Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice.
Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice.
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有证据表明肿瘤坏死因子在裸鼠人类肿瘤恶病质、高钙血症和白细胞增多等副肿瘤综合征中发挥致病作用。
DOI：
10.1172/jci115106
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Mundy,GR
中科院分区：
文献类型：
--
作者：
Yoneda,T;Alsina,MA;Chavez,JB;Bonewald,L;Nishimura,R;Mundy,GR
最近，我们已经建立了一个人鳞状细胞癌的上颌骨（称为MH-85）与高钙血症，白细胞增多，恶病质的文化。MH-85肿瘤细胞在荷瘤裸鼠中引起相同的副肿瘤综合征。我们发现，在MH-85荷瘤小鼠中，脾脏大小增加了6倍。这种增加抑制了肿瘤的生长，并通过手术切除肿瘤而逆转。裸鼠脾切除术前1周或6周后肿瘤接种导致肿瘤生长减少，高钙血症，白细胞增多和恶病质的损害。在MH-85荷瘤动物，已预先通过脾切除术，静脉注射新鲜的正常脾细胞引起立即逆转白细胞增多，高钙血症，恶病质。由于在患者和携带肿瘤的小鼠中存在恶病质表明肿瘤坏死因子（TNF）可能过度产生，我们将抗鼠TNF的多克隆中和抗体注射到荷瘤小鼠中。有一个快速和可重复的降低血液离子钙，伴随着抑制破骨细胞活性。在注射正常免疫血清的小鼠中没有观察到血液离子钙的变化。此外，体重增加，白色细胞计数减少。荷瘤裸鼠的血浆免疫反应性TNF几乎增加了四倍，与对照裸鼠相比。虽然在MH-85培养上清液中检测不到TNF活性，但当与MH-85肿瘤条件培养基一起培养时，巨噬细胞谱系的细胞（包括脾细胞）释放增加量的TNF。这些结果表明，脾细胞因子，如TNF可能会影响这些动物的副肿瘤综合征的高钙血症，白细胞增多，恶病质的发展，以及肿瘤的生长。他们还表明，副肿瘤综合征可能是由于肿瘤的存在刺激正常宿主细胞产生的因子。图片
Recently, we have established a human squamous cell carcinoma of the maxilla (called MH-85) associated with hypercalcemia, leukocytosis, and cachexia in culture. MH-85 tumor cells caused the same paraneoplastic syndromes in tumor-bearing nude mice. We found that there was a sixfold increase in splenic size in MH-85 tumor-bearing mice. This increase paralleled tumor growth and was reversed by surgical removal of the tumor. Splenectomy in nude mice 1 wk before or 6 wk after tumor inoculation resulted in a decrease in tumor growth, and impairment of hypercalcemia, leukocytosis, and cachexia. In MH-85 tumor-bearing animals that had been pretreated by splenectomy, intravenous injection of fresh normal spleen cells caused an immediate reversal of leukocytosis, hypercalcemia, and cachexia. Since the presence of cachexia in both the patient and the mice carrying the tumor suggested tumor necrosis factor (TNF) may be overproduced, we injected polyclonal neutralizing antibodies raised against murine TNF into tumor-bearing mice. There was a rapid and reproducible decrease in blood ionized calcium, accompanied by suppression of osteoclast activity. No changes in blood ionized calcium were seen in mice injected with normal immune sera. In addition, there was an increase in body weight and decrease in white cell count. Plasma immunoreactive TNF was increased almost fourfold in tumor-bearing nude mice compared with control nude mice. Although TNF activity was undetectable in MH-85 culture supernatants, cells of the macrophage lineage, including spleen cells, released increased amounts of TNF when cultured with MH-85 tumor-conditioned media. These results suggest that splenic cytokines such as TNF may influence the development of the paraneoplastic syndromes of hypercalcemia, leukocytosis, and cachexia in these animals, as well as tumor growth. They also show that paraneoplastic syndromes may be due to factors produced by normal host cells stimulated by the presence of the tumor.Images