Griffini P, Smorenburg S M, Vogels I M, Tigchelaar W, Van Noorden C J
Department of Animal Biology and CNR Center for Histochemistry, University of Pavia, Italy.
Clin Exp Metastasis. 1996 Sep;14(4):367-80. doi: 10.1007/BF00123396.
The present study was performed to investigate processes involved in circumvention of the immune system by advanced stages of tumor growth in the liver. The efficacy of Kupffer cells and pit cells against cancer cells was tested in vivo in an experimental model of colon carcinoma metastasis in rat liver. Liver tumors were induced by administration of CC531 colon cancer cells into the vena portae. After 3 weeks, livers were obtained and partly fixed for electron microscopic procedures or frozen in liquid nitrogen for enzyme and immunohistochemistry at the light microscope level. The activation status of Kupffer cells was studied by expression of Ia-antigen (MHC class II) and by measurement of glucose-6-phosphate dehydrogenase (G6PDH) activity in the cells in situ as a measure of production of reactive oxygen species. Large numbers of Kupffer cells were found in liver parenchyma surrounding colon carcinomas when compared with levels in control livers, but these cells were not activated. Large numbers of activated monocytes and macrophages, cytotoxic T cells but only a few pit cells were found to be recruited to the boundary between liver parenchyma and tumors or their stroma. In those areas where cancer cells invaded liver parenchyma, only newly recruited macrophages and some Kupffer cells were present but few cytotoxic T cells or pit cells were found. The low activation status of Kupffer cells both in terms of production of reactive oxygen species and Ia-antigen expression and the absence of significant numbers of pit cells at tumor sites suggest that Kupffer cells and pit cells do not play a significant role in advanced stages of tumor growth. High levels of prostaglandin E2 were detected in the parenchyma of livers containing tumors and transforming growth factor beta was detected in the stroma of the tumors, therefore suggest that cytotoxicity of newly recruited monocytes, macrophages and cytotoxic T cells may be limited in these stages because of local production of these immunosuppressive factors.
本研究旨在探讨肝脏肿瘤生长晚期规避免疫系统所涉及的过程。在大鼠肝脏结肠癌转移的实验模型中，对库普弗细胞和肝血窦壁细胞抗癌细胞的功效进行了体内测试。通过将CC531结肠癌细胞注入门静脉来诱导肝肿瘤。3周后，获取肝脏，部分肝脏固定用于电子显微镜检查，或在液氮中冷冻用于光镜水平的酶学和免疫组织化学检查。通过Ia抗原（MHC II类）的表达以及原位测量细胞中的葡萄糖-6-磷酸脱氢酶（G6PDH）活性作为活性氧产生的指标，来研究库普弗细胞的激活状态。与对照肝脏相比，在结肠癌周围的肝实质中发现大量库普弗细胞，但这些细胞未被激活。大量活化的单核细胞、巨噬细胞、细胞毒性T细胞，但仅发现少数肝血窦壁细胞被募集到肝实质与肿瘤或其基质之间的边界处。在癌细胞侵入肝实质的区域，仅存在新募集的巨噬细胞和一些库普弗细胞，但发现细胞毒性T细胞或肝血窦壁细胞很少。库普弗细胞在活性氧产生和Ia抗原表达方面的低激活状态以及肿瘤部位缺乏大量肝血窦壁细胞表明，库普弗细胞和肝血窦壁细胞在肿瘤生长晚期不发挥重要作用。在含有肿瘤的肝脏实质中检测到高水平的前列腺素E2，在肿瘤基质中检测到转化生长因子β，因此表明在这些阶段新募集的单核细胞、巨噬细胞和细胞毒性T细胞的细胞毒性可能由于这些免疫抑制因子的局部产生而受到限制。
