Unité Mixte de Recherche 702 (UMR S 702), Université Pierre-et-Marie-Curie Paris VI et Institut National de la Santé et de la Recherche Médicale, Hôpital Tenon, Paris, France.
PLoS One. 2013;8(4):e60469. doi: 10.1371/journal.pone.0060469. Epub 2013 Apr 2.
Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.
传统钙蛋白酶是普遍存在的半胱氨酸蛋白酶，其活性受钙信号的促进，并受钙蛋白酶抑制剂（calpastatin）的特异性限制。已经证明钙蛋白酶的表达在人类恶性细胞中增加，但钙蛋白酶/钙蛋白酶抑制剂系统在肿瘤发生中的贡献仍不清楚。它可能在肿瘤细胞本身（细胞生长、迁移和相反的细胞死亡）和/或肿瘤微环境（免疫细胞浸润组织、新血管生成）中发挥重要作用。在这项研究中，我们使用黑色素瘤小鼠模型作为工具，以进一步了解钙蛋白酶在肿瘤进展中的作用。为了确定每个靶标的相对重要性，我们单独在肿瘤和/或宿主中过表达钙蛋白酶抑制剂。我们的数据表明，在肿瘤和宿主中同时抑制钙蛋白酶会抑制肿瘤生长，同时反而会增加转移到区域淋巴结的扩散。具体而言，在黑色素瘤细胞中抑制钙蛋白酶会限制肿瘤在体外和体内的生长，但会通过放大细胞对凋亡的抵抗能力并加速迁移过程来增加扩散。同时，限制在宿主细胞中的钙蛋白酶抑制会削弱肿瘤细胞对肿瘤免疫所需的免疫细胞浸润和血管生成，使肿瘤细胞逃避肿瘤微环境并扩散。具有癌症潜在医学应用的高度特异性钙蛋白酶抑制剂的开发应考虑钙蛋白酶/钙蛋白酶抑制剂系统在初始肿瘤生长和随后的转移扩散中的相反作用。
