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白细胞共培养;来自健康志愿者的MNL）期间检测细胞因子产生，TNF-α和IL-1 β，并且这些细胞因子主要由单核细胞产生。它们可以激活内皮细胞并诱导其表达ELAM-1，这在癌细胞-内皮细胞粘附和肝转移中起重要作用。因此，使用三种人胰腺癌细胞，SW 1990（高肝转移）、CAPAN-2（低转移）和PANC-1（无转移），研究了参与癌细胞上免疫反应的粘附分子的表达。SW 1990细胞均表达HLA-Ⅰ类抗原，但ICAM-1表达较低，与其转移潜能相反。根据这一结果，MNL与SW 1990的粘附和MNL对SW 1990的细胞毒性最小，SW 1990从免疫效应细胞的细胞逃逸最小。 ...更多信息 LAK细胞与NK细胞一样，通过ICAM-1/LFA-1系统识别癌细胞，参与肿瘤转移的发生。通过对手术标本的免疫组化研究ICAM-1表达与临床病理因素的关系，发现组织学类型与有无淋巴结转移或侵犯门脉系统无关，但ICAM-1阴性者肝转移率高于阳性者。除SW 1990外，TNF-α可剂量依赖性地增加癌细胞表面ICAM-1的表达，而TGF-β_1则可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粘附和杀伤作用。最后，研究了TGF-β 1在侵袭和转移中的其他功能作用，其增加转移性SW 1990和CAPAN-2的体外侵袭和体内肝转移的蛋白酶产生，如MMP-2和u-PA。提示TGF-β 1可能通过抑制宿主免疫功能，抑制ICAM-1表达，使癌细胞逃避效应细胞，以自分泌或旁分泌方式增加侵袭转移潜能，从而在胰腺癌肝转移中发挥重要作用。新的治疗应用，抑制肝转移，使用neubizing TGF-β 1抗体或药物，以减少TGF-β 1的生产，应在未来的研究。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