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

在本研究中，白细胞增多和/或高钙血症偶尔发生在口腔恶性肿瘤患者的调查，一些患者只有其中之一，而另一些患者两者兼而有之，白细胞增多和/或高钙血症的潜在机制进行了调查。根据这一事实，将一例高钙血症患者的舌癌接种于裸鼠体内，同时进行体外培养。这些肿瘤细胞分泌高水平的PGE_2，提示其在骨吸收中起重要作用。培养液中高浓度的PGE_2或Ca^<2+>促进肿瘤细胞DNA合成。在使用VX_2癌细胞的进一步研究中，该细胞分泌PGE_2和甲状旁腺激素相关蛋白（PTHrP）。这些体液因素参与了高钙血症的发病机制。血清PGEP_2、PTHrP升高导致顶骨骨髓腔扩大。给药吲哚美辛或PTHRP拮抗剂，PTHRP类似物，阻止了这些因子的骨吸收活性。PGE_2和PTHRP均以自分泌生长因子的形式促进人胃癌细胞的生长。PGE_2或ETHRP刺激VX_2细胞增殖与细胞外游离Ca ^<2 +>内流引起的细胞内游离Ca ^<2 +>瞬时升高密切相关，提示诱导高钙血症是维持VX_2细胞自主生长环境的必要事件。

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.