Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer.
Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer.
复制标题
DOI：
--
复制
发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Suresh Kumar;H. Kishimoto;H. Chua;S. Badve;K. Miller;R. Bigsby;H. Nakshatri
中科院分区：
文献类型：
--
作者：
Suresh Kumar;H. Kishimoto;H. Chua;S. Badve;K. Miller;R. Bigsby;H. Nakshatri
乳腺癌的进展涉及上皮细胞和间质细胞之间的相互作用。这种相互作用是由癌细胞和间质细胞分泌的生长因子和细胞因子介导的。我们先前报道了IL-1α在乳腺癌中的表达，并在体外系统中证明了IL-1α是前转移基因的自分泌和旁分泌诱导剂。为了了解IL-1α在乳腺癌体内进展中的作用，我们研究了高表达分泌型IL-1α(MCF-7IL-1α)的MCF-7乳腺癌细胞在裸鼠体内的生长情况。与亲代细胞相比，McF-7IL-1α细胞形成生长迅速的雌激素依赖性肿瘤。有趣的是，IL-1α的单独表达不足以在体内转移，尽管体外研究表明，在IL-1α表达的癌细胞和成纤维细胞之间的串扰反应中，诱导了几个前转移基因和基质金属蛋白酶的活性。植入MCF-7IL-1α细胞的动物患有恶病质，这与血清瘦素水平的升高有关，但与其他已知的诱发恶病质的细胞因子如IL-6、肿瘤坏死因子或干扰素伽马无关。与对照组相比，患有MCF-7IL-1α细胞来源肿瘤的动物的血清甘油三酯水平较低，但血糖水平不是很低。恶病质与皮肤的表皮和附件结构萎缩有关；据报道，甘油三酯缺乏的小鼠和注射瘦素的ob/ob小鼠的表型相似。只有在MCF-7IL-1α细胞来源的肿瘤中才能检测到小鼠瘦素特异的转录本，这表明IL-1α增加了募集到肿瘤微环境中的基质细胞的瘦素表达。尽管血清瘦素水平升高，但患有MCF-7IL-1α细胞来源肿瘤的动物并没有厌食，这表明肿瘤来源的瘦素只有外周作用，主要针对脂质代谢。综上所述，这些结果表明，癌细胞衍生的细胞因子，如IL-1α，通过影响瘦素依赖的代谢途径诱导恶病质。
Progression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1 alpha in a subset of breast cancers and demonstrated that IL-1 alpha is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1 alpha in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1 alpha (MCF-7IL-1 alpha) in nude mice. MCF-7IL-1 alpha cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1 alpha expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1 alpha-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1 alpha cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1 alpha cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1 alpha cell-derived tumors, which suggests that IL-1 alpha increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1 alpha cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1 alpha, induce cachexia by affecting leptin-dependent metabolic pathways.