Studies on the mechanism of leucocytosis and hypercalcemia associated with head and neck cancer

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In this studies, the mechanism underlying leucocytosis and hypercalcemia associated with malignancy was investigated.In this investigation of leucocytosis and/or hypercalcemia occasionally occurred in patients with oral malignancies, some patients have only one of them, whereas others have both. These results demonstrate that these paraneoplastic syndromes result from different mechanisms.In accordance with this fact, tongue cancer of a patient with hypercalcemia was inoculated into nude mice and, at the same time, cultured in vitro. These tumor cells secrete high level of PGE_2, which is revealefl, to play important roles in bone resorption. Furthermore, high level of PGE_2 or Ca^<2+> in culture medium promoted DNA synthesis of tumor cells. In the further studies used VX_2 cancer cells, the cells secreted PGE_2 and also parathyroid hormone-related protein (PTHrP). These humoral factors are involved in pathogenesis of hypercalcemia. Increase of serum PGEP_2 and PTHrP results in enlargement of bone marrow cavity of parietal bone. Administration of indomethacin or antagonist of PTHRP, PTHRP analogue, prevented a bone resorbing activity of these factors. Both PGE_2 and PTHRP promoted Vxg cell growth as autocrine growth factors. Stimulation of VX_2 cell proliferation by PGE_2 or ETHRP was closely correlated with a transient elevation of intracellular free Ca^<2+> by influx of extracellular free Ca^<2+>.It is, therefore, suggested that induction of the hypercalcemia is an essential event for VX_2 cells to maintain an environment which favors their autonomous growth.