Cahlin C, Körner A, Axelsson H, Wang W, Lundholm K, Svanberg E
Department of Surgery, Sahlgrenska University Hospital, Göteborg University, Sweden.
Cancer Res. 2000 Oct 1;60(19):5488-93.
MCG 101 tumors were implanted sc. on wild-type C57 Bl and gene knockout mice to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-12, IFNgamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] to explain local tumor growth, anorexia, and carcass weight loss in a well-defined model with experimental cachexia. Indomethacin was provided in the drinking water to explore interactions between host and tumor-derived prostaglandins and proinflammatory cytokines for tumor growth. Wild-type tumor-bearing mice developed cachexia because of rapid tumor growth, which were both attenuated in IL-6 gene knockouts. Similar findings were observed after provision of anti-IL-6 to wild-type tumor-bearing mice. Alterations in food intake were not directly related to systemic IL-6 but rather secondarily to IL-6-dependent tumor growth. The absence of host-derived IL-12, IFN-gamma, or the TNF receptor 1 or receptor 2 gene did not attenuate tumor growth or improve subsequent cachexia. Thus, carcass weight loss was not improved by the omission of host cytokine (TNF-alpha, IL-12, or IFN-gamma) except for IL-6. Systemic indomethacin provision decreased plasma prostaglandin E2 in five of six groups of gene knockout tumor-bearing mice, which was associated with improved carcass weight in these groups. Indomethacin seemed to improve food intake to a similar extent in both wild-type and gene knockouts, which agree with the speculation that eicosanoids are more important to explain anorexia than host cytokines. Our results demonstrate that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a more complex fashion than usually presented based on previous information in studies on either anti-cytokine experiments in vivo or on gene knockouts with respect to a "single cytokine model." Overall, host cytokines were quantitatively less important than tumor-derived cytokines to explain net tumor growth, which indirectly explains subsequent cachexia and anorexia.
将MCG 101肿瘤接种于野生型C57 Bl和基因敲除小鼠的皮下，以评估宿主产生的细胞因子[白细胞介素（IL）-6、IL-12、干扰素γ、肿瘤坏死因子（TNF）受体1和TNF受体2]在一个明确的实验性恶病质模型中对局部肿瘤生长、厌食和体重减轻的作用。在饮用水中添加吲哚美辛，以探究宿主和肿瘤来源的前列腺素与促炎细胞因子之间的相互作用对肿瘤生长的影响。野生型荷瘤小鼠因肿瘤快速生长而出现恶病质，而在IL-6基因敲除小鼠中这种情况有所减轻。给野生型荷瘤小鼠注射抗IL-6后也观察到了类似的结果。食物摄入量的改变并非直接与全身IL-6相关，而是继发于IL-6依赖的肿瘤生长。宿主来源的IL-12、干扰素γ或TNF受体1或受体2基因的缺失并未减弱肿瘤生长或改善随后的恶病质。因此，除了IL-6外，缺失宿主细胞因子（TNF-α、IL-12或干扰素γ）并不能改善体重减轻。在六组基因敲除荷瘤小鼠中，有五组给予全身吲哚美辛后血浆前列腺素E2降低，这与这些组体重的改善相关。吲哚美辛似乎在野生型和基因敲除小鼠中对食物摄入量的改善程度相似，这与类花生酸在解释厌食方面比宿主细胞因子更重要的推测一致。我们的结果表明，宿主和肿瘤来源的细胞因子及前列腺素与肿瘤生长相互作用，并以比以往基于体内抗细胞因子实验或“单一细胞因子模型”基因敲除研究中所呈现的更为复杂的方式促进恶病质。总体而言，在解释肿瘤净生长方面，宿主细胞因子在数量上不如肿瘤来源的细胞因子重要，这间接解释了随后的恶病质和厌食。
