The Role of Proteases in Epithelial-To-Mesenchymal Cell Transitions in Cancer
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Cancer and Metastasis Reviews (2019) 38:431–444 https://doi.org/10.1007/s10555-019-09808-2 The role of proteases in epithelial-to-mesenchymal cell transitions in cancer Julia Mitschke1 & Ulrike C. Burk1 & Thomas Reinheckel1,2,3 Published online: 3 September 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as in many diseases with cancer as the most prominent example. Nowadays, a great deal of work and literature concerns the understanding of the process of epithelial-to-mesenchymal transition (EMT) in terms of its molecular regulation and its implications for cancer. Similar statements can certainly be made regarding the investigation of the more than 500 proteases typically encoded by a mammalian genome. Specifically, the impact of proteases on tumor biology has been a long-standing topic of interest. However, although EMT actively regulates expression of many proteases and proteolytic enzymes are clearly involved in survival, division, differentiation, and movements of cells, information on the diverse roles of proteases in EMT has been rarely compiled. Here we aim to conceptually connect the scientific areas of “EMT” and “protease” research by describing how several important classes of proteolytic enzymes are regulated by EMT and how they are involved in initiation and execution of the EMT program. To do so, we briefly introduce the evolving key features of EMT and its regulation followed by discussion of protease involvement in this process. Keywords Metalloprotease . Deubiquitinating enzyme . Desumoylating enzyme . Transmembrane serine protease . Cathepsin 1 Introduction to key characteristics of EMT Hay were able to observe EMT in adult tissues [1]. EMT processes are physiologically activated during tissue Epithelial-to-mesenchymal transition (EMT) is an evolution- and organ development such as gastrulation, heart forma- arily conserved program of cellular plasticity that allows po- tion, neural crest migration, somitogenesis, and palate for- larized, immotile epithelial cells to loosen their cell-cell adhe- mation [2]. In the adult organism, EMT is transiently ac- sion, detach from neighboring cells, and to convert into motile tivated as a response to injury for example during wound mesenchymal cells (Fig. 1). As the term transition implies, healing in the skin or during the postovulatory ovarian EMT is not a binary switch but a gradual transformation remodeling process [3, 4]. In contrast, pathologically through numerous hybrid and intermediate E/M-states in a sustained EMT is a key mechanism of tissue fibrosis in reversible manner. multiple organs and plays a role in the pathophysiology of Historically, EMT has first been described in embryo- skin, renal, and liver fibrosis leading to tissue degenera- genesis, but already in the early 1980s, Greenburg and tion [5–7]. Importantly, pathological activation of EMT is also frequently detected in tumorigenesis [8]. Julia Mitschke and Ulrike C. Burk contributed equally to this work. Induction of EMT is mediated by cues from the micro- environment, such as TGF-β and Wnt-ligands as well as * Thomas Reinheckel cell-intrinsic signals such as metabolic stress or oncogenic [email protected] mutations in the RAS-Raf-Erk pathway (Fig. 1)[9–11]. Both intrinsic and extrinsic signals converge to provoke 1 Institute of Molecular Medicine and Cell Research, University of the expression of EMT-inducing transcription factors Freiburg, 79104 Freiburg, Germany (EMT-TFs) for signal transmission. A small number of 2 German Cancer Consortium (DKTK) and German Cancer Research transcription factors function as core EMT-TFs. They be- Center (DKFZ) Heidelberg, partner site Freiburg, long to the Snail (SNAIL, SLUG), basic helix-loop-helix 79106 Freiburg, Germany (TWIST1), and ZEB (ZEB1, ZEB2) families. These fam- 3 BIOSS Centre for Biological Signalling Studies, University of ilies are not related, and the members differ in structure Freiburg, 79104 Freiburg, Germany 432 Cancer Metastasis Rev (2019) 38:431–444 a EMT epithelial cell-cellcontacts extracellular proteases membrane bound proteases intracellular proteases e.g. MMPs e.g. ADAMs, TTSPs e.g. DUBs, cathepsins b Inducers Epithelial markers EMT transcription factors E-cadherin SNAIL, TWIST, ZEB Epcam Mesenchymal markers oitammalfni N-cadherin Cell-cell adhesion Vimentin desmosomes gap junctions Proteolysis Wnt-ligands ERFG pathway tight junctions DUBs, SENPs, cathepsins, adherens junctions ADAMs, MT-MMPs, TTSPs yawhtap hctoN yawhtap MMPs cortical actin actin stress fibers apical-basal polarity front-rear polarity hypoxia ROS“static” epithelium n motile / “metastatic” cells Fig. 1 Cellular characteristics during EMT. A) Changes in cellular induction of EMT-transcription factors. The following gradual loss of morphology and extracellular matrix organization during EMT. epithelial characteristics is accompanied by a re-organization of the actin Immotile epithelial cells loosen their cell–cell contacts (desmosomes, cytoskeleton leading to an elongated cell shape with loss of cell–cell gap-, tight-, adherens junctions), detach from neighboring cells and con- adhesion, gain of front-rear polarity, and increased invasive and migratory vert into motile mesenchymal cells. Concomitantly, remodeling of extra- abilities. Molecular markers characteristic of different EMT-states, like E- cellular matrix to a state of radially aligned fibers supports cell motility. cadherin and Epcam as well as N-cadherin and Vimentin, are shown. In Intracellular (such as DUBs, SENPs, cathepsins), membrane bound (e.g., general, enhanced proteolysis is characteristic for cells that underwent ADAMs, MT-MMPs, TTSPs), and extracellular proteases (MMPs) con- EMT. Abbreviations: ADAM—a disintegrin and metalloprotease; tribute to these processes by influencing cell signaling, breakdown of the DUB—deubiquinating enzyme; MMP—matrix metalloprotease; MT- basement membrane, and remodeling of the extracellular matrix. B) MMP—membrane type matrix metalloprotease; ROS—reactive oxygen Molecular processes underlying the cellular plasticity during EMT. species; TTSP—type II transmembrane serine protease family; SENP— Cues from the microenvironment (gray box) converge and lead to sentrin specific protease and size, stability, spatiotemporal expression patterns, and pathways, transcription factors, non-coding RNAs, and target gene profile [12]. EMT-TFs control the expression also proteases [11, 23]. of proteins implicated in cell–cell junctions (Claudins, Desmoplakin, Placophilins, Occludin, ZO-3) [13–15], cell polarity (Crumbs3, LGL2, PATJ) [16], cytoskeletal struc- 2 EMT in cancer progression and metastasis ture (reviewed in [17]), and extracellular matrix degrada- tion (MMP-1, MMP-2, MMP-7, MMP-9, MMP-14, EMT in cancer is associated with tumor initiation and progres- MMP-15) [18–22]. The common denominator of all core sion, stemness, survival, and therapy resistance. Classically, EMT-TFs is the direct or indirect repression of the key EMT has been thought to be critical for local invasion and epithelial gene E-cadherin. This dynamic regulation of cancer cell dissemination in the body. Subsequently, the rever- adherens junctions triggers signaling pathways and alter- sal of EMT, termed mesenchymal-to-epithelial transition ations in the organization of the actin cytoskeleton that are (MET), is thought to allow disseminated tumor cells to colo- involved in cell motility. The complex signaling network nize the foreign soil at distant organ sites to form that regulates EMT is active on epigenetic, transcriptional, macrometastases that are often dismal signs for the prognosis and post-transcriptional level and includes signaling of cancer patients [11, 24–26]. Cancer Metastasis Rev (2019) 38:431–444 433 However, EMT plays an active role not only in metastasis roles at different steps of tumorigenesis and invasion—both but also in tumor initiation. In pre-malignant lesions, pro-tumorigenic as well as anti-tumorigenic—depending on oncogene-induced senescence, and apoptosis limit tumor the type and grade of cancer. The contribution of proteases growth through the activation of the p19Arf-p53 and to cancer progression and metastasis was long thought to be p16Ink4A-RB (retinoblastoma protein) oncosuppressive path- limited to extracellular matrix (ECM) and basement mem- ways. These fail-safe barriers prevent conversion from pre- brane breakdown as well as ECM-remodeling, thus enabling malignant lesions to invasive carcinomas. EMT-TF expres- cells to invade adjacent tissue. More recently, it became obvi- sion in pre-malignant tumor states promotes escape from ous that proteases contribute to carcinogenesis not only by oncogene-induced senescence and provides survival advan- paving the way for tumor cells but also by influencing cell tages under different stress conditions even before tumor cell signaling in mitosis, apoptosis, autophagy, and inflammation dissemination occurs. In this respect, TWIST, ZEB, and [34–37]. In the clinics, most protease inhibitors failed due to SNAIL proteins regulate p53 and RB signaling by repressing the redundancy and multifunctionality of the enzymes, which the transcription of upstream activators (like p16Ink4A and led to considerable toxicity or even adverse effects [38, 39]. p15Ink4B) of either pathway as well as by directly downregu- On the other