTH receptors to cause increased calcium reabsorption from renal tubules and increased bone resorption. Other humoral tumour-associated factors likely involve cytokines such as IL-1, IL-6 and TNFα. In addition, such factors enhance the hypercalcaemic effects of PTHrP. In bone, PTHrP produced by tumour cells stimulates osteoclast activity by promoting the expression of the cytokine RANK-L (receptor activator of NFκB ligand) by osteoblastic stromal cells. RANK-L by binding to its cell surface receptor RANK in osteoclast precursors promotes their differentiation and the subsequent osteoclastic bone resorption. Bone-residing tumour cells also produce a number of other important factors (IL-6, IL-8, IL-11, M-CSF) that lead to osteolysis. Consequently, growth factors (TGFβ, IGFs) that are released from resorbed bone cause tumour cell proliferation and further stimulate the production of PTHrP and IL-11 by tumour cells which, in turn, accelerate bone destruction. High concentrations of ionised calcium released from bone may also contribute to the progression of osteolytic lesions by increasing PTHrP production. These findings led to the use of potent bone resorption inhibitors as an effective therapy for malignant hypercalcaemia.

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