Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth
Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth
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DOI：
10.1007/s10585-013-9613-6
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发表时间：
2013
影响因子：
4
通讯作者：
Dirk Weinspach;Bastian Seubert;Susanne Schaten;Katja Honert;S. Sebens;P. Altevogt;A. Krüger
中科院分区：
文献类型：
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作者：
Dirk Weinspach;Bastian Seubert;Susanne Schaten;Katja Honert;S. Sebens;P. Altevogt;A. Krüger
与健康个体相比，癌症患者中 L1 细胞粘附分子 (L1CAM) 的表达经常增加，并且也与实体瘤的不良预后相关。此前，我们发现全长 L1CAM 通过上调纤维肉瘤中的明胶分解活性来促进转移形成。在这项研究中，我们旨在将这一发现扩展到血源性恶性肿瘤和癌症，并具体阐明 L1CAM 对转移级联主要步骤的影响。在一个完善的 T 细胞淋巴瘤自发转移模型中，L1CAM 沉默显着提高了小鼠的存活率，而皮内肿瘤生长保持不变。这与自发转移形成的显着减少相关。 L1CAM 抑制消除了 T 细胞淋巴瘤和癌细胞的转移潜力，如体外迁移和侵袭减少以及体内实验性转移形成减少所证明的。在分子水平上，L1CAM 的沉默导致体外明胶酶 MMP-2 和 -9 的表达减少，并降低体内原发性肿瘤和转移瘤的明胶分解活性。因此，敲低 L1CAM 对迁移、侵袭和体内明胶分解活性具有与特定明胶酶抑制剂 SB-3CT 相似的抑制作用。这一新发现的 L1CAM 对转移级联和 MMP 活性的不同步骤的影响凸显了 L1CAM 导向疗法抑制转移扩散的潜力。
Expression of the L1 cell adhesion molecule (L1CAM) is frequently increased in cancer patients compared to healthy individuals and also linked with bad prognosis of solid tumours. Previously, we could show that full-length L1CAM promotes metastasis formation via up-regulation of gelatinolytic activity in fibrosarcoma. In this study, we aimed to extend this finding to haematogenous malignancies and carcinomas, and to specifically elucidate the impact of L1CAM on major steps of the metastatic cascade. In a well-established T-cell lymphoma spontaneous metastasis model, silencing of L1CAM significantly improved survival of the mice, while intradermal tumour growth remained unaltered. This correlated with significantly decreased spontaneous metastasis formation. L1CAM suppression abrogated the metastatic potential of T-cell lymphoma as well as carcinoma cells as demonstrated by reduced migration and invasion in vitro and reduced formation of experimental metastasis in vivo. At the molecular level, silencing of L1CAM led to reduced expression of gelatinases MMP-2 and -9 in vitro and decreased gelatinolytic activity in primary tumours and metastases in vivo. In accordance, knock down of L1CAM had similar suppressive effects on migration, invasion and in vivo-gelatinolytic activity as treatment with the specific gelatinase inhibitor SB-3CT. This newly discovered impact of L1CAM on distinct steps of the metastatic cascade and MMP activity highlights the potential of possible L1CAM-directed therapies to inhibit metastatic spread.