THE ROLE OF IMMUNE SYSTEM AND DIFFERENTIATION AT MICROENVIRNMENT INVOLVED IN INVASION AND METASTASIS OF PANCREATIC CANCER

在混合白细胞肿瘤细胞培养(MLTC)(胰腺癌细胞与外周血单核细胞共培养；健康志愿者MNL)中检测细胞因子的产生，这些细胞因子主要由单核细胞产生。它们可能激活内皮细胞，诱导其上ELAM-1的表达，在癌细胞-内皮细胞黏附和肝转移中发挥重要作用。因此，利用三种人胰腺癌细胞SW1990(高转移性)、Capan-2(低转移性)和Panc-1(无转移性)，研究了参与免疫反应的黏附分子在癌细胞上的表达。在ALL细胞上检测到HLAI类抗原的表达，而ICAM-1在SW1990中低表达，这与其转移潜能相反。根据这一结果，MNL对SW1990的黏附和对SW1990的细胞毒性最小，并且SW1990的细胞逃逸来自免疫效应细胞Suc…LAK细胞作为NK细胞，利用ICAM-1/LFA-1系统识别癌细胞，可能更多地参与了肿瘤转移的发生。其次，通过免疫组织化学方法研究ICAM-1的表达与临床病理因素的关系，发现ICAM-1的组织学类型与有无淋巴结转移或侵袭门脉系统无关，但ICAM-1表达阴性者较阳性者肝转移发生率高。除SW1990外，肿瘤细胞表面ICAM-1的表达呈剂量依赖性增加，而转化生长因子-β1则显著降低所有细胞表面ICAM-1的表达及淋巴细胞对癌细胞的黏附和细胞毒作用。最后，随着对转化生长因子-β1在侵袭和转移中的其他功能作用的研究，它增加了转移瘤SW1990和Capan-2的体外侵袭和体内肝转移能力，增加了细胞中的蛋白水解酶，如基质金属蛋白酶-2和u-PA。这些结果提示，转化生长因子-β1可能不仅通过抑制宿主免疫功能，而且通过抑制ICAM-1的表达，使癌细胞以自分泌或旁分泌的方式增加侵袭和转移潜能，从而在胰腺癌肝转移中发挥重要作用。应用中和性的转化生长因子-β1抗体或减少转化生长因子-β1产生的药物抑制肝转移的新的治疗应用有待于进一步的研究。较少

The cytokines production, TN7F- alpha and IL-1 beta were detected during the mixed leukocytes tumor cell culture (MLTC) (co-culture of pancreatic cancer cells with perpheral blood mononuclear leukocytes ; MNL from healthy volunteers), and these cytokines were mainly produced by monocytes. They may activate endothelial cells and induce ELAM-1 expression on them which will play an important role in cancer cell-endothelial cell adhesion and liver metastasis. Consequently, the expression of adhesion molecules involved in immune reaction on cancer cells was investigated using three human pancreatic cancer cells, SW1990 (highly liver metastatic), CAPAN-2 (low metastatic) and PANC-1 (no metastatic). While the expressions of HLA class I antigen were detected on all cells, ICAM-1 expression was low in SW1990 contrary to its metastatic potentia. According to this result, MNL adhesion to SW1990 and cytotoxicity of SW1990 by MNL were minimum and cell escape of SW1990 from immune effector cells suc … More h as NK, LAK cells which use ICAM-1/LFA-1 system in cancer cell recognition must be involved in development of metastasis. Next investigating the relationship between ICAM-1 expression and clinicopathological factors by immunochemical study on surgical specimens, histological type and existence of lymphnode's metastasis or invasion to portal system have no relationship, but liver metastasis were highly found in ICAM-1 negative cases compared with positive case. ICAM-1 expressions on cancer cell surface were increased in dose dependent fashion by treatment with TNF- alpha except for SW1990, on the other hand TGF- beta1) significantly decreased ICAM-1 expression on all cells and lymphocyte's adhesion and cytotoxicity to cancer cells. Finally as other functional effects of TGF- beta1 in invasion and metastasis were investigated, it increase protenase productions such as MMP-2 and u-PA, in vitro invasion and in vivo liver metastasis of metastatic SW1990 and CAPAN-2. These findings suggested that TGF- beta1 may play important roles in liver metastasis of pancreatic cancer not only by suppressing host immune function but also by making cancer cells escape from effector cells through inhibiting ICAM-1 expression and increasing invasive and metastatic potential in autocrine or paracrine fashion. New therapeutic application to inhibit liver metastasis using neubizing TGF- beta1 antibody or drugs to decrease the production of TGF- beta1 should be investigated in future study. Less