Department of Neurosurgery, Philipps University Marburg, Baldingerstrasse, Marburg D-35033, Germany.
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Albert-Schweitzer Campus 1, Münster D-48149, Germany.
Clin Sci (Lond). 2019 Jan 11;133(1):83-99. doi: 10.1042/CS20180906. Print 2019 Jan 15.
Ectodomain shedding of extracellular and membrane proteins is of fundamental importance for cell-cell communication in neoplasias. A Disintegrin And Metalloproteinase (ADAM) proteases constitute a family of multifunctional, membrane-bound proteins with traditional sheddase functions. Their protumorigenic potential has been attributed to both, essential (ADAM10 and ADAM17) and 'dispensable' ADAM proteases (ADAM8, 9, 12, 15, and 19). Of specific interest in this review is the ADAM proteinase ADAM8 that has been identified as a significant player in aggressive malignancies including breast, pancreatic, and brain cancer. High expression levels of ADAM8 are associated with invasiveness and predict a poor patient outcome, indicating a prognostic and diagnostic potential of ADAM8. Current knowledge of substrates and interaction partners gave rise to the hypothesis that ADAM8 dysregulation affects diverse processes in tumor biology, attributable to different functional cores of the multidomain enzyme. Proteolytic degradation of extracellular matrix (ECM) components, cleavage of cell surface proteins, and subsequent release of soluble ectodomains promote cancer progression via induction of angiogenesis and metastasis. Moreover, there is increasing evidence for significance of a non-proteolytic function of ADAM8. With the disintegrin (DIS) domain ADAM8 binds integrins such as β1 integrin, thereby activating integrin signaling pathways. The cytoplasmic domain is critical for that activation and involves focal adhesion kinase (FAK), extracellular regulated kinase (ERK1/2), and protein kinase B (AKT/PKB) signaling, further contributing to cancer progression and mediating chemoresistance against first-line therapies. This review highlights the remarkable effects of ADAM8 in tumor biology, concluding that pharmacological inhibition of ADAM8 represents a promising therapeutic approach not only for monotherapy, but also for combinatorial therapies.
细胞外和膜蛋白的胞外域脱落对于肿瘤中的细胞间通讯具有重要意义。解整合素和金属蛋白酶 (ADAM) 蛋白酶构成了具有传统脱落酶功能的多功能膜结合蛋白家族。它们的促肿瘤潜能归因于必需的 (ADAM10 和 ADAM17) 和“可有可无的”ADAM 蛋白酶 (ADAM8、9、12、15 和 19)。在本综述中特别感兴趣的是 ADAM 蛋白酶 ADAM8，它已被确定为包括乳腺癌、胰腺癌和脑癌在内的侵袭性恶性肿瘤的重要参与者。ADAM8 的高表达水平与侵袭性相关，并预测患者预后不良，表明 ADAM8 具有预后和诊断潜力。对底物和相互作用伙伴的现有认识提出了这样的假设，即 ADAM8 失调会影响肿瘤生物学中的多种过程，这归因于多结构域酶的不同功能核心。细胞外基质 (ECM) 成分的蛋白水解降解、细胞表面蛋白的切割以及随后释放的可溶性胞外结构域通过诱导血管生成和转移促进癌症进展。此外，越来越多的证据表明 ADAM8 的非蛋白水解功能具有重要意义。ADAM8 通过解整合素 (DIS) 结构域与整合素（如β1 整合素）结合，从而激活整合素信号通路。细胞质结构域对于该激活至关重要，涉及粘着斑激酶 (FAK)、细胞外调节激酶 (ERK1/2) 和蛋白激酶 B (AKT/PKB) 信号转导，进一步促进癌症进展并介导对一线治疗的化疗耐药性。本综述强调了 ADAM8 在肿瘤生物学中的显著作用，得出结论，ADAM8 的药理学抑制不仅是一种单一疗法，而且是一种组合疗法，代表了一种有前途的治疗方法。
