Molecular mechanisms of cancer cell progression during liver metastasis formation

本研究旨在阐明结肠癌肝转移形成的分子机制。我们的主要兴趣是宿主在转移过程中的反应。我们集中在以下两个研究课题上。(1)转移早期癌细胞与肝脏的粘附和识别机制：结肠癌FH 6单克隆抗体决定簇的表达与肿瘤恶性程度相关结肠癌细胞系KM 12表达FH 6决定簇，FH 6决定簇是一种独特的碳水化合物结构，含有唾液酸化和岩藻糖基化，不被部分抗唾液酸化刘易斯X Ab识别，对内切-β-糖苷酶消化敏感。为了阐明碳水化合物的分子特性，我们通过FUT 6基因转染到缺乏FH 6决定簇表达的KM 12-LX中来人工重建FH 6决定簇。我们发现肝细胞识别肝脏中的FH 6决定簇。我们现在正在确定 ...更多信息 49 kD蛋白作为识别分子的候选物。(2)建立的肝转移形成伴随着微转移周围宿主组织的重建：我们建立了小鼠实验转移模型，该模型再现了微转移周围宿主组织的重建和建立的转移的形成。根据组织化学观察，我们将已建立的转移的形成分为三个步骤：微转移、短暂微转移和已建立的转移。在微转移中，颗粒状的宿主细胞向转移区浸润。在短暂性微转移中，多种类型的宿主细胞浸润。成纤维细胞组织突起，伴有细胞外基质和新生血管，并与周围微转移灶相连。我们认为这一过程作为纤维化形成的初始事件是重要的。已建立的转移瘤富含成纤维细胞间质组织。Colon 38细胞与宿主细胞分开分布于间质组织中。我们推测在转移形成的过程中，有一定的机制将癌细胞和间质分离。少

The aim of this proposal was to elucidate molecular mechanisms of liver metastasis formation of colon cancer. Our main interest was how host respond during the metastasis process. We have concentrated on the following two research subjects.(1) Adhesion and recognition mechanisms between cancer cells and the liver in the early phase of metastasis : Expression of FH6 monoclonal Ab determinant on colon carcinoma correlates malignancy of the tumor. A colon carcinoma cell line KM 12 expresses FH6 determinant, a unique carbohydrate structure on the following points, containing sialylation anfd fucosylation, not recognized by a part of anti-sialyl lewis X Abs, sensitive to endo-β-glycosidase digestion. To elucidate molecular properties of the carbohydrates we artificially reconsituted FH6 determinants by FUT6 gene transfection into KM 12-LX that lacks expression of FH6 determinant. We showed that hepatocytes recognized the FH6 determinant in the liver. We are now determining the structure of … More 49 kD protein as a candidate of the recognition molecule.(2) Established liver metastasis formation accompanied with reconstitution of host tissues around micrometastasis : We have established a mouse experimental metastasis model that reproduces reconstitution of host tissue around micrometastasis and formation of established metastasis. Based on histochemical observations, we have classified the formation of established metastasis into three steps ; micrometastasis, transient micrometastasis, and established metastasis. In micrometastasis, paticular host cells infilrated into the matastasis region. In transient micrometastasis, many types of host cells infiltrated. Fibroblastic tissue protrusion appeared that accompanied with extracellular matrices and neovascularization and linked neighboring micrometastases. We believe that the process is important as an initial event of fibrosis formation. Established metastasis was rich in fibroblastic stromal tissue. Colon 38 cells separately distributed from host cells in the stromal tissue. We postulate a certain mechanism to separate cancer and stroma in the process of established metasiasis formation. Less