Nabeshima Kazuki, Suzumiya Junji, Nagano Mitsuyuki, Ohshima Koichi, Toole Bryan P, Tamura Kazuo, Iwasaki Hiroshi, Kikuchi Masahiro
Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan.
J Pathol. 2004 Mar;202(3):341-51. doi: 10.1002/path.1518.
Degradation of the extracellular matrix by matrix metalloproteinases (MMPs) is a crucial step in tumour invasion and metastasis. In human carcinomas, tumour cell-fibroblast interactions (TFIs) have been demonstrated to play a role in the up-regulation of MMP levels in tumours, and emmprin is a surface molecule on tumour cells that stimulates nearby fibroblasts to produce MMP-1, 2, and 3. T-cell lymphomas frequently show extranodal organ involvement and skin invasion, but a role for TFIs in their invasion has not been examined in detail. This study investigated TFIs in T-cell lymphomas with special reference to emmprin expression and MMP production. Immunohistochemically, only germinal centre cells and some histiocytes expressed emmprin in non-neoplastic lymph nodes (ten cases), while all T-cell lymphomas [14 cases of adult T-cell leukaemia/lymphoma (ATLL), six cases of lymphoblastic lymphoma, seven cases of anaplastic large cell lymphoma, and nine cases of angio-immunoblastic T-cell lymphoma] expressed emmprin strongly and diffusely. FACS analysis of peripheral blood from normal individuals revealed that small fractions of B-cells, T-cells, and monocytes expressed emmprin, whereas emmprin-expressing T-cells were much increased in number, and expressed this protein to a higher level, in ATLL patients. In vitro co-cultures of emmprin-positive HTLV-1-transformed lymphocytes (MT-2) and emmprin-negative human fibroblasts enhanced the production of pro-MMP-2 (gelatinase A) and active MMP-2, compared with cultures of either cell type alone. This stimulation was inhibited by an activity-blocking peptide against emmprin. Moreover, in histopathological sections from patients with ATL skin involvement, MMP-2 was demonstrated in fibroblasts around infiltrating ATL cells, but not in fibroblasts in non-diseased areas. In conclusion, emmprin is overexpressed by T-lymphoma cells, when compared with normal counterparts, and facilitates MMP-2 production via interactions with fibroblasts, which could play a role in stromal invasion by lymphoma cells.
基质金属蛋白酶（MMPs）介导的细胞外基质降解是肿瘤侵袭和转移的关键步骤。在人类癌症中，肿瘤细胞与成纤维细胞的相互作用（TFIs）已被证明在肿瘤中MMP水平的上调中发挥作用，而埃姆普林（emmprin）是肿瘤细胞上的一种表面分子，可刺激附近的成纤维细胞产生MMP-1、2和3。T细胞淋巴瘤经常表现出结外器官受累和皮肤侵袭，但TFIs在其侵袭中的作用尚未得到详细研究。本研究调查了T细胞淋巴瘤中的TFIs，特别关注埃姆普林的表达和MMP的产生。免疫组织化学分析显示，在非肿瘤性淋巴结（10例）中，只有生发中心细胞和一些组织细胞表达埃姆普林，而所有T细胞淋巴瘤[14例成人T细胞白血病/淋巴瘤（ATLL）、6例淋巴母细胞淋巴瘤、7例间变性大细胞淋巴瘤和9例血管免疫母细胞性T细胞淋巴瘤]均强烈且弥漫性地表达埃姆普林。对正常个体外周血的流式细胞术分析显示，一小部分B细胞、T细胞和单核细胞表达埃姆普林，而在ATLL患者中，表达埃姆普林的T细胞数量显著增加，且该蛋白的表达水平更高。与单独培养任何一种细胞类型相比，埃姆普林阳性的HTLV-1转化淋巴细胞（MT-2）与埃姆普林阴性的人成纤维细胞的体外共培养增强了前MMP-2（明胶酶A）和活性MMP-2的产生。这种刺激被一种针对埃姆普林的活性阻断肽所抑制。此外，在ATL皮肤受累患者的组织病理学切片中，浸润的ATL细胞周围的成纤维细胞中显示有MMP-2，但在非病变区域的成纤维细胞中未检测到。总之，与正常对应细胞相比，T淋巴瘤细胞中埃姆普林过度表达，并通过与成纤维细胞的相互作用促进MMP-2的产生，这可能在淋巴瘤细胞的基质侵袭中发挥作用。
