Multiple acquired renal carcinoma tumor capabilities abolished upon silencing of ADAM17
Multiple acquired renal carcinoma tumor capabilities abolished upon silencing of ADAM17
复制标题
DOI：
10.1158/0008-5472.can-06-1595
复制
发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Lee, Stephen
中科院分区：
文献类型：
--
作者：
Franovic, Aleksandra;Robert, Isabelle;Lee, Stephen
细胞凋亡是指导正常细胞增殖和稳态的调节回路中获得性缺陷的表现。这些电路中的大多数通过细胞自主途径运作，而其他电路则可能涉及邻近的微环境。我们报告说，金属蛋白酶ADAM 17起着关键作用，在几个收购肿瘤细胞的能力，通过介导可溶性转化生长因子-α，表皮生长因子受体（EGFR）配体的可用性，从而建立一个关键的自分泌信号通路。人肾癌细胞系中ADAM 17的沉默纠正了与癌细胞相关的关键特征，包括生长自主性，肿瘤炎症和组织侵袭。高度恶性的肾癌癌细胞在不存在ADAM 17的情况下不能形成体内肿瘤，证实了该分子在肿瘤发生中的基本功能。这些数据表明，配体脱落是内源性EGFR激活的关键步骤，并支持靶向人类癌症中的ADAM 17的前瞻性治疗策略。
Malignancy is a manifestation of acquired defects in regulatory circuits that direct normal cell proliferation and homeostasis. Most of these circuits operate through cell autonomous pathways, whereas others potentially involve the neighboring microenvironment. We report that the metalloprotease ADAM17 plays a pivotal role in several acquired tumor cell capabilities by mediating the availability of soluble transforming growth factor-alpha, an epidermal growth factor receptor (EGFR) ligand, and thus the establishment of a key autocrine signaling pathway. Silencing of ADAM17 in human renal carcinoma cell lines corrects critical features associated with cancer cells, including growth autonomy, tumor inflammation, and tissue invasion. Highly malignant renal carcinoma cancer cells fail to form in vivo tumors in the absence of ADAM17, confirming the essential function of this molecule in tumorigenesis. These data show that ligand shedding is a crucial step in endogenous EGFR activation and endorse prospective therapeutic strategies targeting ADAM17 in human cancer.